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Background Endometrial cancer risk stratification may help target interventions, screening, or prophylactic hysterectomy to mitigate the rising burden of this cancer. However, existing prediction models have been developed in select cohorts and have not considered genetic factors. Methods We developed endometrial cancer risk prediction models using data on postmenopausal White women aged 45-85 years from 19 case-control studies in the Epidemiology of Endometrial Cancer Consortium (E2C2). Relative risk estimates for predictors were combined with age-specific endometrial cancer incidence rates and estimates for the underlying risk factor distribution. We externally validated the models in 3 cohorts: Nurses’ Health Study (NHS), NHS II, and the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. Results Area under the receiver operating characteristic curves for the epidemiologic model ranged from 0.64 (95% confidence interval [CI] = 0.62 to 0.67) to 0.69 (95% CI = 0.66 to 0.72). Improvements in discrimination from the addition of genetic factors were modest (no change in area under the receiver operating characteristic curves in NHS; PLCO = 0.64 to 0.66). The epidemiologic model was well calibrated in NHS II (overall expected-to-observed ratio [E/O] = 1.09, 95% CI = 0.98 to 1.22) and PLCO (overall E/O = 1.04, 95% CI = 0.95 to 1.13) but poorly calibrated in NHS (overall E/O = 0.55, 95% CI = 0.51 to 0.59). Conclusions Using data from the largest, most heterogeneous study population to date (to our knowledge), prediction models based on epidemiologic factors alone successfully identified women at high risk of endometrial cancer. Genetic factors offered limited improvements in discrimination. Further work is needed to refine this tool for clinical or public health practice and expand these models to multiethnic populations.

Experimental evidence suggests that alcohol induces cutaneous carcinogenesis, yet epidemiological studies on the link between alcohol intake and skin cancer have been inconsistent. The European Prospective Investigation into Cancer and Nutrition (EPIC) is a prospective cohort initiated in 1992 in 10 European countries. Alcohol intake at baseline and average lifetime alcohol intake were assessed using validated country-specific dietary and lifestyle questionnaires. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated in Cox models. A total of 14 037 skin cancer cases (melanoma: n = 2457; basal-cell carcinoma (BCC): n = 8711; squamous-cell carcinoma (SCC): n = 1928; unknown: n = 941) were identified among 450 112 participants (average follow-up: 15 years). Baseline alcohol intake was positively associated with SCC (>15 vs 0.1-4.9 g/day: HR = 1.44, 95% CI = 1.17-1.77; Ptrend = .001), BCC (HR = 1.12, 95% CI = 1.01-1.23; Ptrend = .04), and melanoma risks in men (HR = 1.17, 95% CI = 0.95-1.44; Ptrend = .17), while associations were more modest in women (SCC: HR = 1.09, 95% CI = 0.90-1.30; Ptrend = .13; BCC: HR = 1.08, 95% CI = 1.00-1.17,Ptrend = .03; melanoma: HR = 0.93, 95% CI = 0.80-1.08, Ptrend = .13). Associations were similar for lifetime alcohol intake, with an attenuated linear trend. Lifetime liquor/spirit intake was positively associated with melanoma (fourth vs first quartile: HR = 1.47, 95% CI = 1.08-1.99; Ptrend = .0009) and BCC risks in men (HR = 1.17, 95% CI = 1.04-1.31;Ptrend = .14). Baseline and lifetime intakes of wine were associated with BCC risk (HR = 1.25 in men; HR = 1.11-1.12; in women). No statistically significant associations were found between beverage types and SCC risk. Intake of beer was not associated with skin cancer risk. Our study suggests positive relationships between alcohol intake and skin cancer risk, which may have important implications for the primary prevention of skin cancer. What's new? Drinking alcohol can make the skin more sensitive to sunlight and vulnerable to skin cancer. Here, the authors conducted a large prospective cohort study to evaluate whether alcohol consumption correlates with skin cancer risk. Among the 450 112 participants, there were 2457 cases of melanoma, 8711 of basal cell carcinoma, and 1928 of squamous cell carcinoma. There was a positive association between alcohol and all three cancer types, stronger in men than in women. The association varied somewhat by beverage type.

BACKGROUND: To examine the associations of animal and plant protein intake with all-cause, cardiovascular and cancer mortality risk in middle-aged Italian men and women with substantially lower animal protein intake than North Americans. METHODS AND RESULTS: Food consumption was assessed by validated Epic semiquantitative FFQs. Multivariable Cox models stratified by center, age, and sex, and adjusted for confounders, estimated associations of animal and plant protein consumption with mortality for all causes, cardiovascular disease, and cancer. After a median follow-up of 15.2 years, 2,449 deaths were identified in 45,009 participants. No significant association between intake of total, animal or plant protein and mortality was found in the fully adjusted models. Substitution of plant protein for animal protein was inversely associated with cardiovascular mortality (HR, 0.47; 95% CI, 0.24–0.92) only in people with at least 1 unhealthy lifestyle risk factor and poor adherence to a Mediterranean diet. Participants in the highest quintile group of animal protein intake had higher glucose, total and LDL cholesterol levels than those in the lowest quintile. In contrast, higher plant protein intake was negatively associated with fasting insulin and cholesterol, despite higher BMI, physical inactivity and starch consumption. CONCLUSIONS: Replacing plant protein for animal protein was associated with lower cardiovascular mortality among individuals with unhealthy lifestyle risk factors. High animal but not plant protein intake is associated with impaired fasting glucose and hypercholesterolemia, despite lower calorie and carbohydrate intake, suggesting that protein source plays crucial roles in modulating cardiometabolic health independently of body weight.

Background Breast Cancer (BC) is a leading public-health issue affecting women on a global scale, accounting for about 500,000 new cases every year in Europe. Thanks to the widespread implementation of screening programs and the improvement in therapies, women with BC live longer but they also are more likely to experience an increased risk of other diseases, including second primary cancer, cardiovascular, and metabolic diseases. Reasons for this increased risk include genetics, shared risk factors, and adverse effects from BC treatment. Methods To analyse the risk of myocardial infarction (MI) and stroke in women with BC considering the potential side effects of treatments, we used data from the Piedmont Longitudinal Study, an administrative cohort based on the record-linkage among census data and several health-administrative databases to include than 4 million inhabitants of an Italian region. Results Among 1,342,333 women ranging from 30 to 75 years old 19,203 had a BC diagnosis in the follow-up period, of whom 206 experienced a subsequent MI and 203 a stroke. Women with BC showed an increased risk for MI (HR: 1.20; 95%CI: 1.05–1.38) and for stroke (HR: 1.58; 95%CI: 1.38–1.82). Chemotherapy seemed to be the major risk factor for MI in BC women, while no different risk by therapy was found for stroke. Conclusion The results of this study supported the hypothesis about the toxic effect of therapies, suggesting both clinicians to routinely and actively screen for these treatment-related toxicities in women with BC and researchers to prioritize personalized treatments in order to minimize potentially devastating side effects.

BACKGROUND: Iron is an essential micronutrient with differing intake patterns and metabolism between men and women. Epidemiologic evidence on the association of dietary iron and its heme and non-heme components with colorectal cancer (CRC) development is inconclusive.METHODS: We examined baseline dietary questionnaire-assessed intakes of total, heme, and non-heme iron and CRC risk in the EPIC cohort. Sex-specific multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) were computed using Cox regression. We modelled substitution of a 1 mg/day of heme iron intake with non-heme iron using the leave one-out method.RESULTS: Of 450,105 participants (318,680 women) followed for 14.2 ± 4.0 years, 6162 (3511 women) developed CRC. In men, total iron intake was not associated with CRC risk (highest vs. lowest quintile, HR Q5vs.Q1:0.88; 95%CI:0.73, 1.06). An inverse association was observed for non-heme iron (HR Q5vs.Q1:0.80, 95%CI:0.67, 0.96) whereas heme iron showed a non-significant association (HR Q5vs.Q1:1.10; 95%CI:0.96, 1.27). In women, CRC risk was not associated with intakes of total (HR Q5vs.Q1:1.11, 95%CI:0.94, 1.31), heme (HR Q5vs.Q1:0.95; 95%CI:0.84, 1.07) or non-heme iron (HR Q5vs.Q1:1.03, 95%CI:0.88, 1.20). Substitution of heme with non-heme iron demonstrated lower CRC risk in men (HR:0.94; 95%CI: 0.89, 0.99). CONCLUSIONS: Our findings suggest potential sex-specific CRC risk associations for higher iron consumption that may differ by dietary sources.

IntroductionThe ability to return to work after a cancer diagnosis is a key aspect of cancer survivorship and quality of life. Studies have reported a significant risk of income loss for cancer survivors; however, there is limited evidence of the Italian context.MethodsThe Work Histories Italian Panel (WHIP)-Salute database was used to select a cohort of incident cases of colorectal cancer (CRC) among workers in the private sector, based on hospital discharges. A propensity score matching was used to find a balanced control group for several confounders. Ordinary least square and logistic regressions were used to estimate the effect of a CRC diagnosis on annual income and the probability of switching from a full-time contract to a part-time one considering 3 years after the diagnosis.ResultsOverall, we identified 925 CRC incident cases from 2006 until 2012. Our results confirm a statistically significant reduction in survivors’ income compared with controls. This reduction was greater in the first year and then tend to decrease, with an average income loss over 3 years of about €12 000. Stratified analyses by sex and position confirmed the overall trend while indicating a strong effect modification. Regarding the switching from full-time to part-time employment, the results were never significant.ConclusionIncome loss does not seem to be related to an increase in part-time contracts, but rather to survivors’ reduced work capacity following the invasive treatments. Further research is needed to investigate the complex dynamics behind this association.

