Impact of Lipoprotein(a) Level on Low-Density Lipoprotein Cholesterol- or Apolipoprotein B-Related Risk of Coronary Heart Disease.

BACKGROUND: Conventional low-density lipoprotein cholesterol (LDL-C) quantification includes cholesterol attributable to lipoprotein(a) (Lp(a)-C) due to their overlapping densities. OBJECTIVES: The purposes of this study were to compare the association between LDL-C and LDL-C corrected for Lp(a)-C (LDLLp(a)corr) with incident coronary heart disease (CHD) in the general population and to investigate whether concomitant Lp(a) values influence the association of LDL-C or apolipoprotein B (apoB) with coronary events. METHODS: Among 68,748 CHD-free subjects at baseline LDLLp(a)corr was calculated as "LDL-C-Lp(a)-C," where Lp(a)-C was 30% or 17.3% of total Lp(a) mass. Fine and Gray competing risk-adjusted models were applied for the association between the outcome incident CHD and: 1) LDL-C and LDLLp(a)corr in the total sample; and 2) LDL-C and apoB after stratification by Lp(a) mass (≥/<90th percentile). RESULTS: Similar risk estimates for incident CHD were found for LDL-C and LDL-CLp(a)corr30 or LDL-CLp(a)corr17.3 (subdistribution HR with 95% CI) were 2.73 (95% CI: 2.34-3.20) vs 2.51 (95% CI: 2.15-2.93) vs 2.64 (95% CI: 2.26-3.10), respectively (top vs bottom fifth; fully adjusted models). Categorization by Lp(a) mass resulted in higher subdistribution HRs for uncorrected LDL-C and incident CHD at Lp(a) ≥90th percentile (4.38 [95% CI: 2.08-9.22]) vs 2.60 [95% CI: 2.21-3.07]) at Lp(a) <90th percentile (top vs bottom fifth; Pinteraction0.39). In contrast, apoB risk estimates were lower in subjects with higher Lp(a) mass (2.43 [95% CI: 1.34-4.40]) than in Lp(a) <90th percentile (3.34 [95% CI: 2.78-4.01]) (Pinteraction0.49). CONCLUSIONS: Correction of LDL-C for its Lp(a)-C content provided no meaningful information on CHD-risk estimation at the population level. Simple categorization of Lp(a) mass (≥/<90th percentile) influenced the association between LDL-C or apoB with future CHD mostly at higher Lp(a) levels.

Prognostic Value of Cardiovascular Biomarkers in the Population.

Importance: Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. Objective: To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Design, Setting, and Participants: Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Exposure: Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. Main Outcomes and Measures: The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. Results: The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Conclusions and Relevance: Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

Perceived work stressors and the transition to burnout among nurses in response to the pandemic: implications for healthcare organizations.

OBJECTIVES: This study aimed to assess the associations of pre-pandemic perceived work stressors and work satisfaction among nurses, including nurse assistants, with burnout profiles and their transitions in response to the pandemic. METHODS: Three hundred and thirty-seven nurses working in an Italian University hospital participated in a longitudinal study including a survey in August 2019 investigating perceived work stressors (assessed using the HSE Indicator Tool), work satisfaction (Work Satisfaction Scale), and burnout (Maslach Burnout Inventory), and a second survey in December 2020 assessing burnout. Using latent transition analysis, we identified burnout profiles and then estimated the associations between work stressors and satisfaction on profiles and transitions. RESULTS: We identified three pre-pandemic profiles, namely engaged (67%), ineffective (15%), and burnout (18%); and three pandemic profiles, namely engaged (37%), exhausted (51%), and severe burnout (12%). The severe burnout profile consisted of 70% nurses classified in the burnout profile before the pandemic. Overall, work stressors and satisfaction were associated with both pre-pandemic and pandemic burnout profiles. Among nurses not in the burnout profile prior to COVID-19, pre-pandemic hostile relationships increased [odds ratio (OR) 1.19, 95% confidence interval (CI) 1.05-1.34] and work satisfaction decreased (OR 0.82, 95% CI 0.68-0.98) the probability to transition to exhausted. Moreover, work satisfaction (OR 0.54, 95% CI 0.32-0.91) and participation in work organization (OR 0.69, 95% CI 0.51-0.93) protected from transitioning to severe burnout. The association between peer support and the transition to exhausted needs further investigation. CONCLUSIONS: Pre-pandemic work stressors and satisfaction were associated with pandemic burnout and burnout transitions. To enhance preparedness for future crises, healthcare managers should carefully assess and tackle work-related constraints affecting nurses.

