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Objectives: We aimed to estimate the fraction of deaths from ovarian cancer attributable to asbestos exposure in Lombardy Region, Italy, using a novel approach that exploits the fact that ovarian cancer asbestos exposure is associated with pleural cancer and other risk factors for breast cancer., Methods: This ecological study is based on the Italian National Institute of Statistics mortality data. We formulate a trivariate Bayesian joint disease model to estimate the attributable fraction (AF) and the number of ovarian cancer deaths attributable to asbestos exposure from the geographic distribution of ovarian, pleural and breast cancer mortality at the municipality level from 2000 to 2018. Expected deaths and standardised mortality ratios were calculated using regional rates., Results: We found shared dependencies between ovarian and pleural cancer, which capture risk factors common to the two diseases (asbestos exposure), and a spatially structured clustering component shared between ovarian and breast cancer, capturing other risk factors. Based on 10 462 ovarian cancer deaths, we estimated that 574 (95% credibility interval 388-819) were attributable to asbestos (AF 5.5%; 95% credibility interval 3.7-7.8). AF reaches 34%-47% in some municipalities with known heavy asbestos pollution., Conclusions: The impact of asbestos on ovarian cancer occurrence can be relevant, particularly in areas with high asbestos exposure. Estimating attributable cases was possible only by using advanced Bayesian modelling to consider other risk factors for ovarian cancer. These findings are instrumental in tailoring public health surveillance programmes and implementing compensation and prevention policies., Competing Interests: Competing interests: CM and DCo served as consultants in litigations concerning asbestos-related diseases., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Epithelial sinonasal cancers (SNC) are rare tumours with recognized associations with known/suspected occupational carcinogens (wood/leather dust, nickel/chromium compounds and formaldehyde). In Italy, a national SNC registry organized as a network of regional registries was established by law in 2008., Aims: To describe SNC time trends, occupational exposures and geographical distribution in Lombardy, North-West Italy, based on population registry data (2008-20)., Methods: The Lombardy SNC Registry records epithelial SNCs using various sources. Interviews to collect occupational history are performed using a standardized questionnaire. Using several standard populations, we calculated yearly crude and age-standardized rates (ASRs per 100,000 person-years). Standardized incidence ratios (SIR) at municipality level were calculated, and Bayesian models were fitted to produce smoothed SIR maps., Results: We recorded 827 cases (553 men, 274 women). Crude (world standardized) ASRs were 0.9 (0.4) in men and 0.4 (0.2) in women, with no time trends. Interviews were obtained for 485 (88%) men and 223 (81%) women. Among men, 217 (45%) had been exposed to occupational carcinogens (wood/leather dust: 150/65 cases, 31%/13%), while only 36 women (16%) were exposed. Among 201 men with adenocarcinoma, exposure to wood/leather dust occurred in 103/50 cases (75%/50%). Areas with elevated SIRs associated with leather dust were found in the Western areas. Exposure to wood dust was more widespread., Conclusions: This study found a high frequency of occupational exposures (wood and leather dust), particularly in men with SNC. Employment in shoe industries clustered in the Western part, while work in furniture industries was less spatially structured., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Society of Occupational Medicine.)

Background/Objectives : Endometriosis is a female chronic inflammatory disease in which endometrial tissue develops outside the uterine cavity. It is a complex pathology, which significantly contributes to morbidity in premenopausal women, leading to chronic pain, infertility, and subfertility negatively impacting physical and emotional well-being and the overall quality of life. The public health burden of endometriosis remains elusive and challenging to determine, and this uncertainty can lead to inadequate healthcare services and treatments. The objective was to estimate the incidence and prevalence of endometriosis in Italy using the hospital discharge records database via a population-based retrospective study, nationwide between 2011 and 2020. Methods : From the National Hospital Discharge Database, we selected all admissions with a diagnosis of endometriosis (ICD-9-CM, codes 617.x), supported by the presence of a procedure code of laparoscopy or any other surgical procedure allowing for direct visualisation of the lesions. The main outcomes measured: incidence and prevalence of endometriosis were estimated for the entire 2011-2020 period and by individual year, analysing the time trend and variability in different geographical areas of Italy. Results : There were a total of 134,667,646 women aged 15-50 years with one or more hospitalisations for endometriosis in all Italian hospitals. The incidence of endometriosis in Italy during this period was 0.839 per 1000 women (CI95% 0.834-0.844), exhibiting a statistically significant decreasing trend over the years. A discernible north-south gradient was observed, with higher rates documented in the northern regions. The prevalence rate stood at 14.0 per 1000 during the same period, and a similar north-south geographical gradient was identifiable in the prevalence rates as well. Conclusions : The utilization of national-level hospital data enables the generation of incidence and prevalence data for endometriosis without variations in methods and definitions, facilitating the evaluation of temporal trends and regional comparisons. Understanding and quantifying this phenomenon is essential for appropriate healthcare planning in various Italian regions.