Background: Migraine is one of the most frequent primary headaches in childhood. The role of thrombotic predisposition in its pathogenesis is debated. Our aim was to analyse the cardiovascular risk factors and family history of major thrombotic events in children with migraine. Methods: A retrospective, single-centre study was performed over 12 years. Our headache centre record database was screened for migraine with aura (MA) and migraine without aura (MO) on the basis of the ICHD-II (until 2013) and III criteria. A control group of otherwise healthy children was recruited. Descriptive and multivariate analyses are provided; significance was set at p < 0.05. Results: Migraine was diagnosed in 930 children (24.7% MA); 73.3% were 9–14 years old. Children with MA were older (p < 0.001). A family history of cerebral ischemic events at ≤50 years old was more commonly reported by children with MA than those with MO (p < 0.001) and those in the control group (p = 0.001). Children with MA showed a higher risk of a family history of cerebral ischemic events at ≤50 years old than children with MO (OR: 2.6) and those in the control group (OR: 3.1). When comparing the family history of DVT, we observed a significantly increased risk for MA vs. MO (OR: 2.9). Conclusion: A family history of cerebral ischemic events at ≤50 years old leads to an increased risk of MA. Further studies are needed to explore such an association.

Breast cancer (BC) is a multifactorial disease caused by an interaction between genetic predisposition and environmental exposures. MicroRNAs are a group of small non-coding RNA molecules, which seem to have a role either as tumor suppressor genes or oncogenes and seem to be related to cancer risk factors. We conducted a systematic review and meta-analysis to identify circulating microRNAs related to BC diagnosis, paying special attention to methodological problems in this research field. A meta-analysis was performed for microRNAs analyzed in at least three independent studies where sufficient data to make analysis were presented. Seventy-five studies were included in the systematic review. A meta-analysis was performed for microRNAs analyzed in at least three independent studies where sufficient data to make analysis were presented. Seven studies were included in the MIR21 and MIR155 meta-analysis, while four studies were included in the MIR10b metanalysis. The pooled sensitivity and specificity of MIR21 for BC diagnosis were 0.86 (95%CI 0.76–0.93) and 0.84 (95%CI 0.71–0.92), 0.83 (95%CI 0.72–0.91) and 0.90 (95%CI 0.69–0.97) for MIR155, and 0.56 (95%CI 0.32–0.71) and 0.95 (95%CI 0.88–0.98) for MIR10b, respectively. Several other microRNAs were found to be dysregulated, distinguishing BC patients from healthy controls. However, there was little consistency between included studies, making it difficult to identify specific microRNAs useful for diagnosis.

Resistin is a polypeptide implicated in inflammatory processes, and as such could be linked to colorectal carcinogenesis. In case-control studies, higher resistin levels have been found in colorectal cancer (CRC) patients compared to healthy individuals. However, evidence for the association between pre-diagnostic resistin and CRC risk is scarce. We investigated pre-diagnostic resistin concentrations and CRC risk within the European Prospective Investigation into Cancer and Nutrition using a nested case-control study among 1293 incident CRC-diagnosed cases and 1293 incidence density-matched controls. Conditional logistic regression models controlled for matching factors (age, sex, study center, fasting status, and women-related factors in women) and potential confounders (education, dietary and lifestyle factors, body mass index (BMI), BMI-adjusted waist circumference residuals) were used to estimate relative risks (RRs) and 95% confidence intervals (CIs) for CRC. Higher circulating resistin concentrations were not associated with CRC (RR per doubling resistin, 1.11; 95% CI 0.94–1.30; p = 0.22). There were also no associations with CRC subgroups defined by tumor subsite or sex. However, resistin was marginally associated with a higher CRC risk among participants followed-up maximally two years, but not among those followed-up after more than two years. We observed no substantial correlation between baseline circulating resistin concentrations and adiposity measures (BMI, waist circumference), adipokines (adiponectin, leptin), or metabolic and inflammatory biomarkers (C-reactive protein, C-peptide, high-density lipoprotein cholesterol, reactive oxygen metabolites) among controls. In this large-scale prospective cohort, there was little evidence of an association between baseline circulating resistin concentrations and CRC risk in European men and women., World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue contre le Cancer (France), Institut Gustave Roussy (France), Mutuelle Generale de l'Education Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe, Federal Ministry of Education & Research (BMBF), Hellenic Health Foundation (Greece), Fondazione AIRC per la ricerca sul cancro, Consiglio Nazionale delle Ricerche (CNR), Netherlands Government Netherlands Government, World Cancer Research Fund International (WCRF), Netherlands Government, Nordforsk, Nordic Centre of Excellence programme on Food, Nutrition and Health (Norway), Instituto de Salud Carlos III, Junta de Andalucia, Principality of Asturias, Regional Government of Basque Country (Spain), Regional Government of Murcia (Spain), Regional Government of Navarra (Spain), Instituto de Salud Carlos III RD06/0020, Swedish Cancer Society, Swedish Scientific Council (Sweden), Regional Government of Skane and Vasterbotten (Sweden), UK Research & Innovation (UKRI), Medical Research Council UK (MRC), Cancer Research UK, Deutsches Krebsforschungszentrum (Germany) ERC-2009-AdG 232997

It is unclear whether diet, and in particular certain foods or nutrients, are associated with lung cancer risk. We assessed associations of 92 dietary factors with lung cancer risk in 327,790 participants in the European Prospective Investigation into Cancer and Nutrition (EPIC). Cox regression yielded adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) per standard deviation (SD) higher intake/day of each food/nutrient. Correction for multiple comparisons was performed using the false discovery rate and identified associations were evaluated in the Netherlands Cohort Study (NLCS). In EPIC, 2,420 incident lung cancer cases were identified during a median of 15 years of follow-up. Higher intakes of fibre (HR per 1 SD higher intake/day=0.91, 95%CI 0.87-0.96), fruit (HR=0.91, 95%CI 0.86-0.96), and vitamin C (HR=0.91, 95%CI 0.86-0.96) were associated with a lower risk of lung cancer, whereas offal (HR=1.08, 95%CI 1.03-1.14), retinol (HR=1.06, 95%CI 1.03-1.10), and beer/cider (HR=1.04, 95%CI 1.02-1.07) intakes were positively associated with lung cancer risk. Associations did not differ by sex and there was less evidence for associations among never smokers. None of the six associations with overall lung cancer risk identified in EPIC were replicated in the NLCS (2,861 cases), however in analyses of histological subtypes, inverse associations of fruit and vitamin C with squamous cell carcinoma were replicated in the NLCS. Overall, there is little evidence that intakes of specific foods and nutrients play a major role in primary lung cancer risk, but fruit and vitamin C intakes seem to be inversely associated with squamous cell lung cancer. This article is protected by copyright. All rights reserved.

At the very beginning of the European spread of SARS-CoV-2, Piedmont was one of the most affected regions in Italy, with a strong impact on healthcare organizations. In this study, we evaluated the characteristics and outcomes of the COVID-19 patients in an entire region during the first three pandemic waves, identifying similarities and differences in the SARS-CoV-2 epidemic’s timeline. We collected the health-administrative data of all the Piedmont COVID-19 patients infected during the first three pandemic waves (1 March 2020–15 April 2020; 15 October 2020–15 December 2020; 1 March 2021–15 April 2021, respectively). We compared differences among the waves in subjects positive for SARS-CoV-2 and in patients admitted to ICU. Overall, 18.621 subjects tested positive during the first wave (405 patients/day), 144.350 (2366.4 patients/day) in the second, and 81.823 (1778.8 patients/day) in the third. In the second and third waves, we observed a reduction in median age, comorbidity burden, mortality in outpatients, inpatients, and patients admitted to ICU, in intubation, invasive ventilation and tracheostomy, and a parallel increase in the use of CPAP. Our study confirmed a trend towards younger and healthier patients over time but also showed an independent effect of the period on mortality and ICU admission. The appearance of new viral variants, the starting of vaccination, and organizational improvements in tracking, outpatients and inpatients management could have influenced these trends.