C-reactive protein modifies lipoprotein(a)-related risk for coronary heart disease: the BiomarCaRE project.

BACKGROUND AND AIMS: Recent investigations have suggested an interdependence of lipoprotein(a) [Lp(a)]-related risk for cardiovascular disease with background inflammatory burden. The aim the present analysis was to investigate whether high-sensitive C-reactive protein (hsCRP) modulates the association between Lp(a) and coronary heart disease (CHD) in the general population. METHODS: Data from 71 678 participants from 8 European prospective population-based cohort studies were used (65 661 without/6017 with established CHD at baseline; median follow-up 9.8/13.8 years, respectively). Fine and Gray competing risk-adjusted models were calculated according to accompanying hsCRP concentration (<2 and ≥2 mg/L). RESULTS: Among CHD-free individuals, increased Lp(a) levels were associated with incident CHD irrespective of hsCRP concentration: fully adjusted sub-distribution hazard ratios [sHRs (95% confidence interval)] for the highest vs. lowest fifth of Lp(a) distribution were 1.45 (1.23-1.72) and 1.48 (1.23-1.78) for a hsCRP group of <2 and ≥2 mg/L, respectively, with no interaction found between these two biomarkers on CHD risk (Pinteraction = 0.82). In those with established CHD, similar associations were seen only among individuals with hsCRP ≥ 2 mg/L [1.34 (1.03-1.76)], whereas among participants with a hsCRP concentration <2 mg/L, there was no clear association between Lp(a) and future CHD events [1.29 (0.98-1.71)] (highest vs. lowest fifth, fully adjusted models; Pinteraction = 0.024). CONCLUSIONS: While among CHD-free individuals Lp(a) was significantly associated with incident CHD regardless of hsCRP, in participants with CHD at baseline, Lp(a) was related to recurrent CHD events only in those with residual inflammatory risk. These findings might guide adequate selection of high-risk patients for forthcoming Lp(a)-targeting compounds.

Systematic Violence Monitoring to Reduce Underreporting and to Better Inform Workplace Violence Prevention Among Health Care Workers: Before-and-After Prospective Study.

BACKGROUND: Monitoring workplace violence (WPV) against health care workers (HCWs) through incident reporting is crucial to drive prevention, but the actual implementation is spotty and experiences underreporting. OBJECTIVE: This study aims to introduce a systematic WPV surveillance in 2 public referral hospitals in Italy and assess underreporting, WPV annual rates, and attributes "before" (2016-2020) and "after" its implementation (November 2021 to 2022). METHODS: During 2016-2020, incident reporting was based on procedures and data collection forms that were neither standardized between hospitals nor specific for aggressions. We planned and implemented a standardized WPV surveillance based on (1) an incident report form for immediate and systematic event notification, adopting international standards for violence definitions; (2) second-level root cause analysis with a dedicated psychologist, assessing violence determinants and impacts and offering psychological counseling; (3) a web-based platform for centralized data collection; and (4) periodic training for workforce coordinators and newly hired workers. We used data from incident reports to estimate underreporting, defined as an observed-to-expected (from literature and the "before" period) WPV ratio less than 1, and the 12-month WPV rates (per 100 HCWs) in the "before" and "after" periods. During the latter period, we separately estimated WPV rates for first and recurrent events. RESULTS: In the "before" period, the yearly observed-to-expected ratios were consistently below 1 and as low as 0.27, suggesting substantial violence underreporting of up to 73%. WPV annual rates declined in 1 hospital (from 1.92 in 2016 to 0.57 in 2020) and rose in the other (from 0.52 to 1.0), with the divergence being attributable to trends in underreporting. Available data were poorly informative to identify at-risk HCW subgroups. In the "after" period, the observed-to-expected ratio rose to 1.14 compared to literature and 1.91 compared to the "before" period, consistently in both hospitals. The 12-month WPV rate was 2.08 (95% CI 1.79-2.42; 1.52 and 2.35 in the 2 hospitals); one-fifth (0.41/2.08, 19.7%) was due to recurrences. Among HCWs, the youngest group (3.79; P<.001), nurses (3.19; P<.001), and male HCWs (2.62; P=.008) reported the highest rates. Emergency departments and psychiatric wards were the 2 areas at increased risk. Physical assaults were more likely in male than female HWCs (45/67, 67.2% vs 62/130, 47.7%; P=.01), but the latter experienced more mental health consequences (46/130, 35.4% vs 13/67, 19.4%; P=.02). Overall, 40.8% (53/130) of female HWCs recognized sociocultural (eg, linguistic or cultural) barriers as contributing factors for the aggression, and 30.8% (40/130) of WPV against female HCWs involved visitors as perpetrators. CONCLUSIONS: A systematic WPV surveillance reduced underreporting. The identification of high-risk workers and characterization of violence patterns and attributes can better inform priorities and contents of preventive policies. Our evaluation provides useful information for the large-scale implementation of standardized WPV-monitoring programs.