The Veneto Region (Northern Italy) conducted a monitoring campaign in the years 2016-2017 in order to evaluate the concentration of per- and polyfluoroalkyl substances (PFASs) in foods in the area affected by the water contamination discovered in 2013. The risk assessment for the resident population was conducted by the Italian National Institute of Health (ISS) in 2018 and updated in 2021. The European Food Safety Agency (EFSA) updated the limits used by ISS, in particular adding a limit for the sum of four PFAS molecules in 2020. In this work, the risk assessment conducted by ISS is reviewed in light of the new limit of 4.4 ng/kg body weight for the sum of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorononanoic acid (PFNA), and perfluorohexanesulfonate (PFHxS). In the adult population (18-65 years), total weekly intakes, calculated for the years preceding 2013, resulted more than ten times the EFSA 2020 limit, more than five times in the intermediate period 2013-2017 - preceding the implementation of mitigation actions through double filtration of the water of the aqueduct -, by more than three times in the period after 2018, and yet by almost seven times for those who supply contaminated groundwater through private wells. The food contribution for those who use filtered water from the aqueduct is equal to 20% of the total weekly income.

Background: Per- and polyfluoroalkyl substances (PFAS) are associated with many adverse health conditions. Among the main effects is carcinogenicity in humans, which deserves to be further clarified. An evident association has been reported for kidney cancer and testicular cancer. In 2013, a large episode of surface, ground and drinking water contamination with PFAS was uncovered in three provinces of the Veneto Region (northern Italy) involving 30 municipalities and a population of about 150,000. We report on the temporal evolution of all-cause mortality and selected cause-specific mortality by calendar period and birth cohort in the local population between 1980 and 2018., Methods: The Italian National Institute of Health pre-processed and made available anonymous data from the Italian National Institute of Statistics death certificate archives for residents of the provinces of Vicenza, Padua and Verona (males, n = 29,629; females, n = 29,518) who died between 1980 and 2018. Calendar period analysis was done by calculating standardised mortality ratios using the total population of the three provinces in the same calendar period as reference. The birth cohort analysis was performed using 20-84 years cumulative standardised mortality ratios. Exposure was defined as being resident in one of the 30 municipalities of the Red area, where the aqueduct supplying drinking water was fed by the contaminated groundwater., Results: During the 34 years between 1985 (assumed as beginning date of water contamination) and 2018 (last year of availability of cause-specific mortality data), in the resident population of the Red area we observed 51,621 deaths vs. 47,731 expected (age- and sex-SMR: 108; 90% CI: 107-109). We found evidence of raised mortality from cardiovascular disease (in particular, heart diseases and ischemic heart disease) and malignant neoplastic diseases, including kidney cancer and testicular cancer., Conclusions: For the first time, an association of PFAS exposure with mortality from cardiovascular disease was formally demonstrated. The evidence regarding kidney cancer and testicular cancer is consistent with previously reported data., (© 2024. The Author(s).)