Background: Alcohol intake is an established risk factor for colorectal cancer (CRC); however, there is limited knowledge on whether changing alcohol drinking habits during adulthood modifies CRC risk.Objective: Leveraging longitudinal exposure assessments on alcohol intake at different ages, we examined the relationship between change in alcohol intake and subsequent CRC risk.Methods: Within the European Prospective Investigation into Cancer and Nutrition, changes in alcohol intake comparing follow-up with baseline assessments were investigated in relation to CRC risk. The analysis included 191,180, participants and 1530 incident CRC cases, with exclusion of the first three years of follow-up to minimize reverse causation. Trajectory profiles of alcohol intake, assessed at ages 20, 30, 40, 50years, at baseline and during follow-up, were estimated using latent class mixed models and related to CRC risk, including 407,605 participants and 5,008 incident CRC cases.Results: Mean age at baseline was 50.2years and the follow-up assessment occurred on average 7.1 years later. Compared to stable intake, a 12 g/day increase in alcohol intake during follow-up was positively associated with CRC risk (HR = 1.15, 95%CI 1.04, 1.25), while a 12 g/day reduction was inversely associated with CRC risk (HR = 0.86, 95%CI 0.78, 0.95). Trajectory analysis showed that compared to low alcohol intake, men who increased their alcohol intake from early- to mid- and late-adulthood by up to 30 g/day on average had significantly increased CRC risk (HR = 1.24; 95%CI 1.08, 1.42), while no associations were observed in women. Results were consistent by anatomical subsite.Conclusions: Increasing alcohol intake during mid-to-late adulthood raised CRC risk, while reduction lowered risk

While the link between cardiovascular and respiratory conditions and air pollution is well-known, recent studies provided a growing body of evidence that polluted air, particularly air with high levels of particulate matter with a diameter smaller than 2.5 micrometers (PM 2.5), can have a range of negative impacts on health, both in terms of mortality and morbidity. It is time to emphasize the role of environmental factors as contributory factors or determinants of both global and individual health levels, and to consider them together as a health priority, as enviropathies (meant as pathologies caused, triggered or worsened by environmental exposure). Bringing attention to harmful air pollution exposure has fostered population studies, which developed accurate quantification of environmental exposure in polluted regions, aiding our understanding of the dose-response relationship between pollutants and diseases. Those efforts have influenced local and global health policy strategies. Now we face the challenge of controlling environmental pollution and limiting individual exposure to prevent or avoid serious health risks. Is it time for enviropathies in everyday clinical practice?

Instituto de Salud Carlos III; Miguel Servet program (CPII20/00009) from the Institute of Health Carlos III (cofunded by the European Social Fund (ESF) – ESF investing in your future) (...), Llaha, F., Cayssials, V., Farràs, M., Agudo, A., Sandström, M., Eriksen, A.K., Tjønneland, A., Boutron-Ruault, M.-C., Laouali, N., Truong, T., Le Cornet, C., Katzke, V., Schulze, M., Palli, D., Krogh, V., Signoriello, S., Tumino, R., Ricceri, F., Skeie, G., Jensen, T.M.E., Chen, S.L.F., Lasheras, C., Rodriguez-Barranco, M., Amiano, P., Huerta, J.M., Guevara, M., Almquist, M., Nilson, L.M., Hennings, J., Papier, K., Heath, A., Weiderpass, E., Rinaldi, S., Zamora-Ros, R.

Background Since 2011 Italy has faced an extraordinary increase in migrants arrivals, mainly from the Mediterranean route, one of the world’s most dangerous journeys. The purpose of the present article is to provide a comprehensive picture of the migrants' health status in the "T. Fenoglio" centre, Settimo Torinese (Turin, Italy). Methods A retrospective cross-sectional study was conducted using data collected from June 2016 to May 2018 on adult migrants (over 18 years old) from Africa, Middle East and South East Asia (Bangladesh, Cambodia, India, Nepal). Data was collected through the migrants' medical records. Descriptive statistics were performed on socio-demographic variables. The diagnosed diseases were anonymously registered and classified according to the International Classification of Primary Care (ICPC-2). Conditional Inference Trees were used to perform a descriptive analysis of the sample and to detect the covariates with the strongest association with the variables Disease on arrival, Disease after arrival, ICPC on arrival and ICPC after arrival. Results Analyzed observations were 9 857. 81.8% were men, median age was 23 (Interquartile range: 20.0–27.4). 70.3% of the sample came from Sub-Saharan Africa. 2 365 individuals (24%) arrived at the centre with at least one disease. On arrival, skin (27.71%), respiratory (14.46%), digestive (14.73%) and generic diseases (20.88%) were the most frequent. During the stay respiratory diseases were the most common (25.70%). The highest probability of arriving with a disease occurred in 2018 and during the period September–November 2016, in particular for people from the Horn of Africa. During this period and also in the first half of 2017, skin diseases were the most reported. In seasons with lower prevalence of diseases on arrival the most common disease code was generic for both men and women (usually fever or trauma). Conclusions This study provides information on the diverse diseases that affect the asylum seekers population. In our sample, the Horn of Africa was the most troubled area of arrival, with severe conditions frequently reported regarding skin diseases, in particular scabies. 2018 was the most critical year, especially for migrants from the Horn of Africa and Sub-Saharan Africa. During the stay at the camp, the prevalence of respiratory diseases increased. However, skin diseases remained the main issue for people from the Horn of Africa. Overall, the most reported diseases in the sample were dermatological, respiratory, digestive and generic diseases, both on arrival and during the stay. A better understanding of the health status of asylum seekers is an important factor to determine a more efficient reception and integration process and a better allocation of economic resources in the context of migrants' health care.

Background: Recent evidence highlights the epidemiological value of blood DNA methylation (DNAm) as surrogate biomarker for exposures to risk factors for non-communicable diseases (NCD). DNAm surrogate of exposures predict diseases and longevity better than self-reported or measured exposures in many cases. Consequently, disease prediction models based on blood DNAm surrogates may outperform current state-of-art prediction models. This study aims to develop novel DNAm surrogates for cardiovascular diseases (CVD) risk factors and develop a composite biomarker predictive of CVD risk. We compared the prediction performance of our newly developed risk score with the state-of-art DNAm risk scores for cardiovascular diseases, the ‘next-generation’ epigenetic clock DNAmGrimAge, and the prediction model based on traditional risk factors SCORE2.Results: Using data from the EPIC Italy cohort, we derived novel DNAm surrogates for BMI, blood pressure, fasting glucose and insulin, cholesterol, triglycerides, and coagulation biomarkers. We validated them in four independent datasets from Europe and the US. Further, we derived a DNAmCVDscore predictive of the time-to-CVD event as a combination of several DNAm surrogates. ROC curve analyses show that DNAmCVDscore outperforms previously developed DNAm scores for CVD risk and SCORE2 for short-term CVD risk. Interestingly, the performance of DNAmGrimAge and DNAmCVDscore was comparable (slightly lower for DNAmGrimAge, although the differences were not statistically significant).Conclusions: We described novel DNAm surrogates for CVD risk factors useful for future molecular epidemiology research, and we described a blood DNAm-based composite biomarker, DNAmCVDscore, predictive of short-term cardiovascular events. Our results highlight the usefulness of DNAm surrogate biomarkers of risk factors in epigenetic epidemiology to identify high-risk populations. In addition, we provide further evidence on the effectiveness of prediction models based on DNAm surrogates and discuss methodological aspects for further improvements. Finally, our results encourage testing this approach for other NCD diseases by training and developing DNAm surrogates for disease-specific risk factors and exposures.

A full-term pregnancy is associated with reduced endometrial cancer risk; however, whether the effect of additional pregnancies is independent of age at last pregnancy is unknown. The associations between other pregnancy-related factors and endometrial cancer risk are less clear. We pooled individual participant data from 11 cohort and 19 case-control studies participating in the Epidemiology of Endometrial Cancer Consortium (E2C2) including 16 986 women with endometrial cancer and 39 538 control women. We used one- and two-stage meta-analytic approaches to estimate pooled odds ratios (ORs) for the association between exposures and endometrial cancer risk. Ever having a full-term pregnancy was associated with a 41% reduction in risk of endometrial cancer compared to never having a full-term pregnancy (OR = 0.59, 95% confidence interval [CI] 0.56-0.63). The risk reduction appeared the greatest for the first full-term pregnancy (OR = 0.78, 95% CI 0.72-0.84), with a further similar to 15% reduction per pregnancy up to eight pregnancies (OR = 0.20, 95% CI 0.14-0.28) that was independent of age at last full-term pregnancy. Incomplete pregnancy was also associated with decreased endometrial cancer risk (7%-9% reduction per pregnancy). Twin births appeared to have the same effect as singleton pregnancies. Our pooled analysis shows that, while the magnitude of the risk reduction is greater for a full-term pregnancy than an incomplete pregnancy, each additional pregnancy is associated with further reduction in endometrial cancer risk, independent of age at last full-term pregnancy. These results suggest that the very high progesterone level in the last trimester of pregnancy is not the sole explanation for the protective effect of pregnancy.

Purpose To examine differences between genders in exposure to psychosocial and ergonomic factors at work and in work-related health, according to different work organization models. Methods The study population included a sample of 9749 (women: 37.1%) and 10,374 (women: 39.9%) employees who participated in the 2010 and 2015 European Working Conditions Surveys, respectively. Multiple Correspondence Analysis was applied to work characteristics reported by workers to estimate principal components, followed by Hierarchical Clustering on principal components to identify clusters of work organization models. Gender differences in exposure to work hazards and health outcomes were assessed through Poisson robust regression. Differences of PRs across organizational models were tested through interaction between gender and type of work organization. Results Three organizational models were identified in 2010, including lean production, Tayloristic production, and a “reflexive production” model, whereas in 2015, a “simple” or traditional model was also found. In 2010, women employed in companies adopting the Tayloristic or the lean production models were more likely than men to be exposed to unfavourable psychosocial and physical work factors, and to report musculoskeletal pain, compared to those belonging to reflexive production. In 2015, a significantly higher female/male ratio persisted in lean production for exposure to high job strain and for carrying/moving heavy loads, whereas gender differences in Tayloristic and traditional production were quite similar to those of reflexive production. Conclusions Our results suggest that employment in workplaces characterized by lower monotony, repetitiveness, and production constraints may contribute to reduce exposure to job strain among working women.