Global Effect of Modifiable Risk Factors on Cardiovascular Disease and Mortality.

BACKGROUND: Five modifiable risk factors are associated with cardiovascular disease and death from any cause. Studies using individual-level data to evaluate the regional and sex-specific prevalence of the risk factors and their effect on these outcomes are lacking. METHODS: We pooled and harmonized individual-level data from 112 cohort studies conducted in 34 countries and 8 geographic regions participating in the Global Cardiovascular Risk Consortium. We examined associations between the risk factors (body-mass index, systolic blood pressure, non-high-density lipoprotein cholesterol, current smoking, and diabetes) and incident cardiovascular disease and death from any cause using Cox regression analyses, stratified according to geographic region, age, and sex. Population-attributable fractions were estimated for the 10-year incidence of cardiovascular disease and 10-year all-cause mortality. RESULTS: Among 1,518,028 participants (54.1% of whom were women) with a median age of 54.4 years, regional variations in the prevalence of the five modifiable risk factors were noted. Incident cardiovascular disease occurred in 80,596 participants during a median follow-up of 7.3 years (maximum, 47.3), and 177,369 participants died during a median follow-up of 8.7 years (maximum, 47.6). For all five risk factors combined, the aggregate global population-attributable fraction of the 10-year incidence of cardiovascular disease was 57.2% (95% confidence interval [CI], 52.4 to 62.1) among women and 52.6% (95% CI, 49.0 to 56.1) among men, and the corresponding values for 10-year all-cause mortality were 22.2% (95% CI, 16.8 to 27.5) and 19.1% (95% CI, 14.6 to 23.6). CONCLUSIONS: Harmonized individual-level data from a global cohort showed that 57.2% and 52.6% of cases of incident cardiovascular disease among women and men, respectively, and 22.2% and 19.1% of deaths from any cause among women and men, respectively, may be attributable to five modifiable risk factors. (Funded by the German Center for Cardiovascular Research (DZHK); ClinicalTrials.gov number, NCT05466825.).

Drinking alcohol in moderation is associated with lower rate of all-cause mortality in individuals with higher rather than lower educational level: findings from the MORGAM project.

The association between socioeconomic status (SES) and alcohol-related diseases has been widely explored. Less is known, however, on whether the association of moderate drinking with all-cause mortality is modified by educational level (EL). Using harmonized data from 16 cohorts in the MORGAM Project (N = 142,066) the association of pattern of alcohol intake with hazard of all-cause mortality across EL (lower = primary-school; middle = secondary-school; higher = university/college degree) was assessed using multivariable Cox-regression and spline curves. A total of 16,695 deaths occurred in 11.8 years (median). In comparison with life-long abstainers, participants drinking 0.1-10 g/d of ethanol had 13% (HR = 0.87; 95%CI: 0.74-1.02), 11% (HR = 0.89; 0.84-0.95) and 5% (HR = 0.95; 0.89-1.02) lower rate of death in higher, middle and lower EL, respectively. Conversely, drinkers > 20 g/d had 1% (HR = 1.01; 0.82-1.25), 10% (HR = 1.10; 1.02-1.19) and 17% (HR = 1.17; 1.09-1.26) higher rate of death. The association of alcohol consumption with all-cause mortality was nonlinear, with a different J-shape by EL levels. It was consistent across both sexes and in various approaches of measuring alcohol consumption, including combining quantity and frequency and it was more evident when the beverage of preference was wine. We observed that drinking in moderation (≤ 10 g/d) is associated with lower mortality rate more evidently in individuals with higher EL than in people with lower EL, while heavy drinking is associated with higher mortality rate more evidently in individuals with lower EL than in people with higher EL, suggesting that advice on reducing alcohol intake should especially target individuals of low EL.

