Interactive effects of long-term exposure to air pollutants on SARS-CoV-2 infection and severity: a northern Italian population-based cohort study.

BACKGROUND: We examined interactions, to our knowledge not yet explored, between long-term exposures to particulate matter (PM 10 ) with nitrogen dioxide (NO 2 ) and ozone (O 3 ) on SARS-CoV-2 infectivity and severity. METHODS: We followed 709,864 adult residents of Varese Province from 1 February 2020 until the first positive test, COVID-19 hospitalization, or death, up to 31 December 2020. We estimated residential annual means of PM 10 , NO 2 and O 3 in 2019 from chemical-transport and random-forest models. We estimated interactive effects of pollutants with urbanicity on SARS-CoV-2 infectivity, hospitalization, and mortality endpoints using Cox regression models adjusted for socio-demographic factors and comorbidities, and additional cases due to interactions using Poisson models. RESULTS: 41,065 individuals were infected, 5,203 were hospitalized and 1,543 died from COVID-19 during follow-up. Mean PM 10 was 1.6 times higher and NO 2 2.6 times higher than WHO limits, with wide gradients between urban and non-urban areas. PM 10 and NO 2 were positively associated with SARS-CoV-2 infectivity and mortality, and PM 10 with hospitalizations in urban areas. Interaction analyses estimated that the effect of PM 10 (per 3.5 µg/m 3 ) on infectivity was strongest in urban areas (HR=1.12, 95%CI:1.09-1.16), corresponding to 854 additional cases per 100,000 person-years, and in areas at high NO 2 co-exposure (HR=1.15, 1.08-1.22). At higher levels of PM 10 co-exposure the protective association of ozone reversed (HR=1.32, 1.17-1.49), yielding to 278 additional cases per µg/m 3 increase in O 3 . We estimated similar interactive effects for severity endpoints. CONCLUSIONS: We estimate that interactive effects between pollutants exacerbated the burden of SARS-CoV-2 pandemic in urban areas.

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.

The independent and interactive effects of changes in overtime and night shifts during the COVID-19 pandemic on burnout among nurses: a longitudinal study.

OBJECTIVES: This study aimed to evaluate the independent and interactive effects of changes in overtime and night shifts on burnout among nurses during the COVID-19 pandemic. METHODS: Nurses working in an Italian university hospital (N=317) completed the Maslach Burnout Inventory in September 2019 and again in December 2020. Based on hospital administrative data, changes in overtime and night shifts in the same years were categorized into three groups each. Linear regressions were used to estimate 2020 burnout differences between exposure groups, controlling for 2019 burnout levels, demographic and work-related characteristics, and to test the interaction between the two exposures. RESULTS: Nurses in the onset of high overtime group had higher emotional exhaustion [4.33, 95% confidence interval (CI) 1.74-6.92], depersonalization (2.10, 95% CI 0.49-3.71), and poor personal accomplishment (2.64, 95% CI 0.55-4.74) compared to stable low overtime nurses. Nurses in the increase in night shifts group had lower emotional exhaustion (-4.49, 95% CI -7.46- -1.52) compared to no night shift nurses. Interaction analyses revealed that this apparently paradoxical effect was limited to stable low overtime nurses only. Moreover, increases in night shifts were associated with higher depersonalization and poor personal accomplishment in nurses in the stable high overtime group. CONCLUSIONS: Increase in overtime is an independent risk factor for burnout among nurses, highlighting the need for specific regulations and actions to address it. Long-standing guidelines for the assignment of night shifts might have contributed to attenuate the impact of their increase on nurses' mental health.

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.

Regional and temporal differences in the associations between cardiovascular disease and its classic risk factors: an analysis of 49 cohorts from 11 European countries.