R-CHOP standard chemotherapy is successful in about 60% of diffuse large B-cell lymphoma (DLBCL) patients. Unresponsive patients have a poor prognosis, and predictive biomarkers of response to R-CHOP are lacking. We conducted the first prospective GWAS study aimed at exploring constitutional biomarkers predictive of R-CHOP efficacy and toxicity. Overall, 216 any-stage chemonaïve DLBCL patients candidate to R-CHOP were enrolled. The median age of the 185 eligible patients was 59.2 years, 49.7% were women and 45.4% were stage I–II patients. According to the Revised International Prognostic Index (R-IPI), 14.1%, 56.8% and 29.2% were in the very good, good and poor prognosis groups, respectively. Of the patients, 85.9% produced a complete response. Highly significant associations (i.e., p < 5 × 10−8) were found between progression-free survival (PFS) and six SNPs (i.e., rs116665727, rs1607795, rs75614943, rs77241831, rs117500207, rs78466241). Additionally, five SNPs (i.e., rs74832512, rs117500207, rs35789195, rs11721010, rs12356569) were highly associated with overall survival (OS). Wild-type patients showed a prolonged PFS or OS compared with patients carrying deleterious alleles (p < 0.001). No association with the adequate significant threshold was observed between SNPs and the objective response or toxicity. In the future, these SNPs, alone or in combination, after a proper validation in an independent cohort, could contribute to improving the prediction of R-CHOP response.

Epidemiologic studies have indicated that cruciferous vegetables can influence the cancer risk; therefore, we examined with a cross-sectional approach the correlation between the frequent consumption of the total cruciferous vegetables and the formation of bulky DNA damage, a biomarker of carcinogen exposure and cancer risk, in the Gen-Air study within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. DNA damage measurements were performed in the peripheral blood of 696 of those apparently healthy without cancer controls, including 379 never-smokers and 317 former smokers from seven European countries by the 32P-postlabeling assay. In the Gen-Air controls, the median intake of cruciferous vegetables was 6.16 (IQR 1.16–13.66) g/day, ranging from 0.37 (IQR 0–6.00) g/day in Spain to 11.34 (IQR 6.02–16.07) g/day in the UK. Based on this information, participants were grouped into: (a) high consumers (>20 g/day), (b) medium consumers (3–20 g/day) and (c) low consumers (

The coordination of EPIC is financially supported by the European Commission (DG-SANCO) and the International Agency for Research on Cancer. The national cohorts are supported by Danish Cancer Society (Denmark); German Cancer Aid, German Cancer Research Center (DKFZ), Federal Ministry of Education and Research (BMBF), Deutsche Krebshilfe, Deutsches Krebsforschungszentrum and Federal Ministry of Education and Research (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy and National Research Council (Italy); Health Research Fund (FIS), PI13/00061 to Granada; PI13/01162 to EPIC-Murcia), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, and the Catalan Institute of Oncology (Spain). This study was in part funded by Wereld Kanker Onderzoek Fonds (WKOF), as part of the World Cancer Research Fund International grant programme (IIG_2016_1636, Principal Investigator: Isabelle Soerjomataram), by the World Cancer Research Fund (WCRF UK) as part of the World Cancer Research Fund International grant programme (IIG_2019_1978, Principal Investigator: Heinz Freisling), and by the French National Cancer Institute (INCA_ N degrees 2020-087, Principal Investigator: Heinz Freisling)., Background: Body mass index (BMI) and cardiometabolic comorbidities such as cardiovascular disease and type 2 diabetes have been studied as negative prognostic factors in cancer survival, but possible dependencies in the mechanisms underlying these associations remain largely unexplored. We analysed these associations in colorectal and breast cancer patients. Methods: Based on repeated BMI assessments of cancer-free participants from four European countries in the European Prospective Investigation into Cancer and nutrition (EPIC) study, individual BMI-trajectories reflecting predicted mean BMI between ages 20 to 50 years were estimated using a growth curve model. Participants with incident colorectal or breast cancer after the age of 50 years were included in the survival analysis to study the prognostic effect of mean BMI and cardiometabolic diseases (CMD) prior to cancer. CMD were defined as one or more chronic conditions among stroke, myocardial infarction, and type 2 diabetes. Hazard ratios (HRs) and confidence intervals (CIs) of mean BMI and CMD were derived using multivariable-adjusted Cox proportional hazard regression for mean BMI and CMD separately and both exposures combined, in subgroups of localised and advanced disease. Results: In the total cohort of 159,045 participants, there were 1,045 and 1,620 eligible patients of colorectal and breast cancer. In colorectal cancer patients, a higher BMI (by 1 kg/m2) was associated with a 6% increase in risk of death (95% CI of HR: 1.02–1.10). The HR for CMD was 1.25 (95% CI: 0.97–1.61). The associations for both exposures were stronger in patients with localised colorectal cancer. In breast cancer patients, a higher BMI was associated with a 4% increase in risk of death (95% CI: 1.00–1.08). CMDs were associated with a 46% increase in risk of death (95% CI: 1.01–2.09). The estimates and CIs for BMI remained similar after adjustment for CMD and vice versa. Conclusions: Our results suggest that cumulative exposure to higher BMI during early to mid-adulthood was associated with poorer survival in patients with breast and colorectal cancer, independent of CMD prior to cancer diagnosis. The association between a CMD diagnosis prior to cancer and survival in patients with breast and colorectal cancer was independent of BMI., European Commission European Commission Joint Research Centre, International Agency for Research on Cancer, Danish Cancer Society, Deutsche Krebshilfe, Helmholtz Association, Federal Ministry of Education & Research (BMBF), Deutsche Krebshilfe Deutsches Krebsforschungszentrum, Fondazione AIRC per la ricerca sul cancro, Instituto de Salud Carlos III PI13/00061 PI13/01162, Regional Governments of Andalucia, Asturias, Basque Government Murcia and Navarra Catalan Institute of Oncology (Spain), Wereld Kanker Onderzoek Fonds (WKOF), World Cancer Research Fund International grant programme IIG_2016_1636, World Cancer Research Fund (WCRF UK), World Cancer Research Fund International grant programme IIG_2019_1978, Institut National du Cancer (INCA) France 2020-087

OBJECTIVE Higher plasma vitamin C levels are associated with lower type 2 diabetes risk, but whether this association is causal is uncertain. To investigate this, we studied the association of genetically predicted plasma vitamin C with type 2 diabetes. RESEARCH DESIGN AND METHODS We conducted genome-wide association studies of plasma vitamin C among 52,018 individuals of European ancestry to discover novel genetic variants. We performed Mendelian randomization analyses to estimate the association of genetically predicted differences in plasma vitamin C with type 2 diabetes in up to 80,983 case participants and 842,909 noncase participants. We compared this estimate with the observational association between plasma vitamin C and incident type 2 diabetes, including 8,133 case participants and 11,073 noncase participants. RESULTS We identified 11 genomic regions associated with plasma vitamin C (P < 5 × 10−8), with the strongest signal at SLC23A1, and 10 novel genetic loci including SLC23A3, CHPT1, BCAS3, SNRPF, RER1, MAF, GSTA5, RGS14, AKT1, and FADS1. Plasma vitamin C was inversely associated with type 2 diabetes (hazard ratio per SD 0.88; 95% CI 0.82, 0.94), but there was no association between genetically predicted plasma vitamin C (excluding FADS1 variant due to its apparent pleiotropic effect) and type 2 diabetes (1.03; 95% CI 0.96, 1.10). CONCLUSIONS These findings indicate discordance between biochemically measured and genetically predicted plasma vitamin C levels in the association with type 2 diabetes among European populations. The null Mendelian randomization findings provide no strong evidence to suggest the use of vitamin C supplementation for type 2 diabetes prevention.

ObjectivesThere is sufficient evidence for a causal association of sinonasal epithelial cancers (SNEC) only for exposure to wood and leather dusts, nickel compounds and employment in isopropyl alcohol production. The aim of this study was to assess whether other occupational hazards are associated with the risk of SNEC for the main histologic types, namely adenocarcinoma (AD) and squamous cell carcinoma (SCC).MethodsThe study population included 375 incident SNEC cases collected from 1996 to 2014 (79% of all diagnosed SNEC) throughout the Piedmont region by the regional Sinonasal Cancer Registry, and 408 hospital controls. Exposure to 17 occupational agents was assigned through expert assessment based on interviews to the subjects on jobs held throughout their working life. The relationship of SNEC with ever and cumulative exposure to the hazards was assessed through unconditional logistic regression models adjusted for age, sex, area of residence, smoking habit, year of enrolment and coexposures.ResultsAD was associated with both ever and cumulative exposure to wood dust, leather dust and organic solvents, and with cumulative exposure to textiles dusts. SCC risk was significantly increased by ever exposure to nickel, chromium and welding fumes, as well as by cumulative exposure to welding fumes, arsenic and organic solvents. A mixed group of other histological types was associated with both ever and cumulative exposure to wood dust and textile dusts.ConclusionsThe associations of SNEC with wood dust, leather dust and nickel were confirmed, while some new associations were observed for other hazards, which merit further investigation.