Aim: Defining the epidemiology of systemic and cardiac amyloidosis (CA) is a contemporary challenge. The present study aimed to estimate incidence and time trends in amyloidosis-related hospitalizations (AH) in Veneto Region (5 million inhabitants, Northeastern Italy)., Methods: International Classification of Diseases (ICD-9) codes were used to identify AH in Veneto from 2010 to 2020. AH were defined as any hospitalization with a discharge summary reporting an ICD-9 code for systemic amyloidosis. Hospitalization for CA was defined as records with ICD-9 code for systemic amyloidosis and ICD-9 code for heart failure,cardiomyopathy or arrhythmia. Hospital/outpatient encounters for carpal tunnel syndrome (CTS) surgeries also were extracted. AH incidence was estimated using a buffer of 5 years., Results: In the time range 2015-2020, the incidence rate of AH was 23.5 cases per 10 6 (95% confidence interval, CI, 21.8; 25.3), mainly affecting patients>65 years (76.2%) and males (63.5%), with a progressively increasing trend (percent annual increase 17%, 95% CI 12; 22%). The 10 year prevalence of AH in 2020 was 124.5 per 10 6 (95% CI 114.9; 134.8). In 2020, annual hospitalized prevalent cases of CA were about 70% of all cases (159/228), mainly patients >65 years and males. Among patients with multiple CTS surgeries, a subsequent code for cardiac disease was found in 913 after a median of 3.9 years, more frequently in men than in women (463/6.526 7.1% versus 450/11.406 3.9%)., Conclusions: In Veneto, we recorded a significantly increasing trend in the incidence of AH, with concordant increasing prevalence estimates., Competing Interests: Declaration of competing interest Dr. De Michieli received honoraria from Pfizer Inc., Alnylam Pharmaceuticals, AstraZeneca. Dr. Cipriani received honoraria from Pfizer Inc., Alnylam Pharmaceuticals, AstraZeneca. The other authors have nothing to disclose., (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: endometriosis is a chronic condition with a significant impact on women's health, featured by endometrial tissue outside the uterine cavity. A limited number of studies have been conducted in the general population, and the true prevalence of endometriosis is unknown for many areas of the country., Objectives: to better estimate the prevalence of endometriosis in three Italian regions (Friuli Venezia Giulia, Tuscany, Apulia) and to assess the relationship between endometriosis and environmental factors in three participating areas (Trieste, Barga, and Taranto), with a focus on Tuscany Region., Design: implementing a specific epidemiological registry for endometriosis, aimed at estimating the incidence and prevalence data. The registry collected information from hospital discharge records and anatomopathological reports of women residing in the three considered regions, aged 15 years or older. Additionally, the analysis includes the assessment of the spatial distribution of endometriosis at both regional and municipal levels in the three study areas. Further research investigations in these areas involve a multilevel screening of a sample of women of childbearing age. Women who test positive in the initial screening (through a self-administered questionnaire) will have the opportunity to undergo a second level of screening, consisting of a gynecological examination, transvaginal ultrasound, a swab for vaginal microbiome analysis, and the collection of blood and urine samples to assess the presence of polychlorinated biphenyls (PCBs) or heavy metals. The adopted scientific approach is based on post-normal science (PNS) concerning the extended peer community., Setting and Participants: women aged 15 years or older residing in the three regions., Main Outcomes Measures: estimating the incidence and prevalence of endometriosis based on data collected from the epidemiological registry. The analysis extends to assessing the spatial distribution of endometriosis at municipal levels in the three areas of interest., Results: the preliminary results of the study allowed for the estimation of the spatial distribution of endometriosis incidence in Tuscany. In particular, it was found that there is variability within the region, with some coastal and North-Western areas showing values 20% higher than the regional average. Cities such as Pisa, Lucca, Livorno, Grosseto, Orbetello, and the Serchio Valley with Barga had a probability of excess risk of more than 90% compared to the regional average., Conclusions: the study is ongoing and requires the active participation of women living in the region to ensure the completeness and accuracy of the collected data. This research effort represents an important contribution to understanding endometriosis in Tuscany and its possible environmental causes.