AIMS: The regional and temporal differences in the associations between cardiovascular disease (CVD) and its classic risk factors are unknown. The current study examined these associations in different European regions over a 30-year period. METHODS AND RESULTS: The study sample comprised 553 818 individuals from 49 cohorts in 11 European countries (baseline: 1982-2012) who were followed up for a maximum of 10 years. Risk factors [sex, smoking, diabetes, non-HDL cholesterol, systolic blood pressure (BP), and body mass index (BMI)] and CVD events (coronary heart disease or stroke) were harmonized across cohorts. Risk factor-outcome associations were analysed using multivariable-adjusted Cox regression models, and differences in associations were assessed using meta-regression. The differences in the risk factor-CVD associations between central Europe, northern Europe, southern Europe, and the UK were generally small. Men had a slightly higher hazard ratio (HR) in southern Europe (P = 0.043 for overall difference), and those with diabetes had a slightly lower HR in central Europe (P = 0.022 for overall difference) compared with the other regions. Of the six CVD risk factors, minor HR decreases per decade were observed for non-HDL cholesterol [7% per mmol/L; 95% confidence interval (CI), 3-10%] and systolic BP (4% per 20 mmHg; 95% CI, 1-8%), while a minor HR increase per decade was observed for BMI (7% per 10 kg/m2; 95% CI, 1-13%). CONCLUSION: The results demonstrate that all classic CVD risk factors are still relevant in Europe, irrespective of regional area. Preventive strategies should focus on risk factors with the greatest population attributable risk.

All classic cardiovascular disease (CVD) risk factors are still relevant in Europe, irrespective of regional area. The differences in the associations of CVD risk factors with overt CVD between regions of Europe are generally small. Minor temporal hazard decreases were observed for non-HDL cholesterol and systolic blood pressure, while a minor hazard increase was observed for body mass index.

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.

Humoral and Cellular Immune Response Elicited by the BNT162b2 COVID-19 Vaccine Booster in Elderly.

Although the safety and efficacy of COVID-19 vaccines in older people are critical to their success, little is known about their immunogenicity among elderly residents of long-term care facilities (LTCFs). A single-center prospective cohort study was conducted: a total IgG antibody titer, neutralizing antibodies against Wild-type, Delta Plus, and Omicron BA.2 variants and T cell response, were measured eight months after the second dose of BNT162b2 vaccine (T0) and at least 15 days after the booster (T1). Forty-nine LTCF residents, with a median age of 84.8 ± 10.6 years, were enrolled. Previous COVID-19 infection was documented in 42.9% of the subjects one year before T0. At T1, the IgG titers increased up to 10-fold. This ratio was lower in the subjects with previous COVID-19 infection. At T1, IgG levels were similar in both groups. The neutralizing activity against Omicron BA.2 was significantly lower (65%) than that measured against Wild-type and Delta Plus (90%). A significant increase of T cell-specific immune response was observed after the booster. Frailty, older age, sex, cognitive impairment, and comorbidities did not affect antibody titers or T cell response. In the elderly sample analyzed, the BNT162b2 mRNA COVID-19 vaccine produced immunogenicity regardless of frailty.

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.

Immunomodulatory role of vitamin D and selenium supplementation in newly diagnosed Graves' disease patients during methimazole treatment.

Introduction: Methimazole (MMI) represents the conventional therapeutic agent for Graves' disease (GD) hyperthyroidism, but MMI efficacy is limited since it marginally affects the underlying autoimmune process. In a previous study, we randomly assigned 42 newly diagnosed GD patients with insufficient vitamin D (VitD) and selenium (Se) levels to treatment with MMI alone (standard) or combined with selenomethionine and cholecalciferol (intervention) and observed a prompter resolution of hyperthyroidism in the intervention group. Methods: In the present study, we aimed to explore changes in peripheral T regulatory (Treg) and circulating natural killer (NK) cell frequency, circulating NK cell subset distribution and function, during treatment. Results: At baseline, circulating total CD3-CD56+NK cells and CD56bright NK cells were significantly higher in GD patients than in healthy controls (HC) (15.7 ± 9.6% vs 9.9 ± 5.6%, p=0.001; 12.2 ± 10.3% vs 7.3 ± 4.1%, p=0.02, respectively); no differences emerged in Treg cell frequency. Frequencies of total NK cells and CD56bright NK cells expressing the activation marker CD69 were significantly higher in GD patients than in HC, while total NK cells and CD56dim NK cells expressing CD161 (inhibitory receptor) were significantly lower. When co-cultured with the K562 target cell, NK cells from GD patients had a significantly lower degranulation ability compared to HC (p<0.001). Following 6 months of treatment, NK cells decreased in both the intervention and MMI-alone groups, but significantly more in the intervention group (total NK: -10.3%, CI 95% -15.8; -4.8% vs -3.6%, CI 95% -9; 1.8%, p=0.09 and CD56bright NK cells: -6.5%, CI 95% -10.1; -3 vs -0.9%, CI 95% -4.4; 2%, p=0.03). Compared to baseline, CD69+ NK cells significantly decreased, while degranulation ability slightly improved, although no differences emerged between the two treatment groups. Compared to baseline, Treg cell frequency increased exclusively in the intervention group (+1.1%, CI 95% 0.4; 1.7%). Discussion: This pilot study suggested that VitD and Se supplementation, in GD patients receiving MMI treatment, modulates Treg and NK cell frequency, favoring a more pronounced reduction of NK cells and the increase of Treg cells, compared to MMI alone. Even if further studies are needed, it is possible to speculate that this immunomodulatory action might have facilitated the prompter and better control of hyperthyroidism in the supplemented group observed in the previous study.