Pre-pandemic burnout and its changes during the COVID-19 outbreak as predictors of mental health of healthcare workers: A lesson to be learned.

The aim of this study was to identify how previously existing burnout and its changes during the pandemic contributed to PTSD symptoms and psychological distress in a cohort of 388 healthcare workers (HCWs). Each HCW was surveyed in Sep 2019 (before COVID-19) and again in Dec 2020-Jan 2021 (during the pandemic) to assess burnout (MBI); and in the second wave only to assess PTSD (PCL-5-SF), psychological distress (GHQ-12) and resilience (CD-RISC-10). Changes in emotional exhaustion (EE) and depersonalisation (DEP) were stronger in HCWs with lower EE and DEP baseline values. HCWs with higher baseline poor personal accomplishment (PPA) improved more than those with lower baseline values. In multivariable-adjusted models, pre-pandemic EE and its changes were equally associated to both outcomes: standardised-ßs of 0.52 and 0.54 for PTSD, respectively; and 0.55 and 0.53 for psychological distress. Changes in DEP were associated with PTSD only (0.10). Changes in PPA had a higher association with psychological distress (0.29) than pre-pandemic PPA (0.13). Resilience was associated with lower psychological distress (-0.25). Preventive actions aimed at reducing EE, e.g., addressing organisational dysfunctions, are needed to mitigate the impact of future crises, whereas improving personal accomplishment levels is a key target to protect HCWs from mental health disorders during a pandemic.

Biomarker-based prediction of fatal and non-fatal cardiovascular outcomes in individuals with diabetes mellitus.

AIMS: The role of biomarkers in predicting cardiovascular outcomes in high-risk individuals is not well established. We aimed to investigate benefits of adding biomarkers to cardiovascular risk assessment in individuals with and without diabetes. METHODS AND RESULTS: We used individual-level data of 95 292 individuals of the European population harmonized in the Biomarker for Cardiovascular Risk Assessment across Europe consortium and investigated the prognostic ability of high-sensitivity cardiac troponin I (hs-cTnI), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP). Cox-regression models were used to determine adjusted hazard ratios of diabetes and log-transformed biomarkers for fatal and non-fatal cardiovascular events. Models were compared using the likelihood ratio test. Stratification by specific biomarker cut-offs was performed for crude time-to-event analysis using Kaplan-Meier plots. Overall, 6090 (6.4%) individuals had diabetes at baseline, median follow-up was 9.9 years. Adjusting for classical risk factors and biomarkers, diabetes [HR 2.11 (95% CI 1.92, 2.32)], and all biomarkers (HR per interquartile range hs-cTnI 1.08 [95% CI 1.04, 1.12]; NT-proBNP 1.44 [95% CI 1.37, 1.53]; hs-CRP 1.27 [95% CI 1.21, 1.33]) were independently associated with cardiovascular events. Specific cut-offs for each biomarker identified a high-risk group of individuals with diabetes losing a median of 15.5 years of life compared to diabetics without elevated biomarkers. Addition of biomarkers to the Cox-model significantly improved the prediction of outcomes (likelihood ratio test for nested models P < 0.001), accompanied by an increase in the c-index (increase to 0.81). CONCLUSION: Biomarkers improve cardiovascular risk prediction in individuals with and without diabetes and facilitate the identification of individuals with diabetes at highest risk for cardiovascular events.

In this work, the role of cardiac biomarkers measured from blood to predict cardiovascular events and death is tested in individuals of the general population and particularly in those with known diabetes. The work is based on a cooperation of different population studies across Europe and includes more than 90 000 individuals, with more than 6000 having diabetes. We could demonstrate that the determination of three cardiac biomarkers helps to identify individuals at highest risk for cardiovascular events (e.g. myocardial infarction or stroke) and death, despite accounting for known cardiovascular risk factors in these individuals. Therefore, these biomarkers should be considered for routine risk assessment for cardiovascular diseases and could improve the early identification of high-risk individuals, consequently leading to an earlier initiation of preventive therapies.