Background: Several observational studies investigated the relationship between environmental cadmium exposure and risk of chronic kidney disease (CKD). However, results from epidemiological studies are conflicting and wide variabilities have been reported., Objectives: We conducted a meta-analysis to evaluate the relationship between environmental cadmium exposure and CKD risk, as assessed by decreased estimated Glomerular Filtration Rate (eGFR) in adults., Methods: PubMed, Embase and the Cochrane library databases were searched for studies published up to July 2023. A random-effects model using the restricted maximum likelihood (REML) method was used to calculate the overall estimate to assess the association between cadmium exposure and eGFR. Subgroup analysis, funnel plot, Egger's test, and the trim-and-fill method were also conducted., Results: Thirty-one articles, 3 cohorts, 2 case-control and 26 cross-sectional studies, across 8 countries, involving 195.015 participants were included. The meta-analysis demonstrated an inverse association between high cadmium exposure and eGFR levels (standardized regression coefficient β = -0.09; 95 % CI = -0.15, -0.04). The subgroup analysis showed that the inverse association was significantly higher for blood cadmium exposure (β = -0.12; 95 % CI = -0.18, -0.06) than for urinary concentrations (β = -0.04; 95 % CI: -0.10, 0.03) or dietary exposure (β = -0.03; 95 % CI = -0.19, 0.14). Stratified analysis by different study design also showed an inverse association between cadmium exposure and eGFR, more evident in the cross-sectional studies (β = -0.11; 95 % CI = -0.18, -0.03) than in the cohort (β = -0.05; 95 % CI = -0.26, 0.17) and in the case-control studies (β = -0.05; 95 % CI = -0.32, 0.21)., Discussion: Our meta-analysis indicated that environmental cadmium exposure is associated with increased risk of CKD, as assessed by decreased eGFR, and this association is more evident for blood cadmium concentrations than for urinary concentrations or dietary exposure. Nevertheless, additional high quality prospective studies are needed to confirm the association between cadmium exposure and risk of CKD., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Purpose: We aimed to investigate the prognostic role of baseline and longitudinal levels of neutrophil-to-lymphocyte ratio (NLR) in patients with metastatic colorectal cancer (mCRC) treated with chemotherapy + bevacizumab (CT + B) or chemotherapy only. Additionally, we investigated whether treatment outcomes were mediated by the longitudinal biomarker., Methods: Data from an Italian randomized phase III trial were used. The main end point was progression-free survival (PFS). To address research questions, a series of joint models of longitudinal and survival data were specified, and the direct and indirect treatment effects were quantified., Results: Data for 239 patients, 113 (47.3%) treated with CT + B and 126 (52.7%) with CT only, were included in the analyses. The effect of NLR seemed to be mediated by the longitudinal trajectory of the biomarker. Only in the patient subgroup treated with CT + B, the baseline NLR retained a direct effect on PFS. Regarding the effect of treatment on PFS, two scenarios were observed. In the subgroup of patients with low baseline, NLR bevacizumab showed a direct protective effect only (hazard ratio [HR], 0.66 [95% CI, 0.45 to 0.98]), whereas in the subgroup with high baseline NLR, there was evidence for an adverse direct effect (HR, 1.63 [95% CI, 1.03 to 2.57]) and a protective indirect-which is mediated by the longitudinal biomarker-effect (HR, 0.71 [95% CI, 0.55 to 0.90])., Conclusion: In our study, inflammatory indexes collected longitudinally showed a significant adverse prognostic role, thus suggesting the collection and use of such data for better clinical decision making. In the specific setting, we considered this is particularly important as the treatment effect seemed to be modified by both the baseline and longitudinal inflammation statuses. However, further research is needed to understand the possible factors underlying these results.

Background and Aim: Scientists and scientific institutions are adopting more extensive participatory models, hoping to revisit the existing relationship between science and society. Though citizen science has become more common in environmental monitoring, it is seldom utilized in environmental epidemiology. In the CitieS-Health project, we co-created epidemiological studies with citizens in five European countries. The aim of this paper is to share our experiences and impart methodological insight into the application of co-created citizen science strategies in environmental epidemiology., Methods: We applied the CitieS-Health framework, involving citizens in all the phases of the studies: identifying research questions, designing research protocols, collecting data, analysing data, interpreting data, formulating conclusions, authoring scientific articles and communicating the results to diverse audiences. These epidemiological studies, conducted in specific areas in Italy, Lithuania, the Netherlands, Slovenia and Spain, covered diverse local environmental issues and health effects ranging from air pollution and mental health to industrial pollution and kidney disease., Results: Together with citizens, we successfully conducted environmental epidemiological studies that generated new scientific knowledge reflecting the concerns and knowledge of citizens. Citizens contributed in all the research activities, including activities beyond formulating the research questions, though the researchers initiated several design discussions and conducted time-consuming and complex tasks (e.g. data analysis, measurement of specific exposures and health outcomes). The challenges we encountered were engaging effectively with citizens throughout the study, harmonizing citizens' knowledge and values with the academics' expertise, managing civic expectations, making complex concepts understandable to citizens and representativeness of participating citizens. The co-created studies were able to empower citizens to address local health concerns by sharing and using scientific knowledge generated from studies., Conclusions: Integration of co-created citizen science in environmental epidemiology is feasible and has the potential to improve the quality of research whilst promoting civic trust in research and results., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests:Frederique Froeling reports financial support was provided by Horizon (2020) research and innovation programme. All co-authors reports financial support was provided by Horizon (2020) research and innovation programme., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

A recent research project using data from a total of 40 cancer registries has provided new epidemiologic insights into the results of efforts for melanoma control in Italy between the 1990s and the last decade. In this article, the authors present a summary and a commentary of their findings. Incidence increased significantly throughout the study period in both sexes. However, the rates showed a stabilization or a decrease in men and women aged below 35 years. The risk of disease increased for successive cohorts born until 1973 (women) and 1975 (men) while subsequently tending to decline. The trend towards decreasing tumor thickness and increasing survival has continued, but a novel favorable prognostic factor has emerged since 2013 for patients - particularly for males - with thick melanoma, most likely represented by molecular targeted therapies and immune checkpoint inhibitors. Due to this, the survival gap between males and females has been filled out. In the meanwhile, and despite the incidence increase, dermatologists have not lowered their threshold to perform skin biopsy. Skin biopsy rate has increased because of the increasingly greater volume of dermatologic office visits, but the proportion of skin biopsies out of dermatologic office visits has remained constant. In summary, an important breakthrough in melanoma control in Italy has taken place. Effective interventions have been implemented across the full scope of care, which involve many large local populations - virtually the whole national population. The strategies adopted during the last three decades represent a valuable basis for further steps ahead in melanoma control in Italy.