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.

Mucosal immune response after the booster dose of the BNT162b2 COVID-19 vaccine.

BACKGROUND: To date, only a few studies reported data regarding the development of mucosal immune response after the BNT162b2-booster vaccination. METHODS: Samples of both serum and saliva of 50 healthcare workers were collected at the day of the booster dose (T3) and after two weeks (T4). Anti-S1-protein IgG and IgA antibody titres and the neutralizing antibodies against the Wuhan wild-type Receptor-Binding Domain in both serum and saliva were measured by quantitative and competitive ELISA, respectively. Data were compared with those recorded after the primary vaccination cycle (T2). Neutralizing antibodies against the variants of concern were measured in those individuals with anti-Wuhan neutralizing antibodies in their saliva. FINDINGS: After eight months from the second dose, IgG decreased in both serum (T2GMC: 23,838.5 ng/ml; T3GMC: 1473.8 ng/ml) and saliva (T2GMC: 12.9 ng/ml; T3GMC: 0.3 ng/ml). Consistently, serum IgA decreased (T2GMC: 48.6 ng/ml; T3GMC: 6.4 ng/ml); however, salivary IgA showed a different behaviour and increased (T2GMC: 0.06 ng/ml; T3GMC: 0.41 ng/ml), indicating a delayed activation of mucosal immunity. The booster elicited higher titres of both IgG and IgA when compared with the primary cycle, in both serum (IgG T4GMC: 98,493.9 ng/ml; IgA T4GMC: 187.5 ng/ml) and saliva (IgG T4GMC: 21.9 ng/ml; IgA T4GMC: 0.65 ng/ml). Moreover, the booster re-established the neutralizing activity in the serum of all individuals, not only against the Wuhan wild-type antigen (N = 50; INH: 91.6%) but also against the variants (Delta INH: 91.3%; Delta Plus INH: 89.8%; Omicron BA.1 INH: 85.1%). By contrast, the salivary neutralizing activity was high against the Wuhan antigen in 72% of individuals (N = 36, INH: 62.2%), but decreased against the variants, especially against the Omicron BA.1 variant (Delta N = 27, INH: 43.1%; Delta Plus N = 24, INH: 35.2%; Omicron BA.1 N = 4; INH: 4.7%). This was suggestive for a different behaviour of systemic immunity observed in serum with respect to mucosal immunity described in saliva (Wald chi-square test, 3 df of interaction between variants and sample type = 308.2, p < 0.0001). INTERPRETATION: The BNT162b2-booster vaccination elicits a strong systemic immune response but fails in activating an effective mucosal immunity against the Omicron BA.1 variant. FUNDING: This work was funded by the Department of Medicine and Surgery, University of Insubria, and supported by Fondazione Umberto Veronesi (COVID-19 Insieme per la ricerca di tutti, 2020), Italy.

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.

Add-On Effect of Selenium and Vitamin D Combined Supplementation in Early Control of Graves' Disease Hyperthyroidism During Methimazole Treatment.