The North Italian Longitudinal Study Assessing the Mental Health Effects of SARS-CoV-2 Pandemic on Health Care Workers-Part I: Study Design and Psychometric Structural Validity of the HSE Indicator Tool and Work Satisfaction Scale.

Literature on the impact of the SARS-CoV-2 pandemic on the mental health of Health Care Workers (HCWs) is mostly based on cross-sectional surveys. We designed a longitudinal study to assess work-related stress and mental health before and after the pandemic onset in a university-hospital in Lombardia region, Italy. We report on sample representativeness and structural validity of questionnaires assessing work stress (HSE Indicator Tool, HSE-IT) and work satisfaction (WS), which were not validated in the HCWs population. n = 1287 HCWs from 67 hospital wards/offices were invited to an online survey in summer 2019 (pre-COVID-19 wave) and again during winter 2020 (COVID-19 wave). Selected hospital wards/offices did not differ from the remaining wards for turn-over and down-sizing rates, overload, sick leaves, and night shifts (Wilcoxon rank tests p-values > 0.05). Participation rates were 70% (n = 805) and 60% (n = 431) in the pre-COVID-19 and COVID-19 waves, respectively. Socio-demographic and work-related characteristics did not impact data completeness nor participation to the COVID-19 wave. While confirming a 7-component structure for HSE-IT, we identified a new factor related to participation in work organization. A one-factor model for WS had satisfactory fit. Our longitudinal study based on a representative sample and adopting validated questionnaires is well-suited to elucidate the role of work conditions on the development of mental health disorders in HCWs.

The North Italian Longitudinal Study Assessing the Mental Health Effects of SARS-CoV-2 Pandemic Health Care Workers-Part II: Structural Validity of Scales Assessing Mental Health.

It is unclear if the factor structure of the questionnaires that were employed by studies addressing the impact of COVID-19 on the mental health of Healthcare Workers (HCW) did not change due to the pandemic. The aim of this study is to assess the factor structure and longitudinal measurement invariance of the Maslach Burnout Inventory (MBI) and the factor structure of the General Health Questionnare-12 (GHQ-12), PTSD Checklist for DSM-5-Short Form (PCL-5-SF), Connor-Davidson Resilience Scale-10 (CD-RISC-10) and Post-Traumatic Growth Inventory-Short Form (PTGI-SF). Out of n = 805 HCWs from a University hospital who responded to a pre-COVID-19 survey, n = 431 were re-assessed after the COVID-19 outbreak. A Confirmatory Factor Analysis (CFA) on the MBI showed adequate fit and good internal consistency only after removal of items 2, 6, 12 and 16. The assumptions of configural and metric longitudinal invariance were met, whereas scalar longitudinal invariance did not hold. CFAs and exploratory bifactor analyses performed using data from the second wave confirmed that the GHQ-12, the PCL-5-SF, the PTGI-SF and the CD-RISC-10 were unidimensional. In conclusion, we found support for a refined version of the MBI. The comparison of mean MBI values in HCWs before and after the pandemic should be interpreted with caution.

Evaluation of menstrual irregularities after COVID-19 vaccination: Results of the MECOVAC survey.

We investigated menstrual irregularities after the first and second doses of the COVID-19 vaccine. Women answered a customised online questionnaire (ClinicalTrial.gov ID: NCT05083065) aimed to assess the vaccine type, the phase of the menstrual cycle during which the vaccine was administered, the occurrence of menstrual irregularities after the first and second doses, and how long this effect lasted. We excluded women with gynaecological and non-gynaecological diseases, undergoing hormonal and non-hormonal treatments, in perimenopause or menopause, as well as those who had irregular menstrual cycles in the last 12 months before vaccine administration. According to our data analysis, approximately 50-60% of reproductive-age women who received the first dose of the COVID-19 vaccine reported menstrual cycle irregularities, regardless of the type of administered vaccine. The occurrence of menstrual irregularities seems to be slightly higher (60-70%) after the second dose. Menstrual irregularities after both the first and second doses of the vaccine were found to self-resolve in approximately half the cases within two months. Based on these results, we suggest to consider these elements during the counselling of women who receive the COVID-19 vaccine, letting them know about the potential occurrence of temporary and self-limiting menstrual cycle irregularities in the subsequent month(s).