We evaluated the prognostic performance of systemic inflammatory response syndrome (SIRS), sequential organ failure assessment (SOFA), quick-SOFA (qSOFA), modified early warning score (MEWS), lactates and procalcitonin in septic patients. Prospective study on adults with sepsis in the Emergency Department (ED). Area under the Receiver operator characteristic curve (AUC) was calculated to assess how scores predict mortality at 30 and 60 days (d) and upon admission to Intensive care unit (ICU). Among 469 patients, mortality was associated with higher SOFA, qSOFA, MEWS and lactates level. ICU admission was associated with higher SOFA, procalcitonin and MEWS. Prognostic performance for mortality were: SOFA AUC 30 d 0.76 (0.69-0.81); 60 d 0.74 (0.68-0.79); qSOFA AUC 30 d 0.72 (0.66-0.79); 60 d 0.73 (0.67-0.78) and lactates AUC 30 d 0.71 (0.60-0.82); 60d 0.65 (0.54- 0.73). For the outcome ICU admission, procalcitonin had the highest AUC [0.66 (0.56-0.64], followed by SOFA [0.61 (0.54-0.69)] and MEWS [0.60 (0.53-0.67)]. SOFA, qSOFA and lactates assessment after arrival in the ED have a good performance in detecting patients at risk of mortality for sepsis. Procalcitonin is useful to select patients that will need ICU admission.

This is the peer reviewed version of the following article: Naudin, S., Margalef, M.S., Hosnijeh, F.S., Nieters, A., Kyrø, C. Tjønneland, A. ... Ferrari, P. (2020) Healthy lifestyle and the risk of lymphoma in the European Prospective Investigation into Cancer and Nutrition study. International Journal of Cancer, 147(6):1649-1656, which has been published in final form at https://doi.org/10.1002/ijc.32977. This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Use of Self-Archived Versions. Limited evidence exists on the role of modifiable lifestyle factors on the risk of lymphoma. In this work, the associations between adherence to healthy lifestyles and risks of Hodgkin lymphoma (HL) and non‐Hodgkin lymphoma (NHL) were evaluated in a large‐scale European prospective cohort. Within the European Prospective Investigation into Cancer and Nutrition (EPIC), 2,999 incident lymphoma cases (132 HL and 2,746 NHL) were diagnosed among 453,808 participants after 15 years (median) of follow‐up. The healthy lifestyle index (HLI) score combined information on smoking, alcohol intake, diet, physical activity and BMI, with large values of HLI expressing adherence to healthy behavior. Cox proportional hazards models were used to estimate lymphoma hazard ratios (HR) and 95% confidence interval (CI). Sensitivity analyses were conducted by excluding, in turn, each lifestyle factor from the HLI score. The HLI was inversely associated with HL, with HR for a 1‐standard deviation (SD) increment in the score equal to 0.78 (95% CI: 0.66, 0.94). Sensitivity analyses showed that the association was mainly driven by smoking and marginally by diet. NHL risk was not associated with the HLI, with HRs for a 1‐SD increment equal to 0.99 (0.95, 1.03), with no evidence for heterogeneity in the association across NHL subtypes. In the EPIC study, adherence to healthy lifestyles was not associated with overall lymphoma or NHL risk, while an inverse association was observed for HL, although this was largely attributable to smoking. These findings suggest a limited role of lifestyle factors in the etiology of lymphoma subtypes.

Oral biopsy is a common surgical practice. To date, few authors have described the healing of mucosal wounds following oral biopsy. The aim of the present single-center, prospective, randomized, controlled study is to evaluate the differences between two chlorhexidine (CHX) mouthrinses and a treatment-free approach in the immediate postoperative period following oral mucosal biopsy. 354 patients were included in this study and were randomly allocated to three groups: A) CHX 0.12% mouthrinse (twice daily, 10 mL rinse for 30 s), B) CHX 0.20% mouthrinse (twice daily, 10 mL rinse for 30 s), and C) no topical treatment. 118 patients were treated in group A and 115 in group B; 121 received no therapy in group C, reporting the greatest improvement in related symptoms. Outcome variables included the age, gender, site and size of lesions, visual analog score (VAS), Oral Health Impact Profile questionnaire (OHIP-14), and number of painkillers taken during the first week post-surgery. Use of a CHX 0.12% mouthrinse exhibited the poorest outcome. On the other hand, best clinical healing was found for patients treated with CHX 0.20%. These findings suggest that regardless of its concentration, CHX was found to be ineffective in reducing related symptoms, whereas CHX 0.20% can be recommended to facilitate enhanced healing.

Emotional Style (ES) refers is the unique way of experiencing emotions while going through life. The Emotional Style Questionnaire (ESQ) is a 24-item self-report measure that evaluate how people vary across the six dimensions of ES, providing an overall score of healthy emotionality. The present study aimed to validate the Italian version of ESQ. In Study 1, 208 healthy volunteers were enrolled. Linguistic and cultural adaptation was carried out and the adaptation’s psychometric properties were investigated. In Study 2 linguistic changes were made to the ESQ items, modifying also the questionnaires used for assessing convergent and divergent validity to better investigate the constructs underlying each dimension. 197 healthy volunteers stratified by age group were enrolled. The final Italian version of the ESQ is therefore composed of 24 items allowing the identification of five subscales and six constructs due to the overlap between Outlook and Resilience. The questionnaire was found to be a valid and reliable measure, with satisfactory psychometric properties. Moreover, as with the original version, the Italian version too can be considered a measure of overall emotional well-being. Future studies should investigate the properties of the ESQ in clinical samples and its correlations with neurobiological characteristics.

International audience; The COVID-19 pandemic introduced changes in people’s lives that affected their mental health. Our study aimed to explore the level of psychological distress in the academic population during the lockdown period and investigate its association with the new working or studying conditions. The study sample included 9364 students and 2159 employees from five Italian universities from the study IO CONTO 2020. We applied linear regression models to investigate the association between home learning or remote working conditions and psychological distress, separately for students and employees. Psychological distress was assessed using the Hospital Anxiety and Depression Scale (HADS). In both students and employees, higher levels of distress were significantly associated with study/work–family conflicts, concerns about their future careers, and inadequacy of equipment; in employees, higher levels of distress were significantly associated with a lack of clarity on work objectives. Our results are in line with previous research on the impact of spaces and equipment in remote working/studying from home. Moreover, the study contributes to deepening the association between well-being and telework–family conflict, which in the literature is still equivocal. Practical implications require academic governance to promote sustainable environments both in remote and hybrid work conditions, by referring to a specific management by objectives approach.

Background: Many studies have shown that socioeconomic position (SEP) is associated with the incidence of malignant tumors at different sites. This study aims to estimate the association between educational level (as proxy for SEP) and cancer incidence and to understand whether the observed associations might be partially explained by lifestyle behaviors. Methods: The analyses were performed on data from the European Prospective Investigation into Cancer and Nutrition (EPIC) study, globally and by sex. We used Cox proportional hazards models together with mediation analysis to disentangle the total effect (TE) of educational level [measured through the Relative Index of Inequality (RII)] on cancer incidence into pure direct (PDE) and total indirect (TIE) effect, unexplained and explained by mediators, respectively. PDE and TIE were then combined to compute the proportions mediated (PM). Results: After an average of 14 years of follow-up, 52,422 malignant tumors were ascertained. Low educated participants showed higher risk of developing stomach, lung, kidney (in women), and bladder (in men) cancers, and, conversely, lower risk of melanoma and breast cancer (in post-menopausal women), when compared with more educated participants. Mediation analyses showed that portions of the TE of RII on cancer could be explained by site-specific related lifestyle behaviors for stomach, lung, and breast (in women). Conclusions: Cancer incidence in Europe is determined at least in part by a socioeconomically stratified distribution of risk factors. Impact: These observational findings support policies to reduce cancer occurrence by altering mediators, such as lifestyle behaviors, particularly focusing on underprivileged strata of the population.