Space-time analysis of mortality risk is useful to evaluate the epidemiologic transitions at the subnational level. In our study, we analysed the death certificate records for lung cancer in Italy in 1995-2016, obtained from the Italian National Institute of Statistics. Our objective was to investigate the spatial-temporal evolution of lung cancer mortality by sex and province of residence (n = 107) using the birth cohort as relevant time axis. We built Bayesian space-time models with space-time interactions. Among males (n = 554 829), mortality peaked in the 1920-1929 cohort, followed by a generalised decline. Among females (n = 158 619), we found novel original evidence for a peak in the 1955-1964 cohort, equivalent to a 35-year delay, with a downward trend being observed thereafter. Over time, the documented north-south decreasing mortality gradient has been replaced by a west-east decreasing gradient. Naples has become the province at highest risk in Italy, both among males and females. This pattern is consistent with an epidemiologic transition of risk factors for lung cancer to the south-west of the country and raises concern, because 5-year age-standardised net survival from the disease in this geographic area is lower than in northern and central Italy. The variability of mortality rates among provinces has changed over time, with an increasing homogeneity for males and an opposite trend for females in the more recent birth cohorts. These unprecedented observations provide evidence for a profound spatio-temporal transition of lung cancer mortality in Italy., (© 2023 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)

Introduction: in time-to-event analysis, competing risks are observed when a subject is at risk of multiple types of events. A competing risk is an event that prevents the event of interest from happening or modifies its chance to occur., Objectives: the purposes of this article are to provide an overview of competing risks analysis and to illustrate its application to the follow-up of breast cancer patients in order to estimate the risk of disease recurrence., Design: cohort study., Setting and Participants: population-based random sample of patients with stage I-III primary female breast cancer diagnosed in 2000-2013, aged 15 years or older, resident in the Forlì health care district (northern Italy), treated surgically and with available information regarding disease laterality., Main Outcome Measures: subhazard ratio, hazard ratio and cumulative incidence function for loco-regional recurrences and distant metastasis during 10 years of follow-up., Methods: breast cancer recurrences were evaluated taking into account death from any cause and occurrence of a second primary breast cancer as competing risks. Recent developments in competing risks methodology were used. The results obtained were compared with those from the Cox regression model, in which the competing risks were not accounted for., Conclusions: estimating the risk of recurrence without accounting for the competing risks resulted in a divergence of the hazard/subhazard functions. Competing risks analysis is preferable when the statistical assumption of independence of end-points may be violated.

Introduction: Mechanisms underlying cardiac arrhythmias are typically driven by abnormalities in cardiac conduction and/or heterogeneities in repolarization time (RT) across the heart. While conduction slowing can be caused by either electrophysiological defects or physical blockade in cardiac tissue, RT heterogeneities are mainly related to action potential (AP) prolongation or abbreviation in specific areas of the heart. Importantly, the size of the area with altered RT and the difference between the short RT and long RT (RT gradient) have been identified as critical determinators of arrhythmogenicity. However, current experimental methods for manipulating RT gradient rely on the use of ion channel inhibitors, which lack spatial and temporal specificity and are commonly only partially reversible. Therefore, the conditions facilitating sustained arrhythmia upon the presence of RT heterogeneities and/or defects in cardiac conduction remain to be elucidated. Methods: We here employ an approach based on optogenetic stimulation in a low-intensity fashion (sub-threshold illumination), to selectively manipulate cardiac electrical activity in defined areas of the heart. Results: As previously described, subthreshold illumination is a robust tool able to prolong action potentials (AP), decrease upstroke velocity as well as slow cardiac conduction, in a fully reversible manner. By applying a patterned sub-threshold illumination in intact mouse hearts constitutively expressing the light-gated ion channel channelrhodopsin-2 (ChR2), we optically manipulate RT gradients and cardiac conduction across the heart in a spatially selective manner. Moreover, in a proof-of-concept assessment we found that in the presence of patterned sub-threshold illumination, mouse hearts were more susceptible to arrhythmias. Hence, this optogenetic-based approach may be able to mimic conduction slowing and RT heterogeneities present in pathophysiological conditions., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Marchal, Biasci, Loew, Biggeri, Campione and Sacconi.)