Long-term exposure to air pollution and COVID-19 incidence: a prospective study of residents in the city of Varese, Northern Italy.

OBJECTIVES: To investigate the association between long-term exposure to airborne pollutants and the incidence of SARS-CoV-2 up to March 2021 in a prospective study of residents in Varese city. METHODS: Citizens of Varese aged ≥18 years as of 31 December 2019 were linked by residential address to 2018 average annual exposure to outdoor concentrations of PM2.5, PM10, NO2, NO and ozone modelled using the Flexible Air quality Regional Model (FARM) chemical transport model. Citizens were further linked to regional datasets for COVID-19 case ascertainment (positive nasopharyngeal swab specimens) and to define age, sex, living in a residential care home, population density and comorbidities. We estimated rate ratios and additional numbers of cases per 1 µg/m3 increase in air pollutants from single- and bi-pollutant Poisson regression models. RESULTS: The 62 848 residents generated 4408 cases. Yearly average PM2.5 exposure was 12.5 µg/m3. Age, living in a residential care home, history of stroke and medications for diabetes, hypertension and obstructive airway diseases were independently associated with COVID-19. In single-pollutant multivariate models, PM2.5 was associated with a 5.1% increase in the rate of COVID-19 (95% CI 2.7% to 7.5%), corresponding to 294 additional cases per 100 000 person-years. The association was confirmed in bi-pollutant models; excluding subjects in residential care homes; and further adjusting for area-based indicators of socioeconomic level and use of public transportation. Similar findings were observed for PM10, NO2 and NO. Ozone was associated with a 2% decrease in disease rate, the association being reversed in bi-pollutant models. CONCLUSIONS: Long-term exposure to low levels of air pollutants, especially PM2.5, increased the incidence of COVID-19. The causality warrants confirmation in future studies; meanwhile, government efforts to further reduce air pollution should continue.

Alcohol intake and total mortality in 142 960 individuals from the MORGAM Project: a population-based study.

AIM: To test the association of alcohol consumption with total and cause-specific mortality risk. DESIGN: Prospective observational multi-centre population-based study. SETTING: Sixteen cohorts (15 from Europe) in the MOnica Risk, Genetics, Archiving and Monograph (MORGAM) Project. PARTICIPANTS: A total of 142 960 individuals (mean age 50 ± 13 years, 53.9% men). MEASUREMENTS: Average alcohol intake by food frequency questionnaire, total and cause-specific mortality. FINDINGS: In comparison with life-time abstainers, consumption of alcohol less than 10 g/day was associated with an average 11% [95% confidence interval (CI) = 7-14%] reduction in the risk of total mortality, while intake > 20 g/day was associated with a 13% (95% CI = 7-20%) increase in the risk of total mortality. Comparable findings were observed for cardiovascular (CV) deaths. With regard to cancer, drinking up to 10 g/day was not associated with either mortality risk reduction or increase, while alcohol intake > 20 g/day was associated with a 22% (95% CI = 10-35%) increased risk of mortality. The association of alcohol with fatal outcomes was similar in men and women, differed somewhat between countries and was more apparent in individuals preferring wine, suggesting that benefits may not be due to ethanol but other ingredients. Mediation analysis showed that high-density lipoprotein cholesterol explained 2.9 and 18.7% of the association between low alcohol intake and total as well as CV mortality, respectively. CONCLUSIONS: In comparison with life-time abstainers, consuming less than one drink per day (nadir at 5 g/day) was associated with a reduced risk of total, cardiovascular and other causes mortality, except cancer. Intake of more than two drinks per day was associated with an increased risk of total, cardiovascular and especially cancer mortality.

Influence of geographical latitude on vitamin D status: cross-sectional results from the BiomarCaRE consortium.