Background Recent evidence highlights the epidemiological value of blood DNA methylation (DNAm) as surrogate biomarker for exposure to risk factors for non-communicable diseases (NCD). DNAm surrogate of exposures predicts diseases and longevity better than self-reported or measured exposures in many cases. Consequently, disease prediction models based on blood DNAm surrogates may outperform current state-of-the-art prediction models. This study aims to develop novel DNAm surrogates for cardiovascular diseases (CVD) risk factors and develop a composite biomarker predictive of CVD risk. We compared the prediction performance of our newly developed risk score with the state-of-the-art DNAm risk scores for cardiovascular diseases, the ‘next-generation’ epigenetic clock DNAmGrimAge, and the prediction model based on traditional risk factors SCORE2. Results Using data from the EPIC Italy cohort, we derived novel DNAm surrogates for BMI, blood pressure, fasting glucose and insulin, cholesterol, triglycerides, and coagulation biomarkers. We validated them in four independent data sets from Europe and the USA. Further, we derived a DNAmCVDscore predictive of the time-to-CVD event as a combination of several DNAm surrogates. ROC curve analyses show that DNAmCVDscore outperforms previously developed DNAm scores for CVD risk and SCORE2 for short-term CVD risk. Interestingly, the performance of DNAmGrimAge and DNAmCVDscore was comparable (slightly lower for DNAmGrimAge, although the differences were not statistically significant). Conclusions We described novel DNAm surrogates for CVD risk factors useful for future molecular epidemiology research, and we described a blood DNAm-based composite biomarker, DNAmCVDscore, predictive of short-term cardiovascular events. Our results highlight the usefulness of DNAm surrogate biomarkers of risk factors in epigenetic epidemiology to identify high-risk populations. In addition, we provide further evidence on the effectiveness of prediction models based on DNAm surrogates and discuss methodological aspects for further improvements. Finally, our results encourage testing this approach for other NCD diseases by training and developing DNAm surrogates for disease-specific risk factors and exposures.

to describe the epidemiology of SARS-CoV-2 infection in relation with the use of nasal swabs in the immigrant population in Italy, using data from the COVID-19 national surveillance system and to verify if a difference is present comparing natives and immigrant.descriptive study based on longitudinal health-administrative data.general population of six Italian Regions (Piedmont, Lombardy, Veneto, Emilia-Romagna, Tuscany, Lazio) covering about 55% of the resident population and 72% of foreigners' population.regional rates of access to at least a nasal swab, separately by country of origin.across all the periods, a lower rate in the foreigners' group was observed, with the only exception of the period May-June 2021. Considering separately High Migratory Pressure Countries (HMPCs) and Highly Developed Countries (HDCs), a higher proportion of nasal swabs performed in people coming from HDC with respect to HMPCs and natives was noticed. This observation is consistent in males and females.during the first wave of the pandemic, Italians have had a higher proportion of nasal swabs compared to migrants across all Regions. This difference disappeared in the following periods, probably due to a major availability of diagnostic tests.

Background Patients that arrive in the emergency department (ED) with COVID-19-like syndromes testing negative at the first RT-PCR represent a clinical challenge because of the lack of evidence about their management available in the literature. Our first aim was to quantify the proportion of patients testing negative at the first RT-PCR performed in our Emergency Department (ED) that were confirmed as having COVID-19 at the end of hospitalization by clinical judgment or by any subsequent microbiological testing. Secondly, we wanted to identify which variables that were available in the first assessment (ED variables) would have been useful in predicting patients, who at the end of the hospital stay were confirmed as having COVID-19 (false-negative at the first RT-PCR). Methods We retrospectively collected data of 115 negative patients from2020, March 1st to 2020, May 15th. Three experts revised patients’ charts collecting information on the whole hospital stay and defining patients as COVID-19 or NOT-COVID-19. We compared ED variables in the two groups by univariate analysis and logistic regression. Results We classified 66 patients as COVID-19 and identified the other 49 as having a differential diagnosis (NOT-COVID), with a concordance between the three experts of 0.77 (95% confidence interval (95%CI) 0.66- 0.73). Only 15% of patients tested positive to a subsequent RT-PCR test, accounting for 25% of the clinically suspected. Having fever (odds ratio (OR) 3.32, (95%CI 0.97-12.31), p = 0.06), showing a typical pattern at the first lung ultrasound (OR 6.09, (95%CI 0.87-54.65), p = 0.08) or computed tomography scan (OR 4.18, (95%CI 1.11-17.86), p = 0.04) were associated with a higher probability of having COVID-19. Conclusions In patients admitted to ED with COVID-19 symptoms and negative RT-PCR a comprehensive clinical evaluation integrated with lung ultrasound and computed tomography could help to detect COVID-19 patients with a false negative RT-PCR result.

Emotional styles concern the ways in which individuals adapt and respond to the world and can be defined using six dimensions: outlook, resilience, social intuition, self-awareness, sensitivity to context and attention. The Emotional Style Questionnaire (ESQ) assesses how people vary across the dimensions and gauges an individual’s overall level of emotional health. An Italian version of the ESQ (ESQ-ITA) could favour the understanding of cultural characteristics concerning emotions and personality within the Italian population, with both clinical and social implications. The aim of the present study is to validate the ESQ in the Italian language and to assess its psychometric properties. Two studies were conducted. Study 1 examined construct validity, internal consistency, and test–retest reliability, through Exploratory Factor Analysis (EFA) and Confirmatory Factor Analysis (CFA), Cronbach’s alpha estimates, and by estimating the Spearman’s rank correlation Study 2 examined construct validity and internal consistency through the CFA and Cronbach’s alpha estimates and investigated criterion validity by correlating the ESQ-ITA dimensions with the corresponding scales or subscales used for the validation estimating, again, the Spearman’s rank correlation coefficient Study 2 also examined the criterion validity of the validated scales and the ESQ-ITA overall score to assess its suitability as an indicator of emotional health. ESQ-ITA was confirmed to be reliable and stable. The correlation between the ESQ-ITA overall score and the other scales and questionnaires supports the use of ESQ-ITA to measure emotional health. The Italian version of the ESQ opens up the possibility to enrich the research landscape with new knowledge that will be useful for advancing the pathogenetic and therapeutic aspects of psychological distress and emotional dysregulation.

Background Since the outbreak of the COVID-19 pandemic, identifying the main risk factors has been imperative to properly manage the public health challenges that the pandemic exposes, such as organizing effective vaccination campaigns. In addition to gender and age, multimorbidity seems to be 1 of the predisposing factors coming out of many studies investigating the possible causes of increased susceptibility to SARS-CoV-2 infection and adverse outcomes. However, only a few studies conducted have used large samples. Objective The objective is to evaluate the association between multimorbidity, the probability to be tested, susceptibility, and the severity of SARS-CoV-2 infection in the Piedmont population (Northern Italy, about 4 million inhabitants). For this purpose, we considered 5 main outcomes: access to the swab, positivity to SARS-CoV-2, hospitalization, intensive care unit (ICU) admission, and death within 30 days from the first positive swab. Methods Data were obtained from different Piedmont health administrative databases. Subjects aged from 45 to 74 years and infections diagnosed from February to May 2020 were considered. Multimorbidity was defined both with the Charlson Comorbidity Index (CCI) and by identifying patients with previous comorbidities, such as diabetes and oncological, cardiovascular, and respiratory diseases. Multivariable logistic regression models (adjusted for age and month of infection and stratified by gender) were performed for each outcome. Analyses were also conducted by separating 2 age groups (45-59 and 60-74 years). Results Of 1,918,549 subjects, 85,348 (4.4%) performed at least 1 swab, of whom 12,793 (14.9%) tested positive for SARS-CoV-2. Of these 12,793 subjects, 4644 (36.3%) were hospitalized, 1508 (11.8%) were admitted to the ICU, and 749 (5.9%) died within 30 days from the first positive swab. Individuals with a higher CCI had a higher probability of being swabbed but a lower probability of testing positive. We observed the same results when analyzing subjects with previous oncological and cardiovascular diseases. Moreover, especially in the youngest group, we identified a greater risk of being hospitalized and dying. Among comorbidities considered in the study, respiratory diseases seemed to be the most likely to increase the risk of having a positive swab and worse disease outcomes. Conclusions Our study shows that patients with multimorbidity, although swabbed more frequently, are less likely to get infected with SARS-CoV-2, probably due to greater attention on protective methods. Moreover, a history of respiratory diseases is a risk factor for a worse prognosis of COVID-19. Nonetheless, whatever comorbidities affect the patients, a strong dose-response effect was observed between an increased CCI score and COVID-19 hospitalization, ICU admission, and death. These results are important in terms of public health because they help in identifying a group of subjects who are more prone to worse SARS-CoV-2 outcomes. This information is important for promoting targeted prevention and developing policies for the prioritization of public health interventions.