(1) Objective: In many Western countries, survival from vulvar squamous cell carcinoma (VSCC) has been stagnating for decades or has increased insufficiently from a clinical perspective. In Italy, previous studies on cancer survival have not taken vulvar cancer into consideration or have pooled patients with vulvar and vaginal cancer. To bridge this knowledge gap, we report the trend in survival from vulvar cancer between 1990 and 2015. (2) Methods: Thirty-eight local cancer registries covering 49% of the national female population contributed the records of 6274 patients. Study endpoints included 1- and 2-year net survival (NS) calculated using the Pohar-Perme estimator and 5-year NS conditional on having survived two years (5|2-year CNS). The significance of survival trends was assessed with the Wald test on the coefficient of the period of diagnosis, entered as a continuous regressor in a Poisson regression model. (3) Results: The median patient age was stable at 76 years. One-year NS decreased from 83.9% in 1990-2001 to 81.9% in 2009-2015 and 2-year NS from 72.2% to 70.5%. Five|2-year CNS increased from 85.7% to 86.7%. These trends were not significant. In the age stratum 70-79 years, a weakly significant decrease in 2-year NS from 71.4% to 65.7% occurred. Multivariate analysis adjusting for age group at diagnosis and geographic area showed an excess risk of death at 5|2-years, of borderline significance, in 2003-2015 versus 1990-2002. (4) Conclusions: One- and 2-year NS and 5|2-year CNS showed no improvements. Current strategies for VSCC control need to be revised both in Italy and at the global level.

Background: The global increase in incidence of cutaneous malignant melanoma (CMM) occurring in the past decades has been partly attributed to increased diagnostic scrutiny of early lesions, with a potential phenomenon of overdiagnosis. The reported positive linear relation between skin biopsy rate and incidence of early CMM is compatible with this hypothesis., Objectives: We explored the ecological association between the trends in annual dermatologic office visit rates, skin biopsy rates, incidence rates of in situ and invasive CMM by tumour thickness category, and CMM mortality rates in the Emilia-Romagna Region (northern Italy)., Methods: Four cancer registries covering a population of 2,696,000 provided CMM incidence data for the years 2003-2017. Dermatologic office visit rates and skin biopsy rates were calculated using the Regional outpatient care database. All rates were age-standardized. Trends were described with the estimated average annual per cent change (EAAPC). Correlations were tested with the Spearman correlation coefficient., Results: Incidence increased significantly. The increase was steeper for in situ CMM (EAAPC: men, 10.2; women, 6.9) followed by CMM <0.8 mm thick (9.1; 5.2), but the rates grew significantly for most subgroups of CMMs ≥0.8 mm thick. Mortality decreased significantly among women (-2.3) and non-significantly among men. For dermatologic office visit rate and skin biopsy rate the EAAPC were, respectively, 1.7 and 1.8 for men and 1.2 and 0.9 for women. Annual dermatologic office visit rate correlated with skin biopsy rate in both sexes. However, the proportion of skin biopsies out of dermatologic office visits was constant across the years (range: men, 0.182-0.216; women, 0.157-0.191)., Conclusions: In Italy, the increasing CMM incidence trend is, at least in part, genuine. Overdiagnosis-if any-is due to an increased patient presentation at dermatologic offices and not to a lower dermatologic threshold to perform biopsy., (© 2022 The Authors. Journal of the European Academy of Dermatology and Venereology published by John Wiley & Sons Ltd on behalf of European Academy of Dermatology and Venereology.)