Even though sunlight is viewed as the most important determinant of 25-hydroxyvitamin D (25(OH)D) status, several European studies have observed higher 25(OH)D concentrations among north-Europeans than south-Europeans. We studied the association between geographical latitude (derived from ecological data) and 25(OH)D status in six European countries using harmonised immunoassay data from 81 084 participants in the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project (male sex 48·9 %; median age 50·8 years; examination period 1984-2014). Quantile regression models, adjusted for age, sex, decade and calendar week of sampling and time from sampling to analysis, were used for between-country comparisons. Up until the median percentile, the ordering of countries by 25(OH)D status (from highest to lowest) was as follows: Sweden (at 65·6-63·8°N), Germany (at 48·4°N), Finland (at 65·0-60·2°N), Italy (at 45·6-41·5°N), Scotland (at 58·2-55·1°N) and Spain (at 41·5°N). From the 75th percentile and upwards, Finland had higher values than Germany. As an example, using the Swedish cohort as a comparator, the median 25(OH)D concentration was 3·03, 3·28, 5·41, 6·54 and 9·28 ng/ml lower in the German, Finnish, Italian, Scottish and Spanish cohort, respectively (P-value < 0·001 for all comparisons). The ordering of countries was highly consistent in subgroup analyses by sex, age, and decade and season of sampling. In conclusion, we confirmed the previous observation of a north-to-south gradient of 25(OH)D status in Europe, with higher percentile values among north-Europeans than south-Europeans.

Mucosal immune response in BNT162b2 COVID-19 vaccine recipients.

BACKGROUND: Although the BNT162b2 COVID-19 vaccine is known to induce IgG neutralizing antibodies in serum protecting against COVID-19, it has not been studied in detail whether it could generate specific immunity at mucosal sites, which represent the primary route of entry of SARS-CoV-2. METHODS: Samples of serum and saliva of 60 BNT162b2-vaccinated healthcare workers were collected at baseline, two weeks after the first dose and two weeks after the second dose. Anti-S1-protein IgG and IgA total antibodies titres and the presence of neutralizing antibodies against the Receptor Binding Domain in both serum and saliva were measured by quantitative and by competitive ELISA, respectively. FINDINGS: Complete vaccination cycle generates a high serum IgG antibody titre as a single dose in previously infected seropositive individuals. Serum IgA concentration reaches a plateau after a single dose in seropositive individuals and two vaccine doses in seronegative subjects. After the second dose IgA level was higher in seronegative than in seropositive subjects. In saliva, IgG level is almost two orders of magnitude lower than in serum, reaching the highest values after the second dose. IgA concentration remains low and increases significantly only in seropositive individuals after the second dose. Neutralizing antibody titres were much higher in serum than in saliva. INTERPRETATION: The mRNA BNT162b2 vaccination elicits a strong systemic immune response by drastically boosting neutralizing antibodies development in serum, but not in saliva, indicating that at least oral mucosal immunity is poorly activated by this vaccination protocol, thus failing in limiting virus acquisition upon its entry through this route. FUNDING: This work was funded by the Department of Medicine and Surgery, University of Insubria, and partially supported by Fondazione Umberto Veronesi (COVID-19 Insieme per la ricerca di tutti, 2020).

Association of glycated hemoglobin A1c levels with cardiovascular outcomes in the general population: results from the BiomarCaRE (Biomarker for Cardiovascular Risk Assessment in Europe) consortium.