Funding [WCRF 2015/1391, PI: M. Jenab] was obtained from Wereld Kanker Onderzoek Fonds (WKOF), as part of the World Cancer Research Fund International grant program. The coordination of EPIC is financially supported by International Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Generale de lEducation Nationale, Institut National de la Sante et de la Recherche Medicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro-AIRC-Italy, Compagnia di SanPaolo and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Regional Governments of Andalucia, Asturias, Basque Country, Murcia and Navarra, the Catalan Institute of OncologyICO (Spain); Swedish Cancer Society, Swedish Research Council and County Councils of Skane and Vaesterbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom). The EPIC-Norfolk study (DOI 10.22025/2019.10.105.00004) received funding from the Medical Research Council (MR/N003284/1 and MC-UU_12015/1) and Cancer Research UK (C864/A14136). V. Fedirko is supported by the Cancer Prevention and Research Institute of Texas (CPRIT) Rising Stars Award (Grant ID RR200056). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., Advanced glycation end-products (AGEs) may promote oxidative stress and inflammation and have been linked to multiple chronic diseases, including cancer. However, the association of AGEs with mortality after colorectal cancer (CRC) diagnosis has not been previously investigated. Multivariable Cox proportional hazards models were used to calculate hazard ratios and corresponding 95% confidence intervals for associations between dietary intake of AGEs with CRC-specific and all-cause mortality among 5801 participant cases diagnosed with CRC in the European Prospective Investigation into Cancer and Nutrition study between 1993 and 2013. Dietary intakes of AGEs were estimated using country-specific dietary questionnaires, linked to an AGE database, that accounted for food preparation and processing. During a median of 58 months of follow-up, 2421 cases died (1841 from CRC). Individually or combined, dietary intakes of AGEs were not associated with all-cause and CRC-specific mortality among cases. However, there was a suggestion for a positive association between AGEs and all-cause or CRC-specific mortality among CRC cases without type II diabetes (all-cause, P-interaction = 0.05) and CRC cases with the longest follow-up between recruitment and cancer diagnosis (CRC-specific, P-interaction = 0.003; all-cause, P-interaction = 0.01). Our study suggests that pre-diagnostic dietary intakes of AGEs were not associated with CRC-specific or all-cause mortality among CRC patients. Further investigations using biomarkers of AGEs and stratifying by sex, diabetes status, and timing of exposure to AGEs are warranted., Wereld Kanker Onderzoek Fonds (WKOF), World Cancer Research Fund International grant program WCRF 2015/1391, World Health Organization, Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, Danish Cancer Society, Ligue Contre le Cancer (France) Institut Gustave Roussy (France) Mutuelle Generale de lEducation Nationale (France), Institut National de la Sante et de la Recherche Medicale (Inserm), Deutsche Krebshilfe German Cancer Research Center (DKFZ) (Germany) German Institute of Human Nutrition Potsdam-Rehbruecke (DIfE) (Germany), Federal Ministry of Education & Research (BMBF), Fondazione AIRC per la ricerca sul cancro Compagnia di San Paolo Consiglio Nazionale delle Ricerche (CNR), Netherlands Government, World Cancer Research Fund International (WCRF), Health Research Fund (FIS) - Instituto de Salud Carlos III (ISCIII), Junta de Andalucia Regional Government of Asturias (Spain) Regional Government of Basque Country (Spain) Regional Government of Murcia (Spain) Regional Government of Navarra (Spain) Catalan Institute of OncologyICO (Spain), Swedish Cancer Society Swedish Research Council County Council of Skane (Sweden) County Council of Vaesterbotten (Sweden), Cancer Research UK 14136 C8221/A29017, UK Research & Innovation (UKRI) Medical Research Council UK (MRC) 1000143 MR/M012190/1 UK Research & Innovation (UKRI) Medical Research Council UK (MRC), European Commission MR/N003284/1 MC-UU_12015/1, Cancer Research UK C864/A14136, Cancer Prevention and Research Institute of Texas (CPRIT) Rising Stars Award RR200056

Few epidemiological studies have assessed the risk of parkinsonisms after prolonged use of neuroleptics. We aimed to examine the long-term risk of degenerative parkinsonisms (DP) associated with previous use of neuroleptics.All residents in Piedmont, Northern-west Italy, older than 39 years (2,526,319 subjects), were retrospectively followed up from 2013 to 2017. Exposure to neuroleptics was assessed through the regional archive of drug prescriptions. The development of DP was assessed using the regional archives of both drug prescriptions and hospital admissions. We excluded prevalent DP cases at baseline as well as those occurred in the first 18 months (short-term risk). The risk of DP associated with previous use of neuroleptics was examined through Cox regression, using a matched cohort design.The risk of DP was compared between 63,356 exposed and 316,779 unexposed subjects. A more than threefold higher risk of DP was observed among subjects exposed to antipsychotics, compared to those unexposed (HR = 3.27, 95% CI 3.00-3.57), and was higher for exposure to atypical than typical antipsychotics. The risk decreased after 2 years from therapy cessation but remained significantly elevated (HR = 2.38, 95% CI 1.76-3.21).These results indicate a high risk of developing DP long time from the start of use and from the cessation for both typical and atypical neuroleptics, suggesting the need of monitoring treated patients even after long-term use and cessation.

Background Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed because of measurement error in self-reported assessments. Biomarkers of habitual alcohol intake may provide novel insight into the relationship between alcohol and cancer risk. Methods Untargeted metabolomics was used to identify metabolites correlated with self-reported habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n = 454). Statistically significant correlations were tested in independent datasets of controls from case-control studies nested within EPIC (n = 280) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n = 438) study. Conditional logistic regression was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies. Results Two metabolites displayed a dose-response association with self-reported alcohol intake: 2-hydroxy-3-methylbutyric acid and an unidentified compound. A 1-SD (log2) increase in levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR = 2.54, 95% CI = 1.51 to 4.27) and pancreatic cancer (OR = 1.43, 95% CI = 1.03 to 1.99) in EPIC and liver cancer (OR = 2.00, 95% CI = 1.44 to 2.77) and liver disease mortality (OR = 2.16, 95% CI = 1.63 to 2.86) in ATBC. Conversely, a 1-SD (log2) increase in questionnaire-derived alcohol intake was not associated with HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with liver disease mortality (OR = 2.19, 95% CI = 1.60 to 2.98) in ATBC. Conclusions 2-hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies.

Publisher Copyright: Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved. BACKGROUND: Few studies have examined the interactions between individual socioeconomic position and neighbourhood deprivation and the findings so far are heterogeneous. Using a large sample of diverse cohorts, we investigated the interaction effect of neighbourhood socioeconomic deprivation and individual socioeconomic position, assessed using education, on mortality. METHODS: We did a longitudinal multicohort analysis that included six cohort studies participating in the European LIFEPATH consortium: the CoLaus (Lausanne, Switzerland), E3N (France), EPIC-Turin (Turin, Italy), EPIPorto (Porto, Portugal), Melbourne Collaborative Cohort Study (Melbourne, VIC, Australia), and Whitehall II (London, UK) cohorts. All participants with data on mortality, educational attainment, and neighbourhood deprivation were included in the present study. The data sources were the databases of each cohort study. Poisson regression was used to estimate the mortality rates and associations (relative risk, 95% CIs) with neighbourhood deprivation (Q1 being least deprived to Q5 being the most deprived). Baseline educational attainment was used as an indicator of individual socioeconomic position. Estimates were combined using pooled analysis and the relative excess risk due to the interaction was computed to identify additive interactions. FINDINGS: The cohorts comprised a total population of 168 801 individuals. The recruitment dates were 2003-06 for CoLaus, 1989-91 for E3N, 1992-98 for EPIC-Turin, 1999-2003 for EPIPorto, 1990-94 for MCCS, and 1991-94 for Whitehall II. We use baseline data only and mortality data obtained using record linkage. Age-adjusted mortality rates were higher among participants residing in more deprived neighbourhoods than those in the least deprived neighbourhoods (Q1 least deprived neighbourhoods, 369·7 per 100 000 person-years [95% CI 356·4-383·2] vs Q5-most deprived neighbourhoods 445·7 per 100 000 person-years [430·2-461·7]), but the magnitude of the association varied according to educational attainment (relative excess risk due to interaction=0·18, 95% CI 0·08-0·28). The relative risk for Q5 versus Q1 was 1·31 (1·23-1·40) among individuals with primary education or less, but less pronounced among those with secondary education (1·12; 1·04-1·21) and tertiary education (1·16; 1·07-1·27). Associations remained after adjustment for individual-level factors, such as smoking, physical activity, and alcohol intake, among others. INTERPRETATION: Our study suggests that the detrimental health effect of living in disadvantaged neighbourhoods is more pronounced among individuals with low education attainment, amplifying social inequalities in health. This finding is relevant to policies aimed at reducing health inequalities, suggesting that these issues should be addressed at both the individual level and the community level. FUNDING: The European Commission, European Regional Development Fund, the Portugese Foundation for Science and Technology.