Prompt and stable control of hyperthyroidism is fundamental to avoid the detrimental effects of thyroid hormone excess, and antithyroid drugs, mainly methimazole (MMI), represent the first-line treatment for Graves' disease (GD) hyperthyroidism. Decreased serum concentrations of selenium (Se) and calcifediol (25(OH)D, VitD) have been reported in newly diagnosed GD patients in observational studies. Low Se levels might exacerbate oxidative stress by compromising the antioxidant machinery's response to reactive oxygen species, and low VitD levels might hamper the anti-inflammatory immune response. We performed a randomized controlled clinical trial (EudraCT 2017-00505011) to investigate whether Se and cholecalciferol (VitD) addition to MMI is associated with a prompter control of hyperthyroidism. Forty-two consecutive patients with newly-onset GD and marginal/insufficient Se and VitD levels were randomly assigned to treatment with either MMI monotherapy or MMI combined with Se and VitD. Se treatment was withdrawn after 180 days, while the other treatments were continued. Combination therapy resulted in a significantly greater reduction in serum FT4 concentration at 45 days (-37.9 pg/ml, CI 95%, -43.7 to -32.2 pg/ml) and 180 days (-36.5 pg/ml, CI 95%, -42 to -30.9 pg/ml) compared to MMI monotherapy (respectively: -25.7 pg/ml, CI 95%, -31.6 to -19.7 pg/ml and -22.9 pg/ml, CI 95%, -28 to -17.3 pg/ml, p 0.002). Data at 270 days confirmed this trend (-37.8 pg/ml, CI 95%, -43.6 to -32.1 pg/ml vs -24.4 pg/ml, CI 95%, -30.3 to -18.4 pg/ml). The quality of life (QoL) score was investigated by the validated "Thyroid-related Patient-Reported Outcome" questionnaire (ThyPRO). ThyPRO composite score showed a greater improvement in the intervention group at 45 days (-14.6, CI 95%, -18.8 to -10.4), 180 (-9, CI 95%, -13.9 to -4.2) and 270 days (-14.3, CI 95%, -19.5 to -9.1) compared to MMI group (respectively, -5.2, CI 95%, -9.5 to -1; -5.4, CI 95%, -10.6 to -0.2 and -3.5, CI 95%, -9 to -2.1, p 0-6 months and 6-9 months <0.05). Our results suggest that reaching optimal Se and VitD levels increases the early efficacy of MMI treatment when Se and VitD levels are suboptimal.

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).

Simple cardiovascular risk stratification by replacing total serum cholesterol with anthropometric measures: The MORGAM prospective cohort project.

To assess whether anthropometric measures (body mass index [BMI], waist-hip ratio [WHR], and estimated fat mass [EFM]) are independently associated with major adverse cardiovascular events (MACE), and to assess their added prognostic value compared with serum total-cholesterol. The study population comprised 109,509 individuals (53% men) from the MORGAM-Project, aged 19-97 years, without established cardiovascular disease, and not on antihypertensive treatment. While BMI was reported in all, WHR and EFM were reported in âˆ¼52,000 participants. Prognostic importance of anthropometric measurements and total-cholesterol was evaluated using adjusted Cox proportional-hazards regression, logistic regression, area under the receiver-operating-characteristic curve (AUCROC), and net reclassification improvement (NRI). The primary endpoint was MACE, a composite of stroke, myocardial infarction, or death from coronary heart disease. Age interacted significantly with anthropometric measures and total-cholesterol on MACE (P ≤ 0.003), and therefore age-stratified analyses (<50 versus ≥ 50 years) were performed. BMI, WHR, EFM, and total-cholesterol were independently associated with MACE (P ≤ 0.003) and resulted in significantly positive NRI when added to age, sex, smoking status, and systolic blood pressure. Only total-cholesterol increased discrimination ability (AUCROC difference; P < 0.001). In subjects < 50 years, the prediction model with total-cholesterol was superior to the model including BMI, but not superior to models containing WHR or EFM, while in those ≥ 50 years, the model with total-cholesterol was superior to all models containing anthropometric variables, whether assessed individually or combined. We found a potential role for replacing total-cholesterol with anthropometric measures for MACE-prediction among individuals < 50 years when laboratory measurements are unavailable, but not among those ≥ 50 years.