BACKGROUND: Biomarkers may contribute to improved cardiovascular risk estimation. Glycated hemoglobin A1c (HbA1c) is used to monitor the quality of diabetes treatment. Its strength of association with cardiovascular outcomes in the general population remains uncertain. This study aims to assess the association of HbA1c with cardiovascular outcomes in the general population. METHODS: Data from six prospective population-based cohort studies across Europe comprising 36,180 participants were analyzed. HbA1c was evaluated in conjunction with classical cardiovascular risk factors (CVRFs) for association with cardiovascular mortality, cardiovascular disease (CVD) incidence, and overall mortality in subjects without diabetes (N = 32,496) and with diabetes (N = 3684). RESULTS: Kaplan-Meier curves showed higher event rates with increasing HbA1c levels (log-rank-test: p < 0.001). Cox regression analysis revealed significant associations between HbA1c (in mmol/mol) in the total study population and the examined outcomes. Thus, a hazard ratio (HR) of 1.16 (95% confidence interval (CI) 1.02-1.31, p = 0.02) for cardiovascular mortality, 1.13 (95% CI 1.03-1.24, p = 0.01) for CVD incidence, and 1.09 (95% CI 1.02-1.17, p = 0.01) for overall mortality was observed per 10 mmol/mol increase in HbA1c. The association with CVD incidence and overall mortality was also observed in study participants without diabetes with increased HbA1c levels (HR 1.12; 95% CI 1.01-1.25, p = 0.04) and HR 1.10; 95% CI 1.01-1.20, p = 0.02) respectively. HbA1c cut-off values of 39.9 mmol/mol (5.8%), 36.6 mmol/mol (5.5%), and 38.8 mmol/mol (5.7%) for cardiovascular mortality, CVD incidence, and overall mortality, showed also an increased risk. CONCLUSIONS: HbA1c is independently associated with cardiovascular mortality, overall mortality and cardiovascular disease in the general European population. A mostly monotonically increasing relationship was observed between HbA1c levels and outcomes. Elevated HbA1c levels were associated with cardiovascular disease incidence and overall mortality in participants without diabetes underlining the importance of HbA1c levels in the overall population.

Occupational class differences in ankle-brachial index and pulse wave velocity measurements to detect subclinical vascular disease.

BACKGROUND: High pulse wave velocity (PWV) and low ankle brachial index (ABI) have been proposed as surrogate end-points for cardiovascular disease (CVD). OBJECTIVES: In a cross-sectional setting, we aimed at assessing the distributions of PWV and ABI among occupational classes (OC) in a population-based ever-employed salaried sample. METHODS: We enrolled 1388 salaried CVD-free workers attending a CVD population-based survey, the RoCAV study, and classified them into four OC, based on current or last job title: manager/director (MD), non-manual (NMW), skilled-manual (SMW) and (UMW) unskilled-manual workers. We derived brachial-ankle PWV and ABI from four-limb blood pressures measurements, then carotid-femoral PWV (cfPWV) was estimated. We estimated the OC gradients in cfPWV and ABI using linear and logistic regression models. RESULTS: Compared to MD (reference category), UMW had higher age- and BMI-adjusted cfPWV mean values both in men (0.63 m/s; 95%CI:0.11-1.16) and women (1.60 m/s; 0.43-2.77), only marginally reduced when adjusting for CVD risk factors. Decreased ABI mean values were also detected in lower OC. The overall detection rate of abnormal cfPWV (≥12 m/s) or ABI (≤0.9) values was 28%. Compared to MD, the prevalence of abnormal cfPWV or ABI was higher in NMW (OR=1.77; 95%CI:1.12-2.79), SMW (1.71; 1.05-2.78) and UMW (2.72; 1.65-4.50). Adjustment for CVD risk factors used in risk score equations did not change the results. DISCUSSION: We found a higher prevalence of abnormal values of arterial stiffness measures in lower OC, and these differences were not explained by traditional CVD risk factors. These may be presumably determined by additional work- and environmental-related risk factors.

Roles of allostatic load, lifestyle and clinical risk factors in mediating the association between education and coronary heart disease risk in Europe.

BACKGROUND: Previous studies have shown that differential exposure to lifestyle factors may mediate the association between education and coronary heart diseases (CHD). However, few studies have examined the potential roles of allostatic load (AL) or differential susceptibility. METHODS: 25 310 men and 26 018 women aged 35-74 and CHD free at baseline were identified from 21 European cohorts and followed for a median of 10 years, to investigate the mediating role of AL, as well as of smoking, alcohol use and body mass index (BMI), on educational differences in CHD incidence, applying marginal structural models and three-way decomposition. RESULTS: AL is a mediator of the association between educational status and CHD incidence, with the highest proportion mediated observed among women and largely attributable to differential exposure, (28% (95% CI 19% to 44%)), with 8% (95% CI 0% to 16%) attributable to differential susceptibility. The mediating effects of smoking, alcohol and BMI, compared with AL, were relatively small for both men and women. CONCLUSION: Overall, the educational inequalities in CHD incidence were partially mediated through differential exposure to AL. By contrast, the mediation of the educational gradient in CHD by investigated lifestyle risk factors was limited. As differential susceptibility in men was found to have a predominant role in the accumulation of AL in low educational classes, the investigation of AL-related risk factors is warranted.