This work was funded by the Wereld Kanker Onderzoek Fonds (WKOF), as part of the World Cancer Research Fund (WCRF) International grant program (WCRF 2015-1391, P.I. Mazda Jenab, International Agency for Research on Cancer). This work was partially financially supported by the Fondation de France (FDF grant no. 00081166 to H. Freisling and FDF grant no. 00089811 to A.-L. Mayen). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript., The authors would like to thank the EPIC study participants and staff for their valuable contribution to this research. The authors would also like to thank Bertrand Hemon for the preparation of the databases. The coordination of EPIC is financially supported by the Inter national Agency for Research on Cancer (IARC) and also by the Department of Epidemiology and Biostatistics, School of Public Health, Imperial College London, which has additional infrastructure support provided by the NIHR Imperial Biomedical Research Centre (BRC). The national cohorts are supported by: Danish Cancer Society (Denmark); Ligue Contre le Cancer, Institut Gustave Roussy, Mutuelle Générale de l’Education Nationale, Institut National de la Santé et de la Recherche Médicale (INSERM) (France); German Cancer Aid, German Cancer Research Center (DKFZ), German Insti tute of Human Nutrition Potsdam-Rehbruecke (DIfE), Federal Ministry of Education and Research (BMBF) (Germany); Associazione Italiana per la Ricerca sul Cancro (AIRC), Compagnia di San Paolo, and National Research Council (Italy); Dutch Ministry of Public Health, Welfare and Sports (VWS), Netherlands Cancer Registry (NKR), LK Research Funds, Dutch Prevention Funds, Dutch ZON (Zorg Onderzoek Nederland), World Cancer Research Fund (WCRF), Statistics Netherlands (The Netherlands); Health Research Fund (FIS), Instituto de Salud Carlos III (ISCIII), Regional Govern ments of Andalucía, Asturias, the Basque Country, Murcia, and Navarra, and the Catalan Institute of Oncology (ICO) (Spain); Swedish Cancer Society, Swedish Research Council, and County Councils of Skåne and Västerbotten (Sweden); Cancer Research UK (14136 to EPIC-Norfolk; C8221/A29017 to EPIC-Oxford), Medical Research Council (1000143 to EPIC-Norfolk; MR/M012190/1 to EPIC-Oxford) (United Kingdom). We are grateful to all of the participants who have been part of the project and to the many members of the study teams at the University of Cambridge who have enabled this research. We acknowledge the use of data from the EPIC-Aarhus cohort, PI Kim Overvad. We thank the CERCA Programme/Generalitat de Catalunya for institutional support., Dietary advanced glycation end-products (dAGEs) have been hypothesized to be associated with a higher risk of colorectal cancer (CRC) by promoting inflammation, metabolic dysfunction, and oxidative stress in the colonic epithelium. However, evidence from prospective cohort studies is scarce and inconclusive. We evaluated CRC risk associated with the intake of dAGEs in the European Prospective Investigation into Cancer and Nutrition (EPIC) study. Dietary intakes of three major dAGEs: N-epsilon-carboxy-methyllysine (CML), N-epsilon-carboxyethyllysine (CEL), and N-delta-(5-hydro-5-methyl-4-imidazolon-2-yl)-ornithine (MG-H1) were estimated in 450,111 participants (median follow-up = 13 years, with 6162 CRC cases) by matching to a detailed published European food composition database. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the associations of dAGEs with CRC were computed using multivariable-adjusted Cox regression models. Inverse CRC risk associations were observed for CML (HR comparing extreme quintiles: HRQ5vs.(Q1) = 0.92, 95% CI = 0.85-1.00) and MG-H1 (HRQ5vs.(Q1) = 0.92, 95% CI = 0.85-1.00), but not for CEL (HRQ5vs.(Q1) = 0.97, 95% CI = 0.89-1.05). The associations did not differ by sex or anatomical location of the tumor. Contrary to the initial hypothesis, our findings suggest an inverse association between dAGEs and CRC risk. More research is required to verify these findings and better differentiate the role of dAGEs from that of endogenously produced AGEs and their precursor compounds in CRC development., Wereld Kanker Onderzoek Fonds (WKOF), World Cancer Research Fund (WCRF) International grant program (WCRF) 2015-1391, Fondation de France 00081166- 00089811

Pooling metabolomics data across studies is often desirable to increase the statistical power of the analysis. However, this can raise methodological challenges as several preanalytical and analytical factors could introduce differences in measured concentrations and variability between datasets. Specifically, different studies may use variable sample types (e.g., serum versus plasma) collected, treated and stored according to different protocols, and assayed in different laboratories using different instruments. To address these issues, a new pipeline was developed to normalize and pool metabolomics data through a set of sequential steps: (i) exclusions of the least informative observations and metabolites and removal of outliers; imputation of missing data; (ii) identification of the main sources of variability through PC-PR2 analysis; (iii) application of linear mixed models to remove unwanted variability, including samples’ originating study and batch, and preserve biological variations while accounting for potential differences in the residual variances across studies. This pipeline was applied to targeted metabolomics data acquired using Biocrates AbsoluteIDQ kits in eight case-control studies nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Comprehensive examination of metabolomics measurements indicated that the pipeline improved the comparability of data across the studies. Our pipeline can be adapted to normalize other molecular data, including biomarkers as well as proteomics data, and could be used for pooling molecular datasets, for example in international consortia, to limit biases introduced by inter-study variability. This versatility of the pipeline makes our work of potential interest to molecular epidemiologists.

Educational inequalities in mortality have been observed for decades, however the underlying biological mechanisms are not well known. We assessed the mediating role of altered aging of immune cells functioning captured by DNA methylation changes in blood (known as epigenetic clocks) in educational associated all-cause mortality. Data were from eight prospective population-based cohort studies, representing 13,021 participants. We found educational inequalities in mortality were larger for men than for women, estimated by hazard differences and ratios. Epigenetic clocks explained approximately 50% of educational inequalities in mortality for men, while the proportion was small for women. Most of this mediation was explained by differential effects of unhealthy lifestyles and morbidities of the WHO risk factors for premature mortality. These results support DNA methylation-based epigenetic aging as a signature of educational inequalities in life expectancy emphasizing the need for policies to address the unequal social distribution of these WHO risk factors.

Exposure to agents acting on the renin-angiotensin system was not associated with a risk increase of COVID-19 infection in 2 Italian matched case-control studies, 1 nested in hypertensive patients and the other in patients with cardiovascular diseases or diabetes.

Background The relation of dairy product consumption to health and mortality is controversial. Objectives We investigated associations of consumption of various dairy products with mortality in the Italian cohort of the European Prospective Investigation into Cancer and Nutrition (EPIC)-Italy study. Methods Dairy product consumption was assessed by validated semiquantitative FFQs. Multivariable Cox models stratified by center, age, and sex and adjusted for confounders estimated associations of milk (total, full fat, and reduced fat), yogurt, cheese, butter, and dairy calcium consumption with mortality for cancer, cardiovascular disease, and all causes. Nonlinearity was tested by restricted cubic spline regression. Results After a median follow-up of 14.9 y, 2468 deaths were identified in 45,009 participants: 59% from cancer and 19% from cardiovascular disease. No significant association of consumption of any dairy product with mortality was found in the fully adjusted models. A 25% reduction in risk of all-cause mortality was found for milk intake from 160 to 120 g/d (HR: 0.75; 95% CI: 0.61, 0.91) but not for the highest (>200 g/d) category of intake (HR: 0.95; 95% CI: 0.84, 1.08) compared with nonconsumption. Associations of full-fat and reduced-fat milk consumption with all-cause and cause-specific mortality were similar to those for milk as a whole. Conclusions In this Italian cohort characterized by low to average milk consumption, we found no evidence of a dose-response association between milk consumption and mortality and also no association of consumption of other dairy products investigated with mortality.

Background and objectives Blood is a critical resource for responding to mass casualty incidents (MCI). The main framework for transfusion preparedness is the American Association of Blood Bank (AABB) Disaster Operation Handbook. A disaster preparedness plan for co-ordinated blood supply was issued in Italy in 2016. Aim To assess the level of preparedness of the Transfusion Centers (TS) in the Piedmont region, to evaluate the applicability of AABB checklist and to evaluate the application of the Italian plan. Materials and methods We surveyed all the Regional Transfusion Centers (TS) using the AABB checklist, addressing 74 priority action items grouped according to 16 preparedness domains. The Italian 2016 plan has been considered the regulatory cut-off and hospitals were stratified based on the type and the TS workload. A principal component analysis (PCA) was conducted to summarize the variance among centres. Results Twenty-one out of 25 TS agreed to participate. Eighty-one % were at high and 18% were at medium level of preparedness. All but two centres were above the cut-off determined by the Italian law. A significant better preparedness was found in medium size hospitals compared to bigger and smaller hospitals. Other than that, the different TS showed a quite homogeneous distribution of preparedness variance. Conclusions This study demonstrated a good level of preparedness in the Piemonte TS, above the Italian law requirements in the majority of TS. The AABB checklist could be used to highlight gaps and needs in the regional TS networks in case of emergency crisis.

While the link between cardiovascular and respiratory conditions and air pollution is well-known, recent studies provided a growing body of evidence that polluted air, particularly air with high levels of particulate matter with a diameter smaller than 2.5 micrometers (PM 2.5), can have a range of negative impacts on health, both in terms of mortality and morbidity. It is time to emphasize the role of environmental factors as contributory factors or determinants of both global and individual health levels, and to consider them together as a health priority, as enviropathies (meant as pathologies caused, triggered or worsened by environmental exposure). Bringing attention to harmful air pollution exposure has fostered population studies, which developed accurate quantification of environmental exposure in polluted regions, aiding our understanding of the dose-response relationship between pollutants and diseases. Those efforts have influenced local and global health policy strategies. Now we face the challenge of controlling environmental pollution and limiting individual exposure to prevent or avoid serious health risks. Is it time for enviropathies in everyday clinical practice?

Objectives Patients who arrive at the emergency department (ED) with COVID-19, who test negative at the first real-time polymerase chain reaction (RT-PCR), represent a clinical challenge. This study aimed to evaluate if the clinical manifestation at presentation, the laboratory and imaging results, and the prognosis of COVID-19 differ in patients who tested negative at the first RT-PCR compared with those who tested positive and also to evaluate if comorbid conditions patient-related or the period of arrival are associated with negative testing. Study design We retrospectively collected clinical data of patients who accessed the ED from March 1 to May 15, 2020. Methods We compared clinical variables, comorbid conditions, and clinical outcomes in the two groups by univariate analysis and logistic regression. Results Patients who tested negative at the first RT-PCR showed a higher prevalence of cardiopathy, immunosuppression, and diabetes, as well as a higher leukocyte and lower lymphocyte counts compared with patients who tested positive. A bilateral interstitial syndrome and a typical pattern at computed tomography scan were prevalent in the test-negative group. Test-negative patients were more likely to be admitted to the hospital but less likely to need admission in a high level of care ward. The false-negative rate increased from March to May. Conclusion False-negative RT-PCR COVID-19 patients present a similar spectrum of symptoms compared with positive cohort, but more comorbidities. Imaging helps to identify them. True positives had a higher risk of serious complications.