Objectives: To develop the Functional Risk Index for Dependence in Ambulation (FRIDA) score, a nomogram to predict individual risk of dependence in ambulation at discharge from postacute rehabilitation and validate its performance temporally and spatially., Study Design and Setting: We analyzed the database of a multicenter prospective observational quality cohort study conducted from January 2012 to March 2016, including data from 8,796 consecutive inpatients who underwent rehabilitation after stroke, hip fracture, lower limb joint replacement, debility, and other neurologic, orthopedic, or miscellaneous conditions., Results: A total of 3,026 patients (34.4%) were discharged dependent in ambulation. In the training set of 5,162 patients (58.7%), Lasso-regression selected advanced age, premorbid disability, and eight indicators of medical and functional adverse syndromes at baseline to establish the FRIDA score. At the temporal validation obtained on an external set of 3,234 patients (41.3%), meta-analyses showed that the FRIDA score had good and homogeneous discrimination (summary area under the curve 0.841, 95% confidence interval = 0.826-0.855, I 2 = 0.00%) combined with accurate calibration (summary Log O/E ratio 0.017, 95% confidence interval -0.155 to 0.190). These performances remained stable at spatial validation obtained on 3,626 patients, with substantial heterogeneity of estimates across nine facilities. Decision curve analyses showed that a FRIDA score-supported strategy far outperformed the usual "treat all" approach in each impairment categories., Conclusion: The FRIDA score is a new clinically useful tool to predict an individual risk for dependence in ambulation at rehabilitation discharge in many different disabilities, and may also reflect well the case-mix composition of the rehabilitation facilities., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

The SENTIERI Project analyses the health profile of the populations residing in Italian national priority contaminated sites in specific calendar periods using a cross-sectional approach. An aspect that has not been evaluated so far is the analysis over a long period, for understanding the changes in health profiles over time and studying them also in function of the changes occurred in the territories. This article studies temporal trends by birth cohort and calendar period for overall mortality and lung cancer mortality from 1980 to 2018, separately for men and women, for three sites: Priolo (Sicily Region, Southern Italy), Pitelli (Liguria Region, Northern Italy), and Terni-Papigno (Umbria Region, Central Italy). A method for selecting the temporal model that best fits the data is then proposed. General mortality presents complex temporal profiles when considering cumulative risks, and usually the most important temporal axis is the birth cohort for cumulative SMRs (i.e., after adjusting for trends in the reference population). For lung cancer, the most important time axis is the birth cohort and the age-cohort model is the most appropriate, in particular for men of Priolo and Terni.

Objective: To discuss the results of the KETASER01 trial and the reasons for its failure, particularly in view of future studies., Methods: KETASER01 is a multicenter, randomized, controlled, open-label, sequentially designed, non-profit Italian study that aimed to assess the efficacy of ketamine compared with conventional anesthetics in the treatment of refractory convulsive status epilepticus (RCSE) in children., Results: During the 5-year recruitment phase, a total of 76 RCSEs treated with third-line therapy were observed in five of the 10 participating Centers; only 10 individuals (five for each study arm; five females, mean age 6.5 ± 6.3 years) were enrolled in the KETASER01 study. Two of the five patients (40%) in the experimental arm were successfully treated with ketamine and two of the five (40%) children in the control arm, where successfully treated with thiopental. In the remaining six (60%) enrolled patients, RCSE was not controlled by the randomized anesthetic(s)., Significance: The KETASER01 study was prematurely halted due to low eligibility of patients and no successful recruitment. No conclusions can be drawn regarding the objectives of the study. Here, we discuss the KETASER01 results and critically analyze the reasons for its failure in view of future trials., (© 2022 The Authors. Epilepsia Open published by Wiley Periodicals LLC on behalf of International League Against Epilepsy.)

Background: This study aimed to evaluate the effectiveness of a biennial faecal immunochemical test (FIT) screening programme in reducing annual colorectal cancer (CRC) incidence in its dynamic target population., Methods: The target population included over 1,000,000 persons aged 50-69 living in a region of northern Italy. The average annual response rate to invitation was 51.4%. Each observed annual age-standardised (Europe) rate per 100,000 persons between 2005, the year of introduction of the programme, and 2016 was compared with each expected annual rate as estimated with age-period-cohort (men) and age-period (women) models., Results: For both sexes, the rates observed in 1997-2004 and those expected in 2005-2016 were stable. Observed rates increased in 2005, peaked in 2006 (the first full year of screening), dropped significantly below the expected level in 2009, and continued to decrease until 2013 (the eighth full year), after which no further significant changes occurred. In the pooled years 2013-2016, the observed incidence rate per 100,000 persons was 102.2 [95% CI: 97.4, 107.1] for men, 75.6 [95% CI: 71.6, 79.7] for women and 88.4 [95% CI: 85.3, 91.5] for both sexes combined, with an observed:expected incidence rate ratio of 0.68 [95% CI: 0.65, 0.71], 0.79 [95% CI: 0.76, 0.82] and 0.72 [95% CI: 0.66, 0.81], respectively., Discussion: The study provided multiple consistent proofs of a causal relationship between the introduction of screening and a stable 28% decrease in annual CRC incidence after eight years., (© 2022. The Author(s).)

Numerous studies have been conducted worldwide to investigate if an association exists between meteorological factors and the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection incidence. Although research studies provide conflicting results, which can be partially explained by different methods used, some clear trends emerge on the role of weather conditions and SARS-CoV-2 infection, especially for temperature and humidity. This study sheds more light on the relationship between meteorological factors and SARS-CoV-2 infection incidence in 23 Italian and 52 Spanish cities. For the purposes of this study, daily air temperature, absolute and relative humidity, wind speed, ultraviolet radiation, and rainfall are considered exposure variables. We conducted a two-stage meta-regression. In the first stage, we estimated the exposure-response association through time series regression analysis at the municipal level. In the second stage, we pooled the association parameters using a meta-analytic model. The study demonstrates an association between meteorological factors and SARS-CoV-2 infection incidence. Specifically, low levels of ambient temperatures and absolute humidity were associated with an increased relative risk. On the other hand, low and high levels of relative humidity and ultraviolet radiation were associated with a decreased relative risk. Concerning wind speed and rainfall, higher values contributed to the reduction of the risk of infection. Overall, our results contribute to a better understanding of how the meteorological factors influence the spread of the SARS-CoV-2 and should be considered in a wider context of existing robust literature that highlight the importance of measures such as social distancing, improved hygiene, face masks and vaccination campaign., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The long-term increase in survival from cutaneous malignant melanoma (CMM) is generally attributed to the decreasing trend in tumour thickness, the single most important prognostic factor., Objectives: To determine the relative contribution of decreased tumour thickness to the favourable trend in survival from CMM in Italy., Methods: Eleven local cancer registries covering a population of 8 056 608 (13.4% of the Italian population in 2010) provided records for people with primary CMM registered between 2003 and 2017. Age-standardized 5-year net survival was calculated. Multivariate analysis of 5-year net survival was undertaken by calculating the relative excess risk (RER) of death. The relative contribution of the decrease in tumour thickness to the RER of death was evaluated using a forward stepwise flexible parametric survival model including the available prognostic factors., Results: Over the study period, tumour thickness was inversely associated with 5-year net survival and multivariate RER in both sexes. The median thickness was 0.90 mm in 2003-2007, 0.85 mm in 2008-2012 and 0.75 mm in 2013-2017 among male patients, and 0.78 mm, 0.77 mm and 0.68 mm among female patients, respectively. The 5-year net survival was 86.8%, 89.2% and 93.2% in male patients, and 91.4%, 92.0% and 93.4% in female patients, respectively. In 2013-2017, male patients exhibited the same survival as female patients despite having thicker lesions. For them, the increasing survival trend was more pronounced with increasing thickness, and the inclusion of thickness in the forward stepwise model made the RER in 2013-2017 vs. 2003-2007 increase from 0.64 [95% confidence interval (CI) 0.51-0.80] to 0.70 (95% CI 0.57-0.86). This indicates that the thickness trend accounted for less than 20% of the survival increase. For female patients, the results were not significant but, with multiple imputation of missing thickness values, the RER rose from 0.74 (95% CI 0.58-0.93) to 0.82 (95% CI 0.66-1.02) in 2013-2017., Conclusions: For male patients in particular, decrease in tumour thickness accounted for a small part of the improvement in survival observed in 2013-2017. The introduction of targeted therapies and immune checkpoint inhibitors in 2013 is most likely to account for the remaining improvement., (© 2022 The Authors. British Journal of Dermatology published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

Vinyl-chloride monomer (VCM) is classified as a known carcinogen of the liver; for lung cancer, some results suggest a potential association with polyvinyl chloride (PVC) dust. We evaluated the relationship between lung cancer mortality and exposure as PVC baggers in a cohort of workers involved in VCM production and polymerization in Porto Marghera (Venice, Italy) considering both employment status and smoking habits. The workers were studied between 1973 and 2017. A subset of them (848 over 1658) was interviewed in the 2000s to collect information about smoking habits and alcohol consumption. Missing values were imputed by the Multivariate Imputation by Chained Equations (MICE) algorithm. We calculated standardized mortality ratios (SMR) and 95% confidence intervals (95% CIs) using regional reference rates by task (never, ever, and exclusively baggers) and by smoking habits. Mortality rate ratios (MRR), adjusted for age, calendar time, time since first exposure, and smoking habits, were obtained via Poisson regression using Rubin's rule to combine results from imputed datasets calculating the fraction of information due to non-response. Lung cancer mortality was lower than the regional reference in the whole cohort (lung cancer SMR = 0.92; 95% CI 0.75-1.11). PVC baggers showed a 50% increase in lung cancer mortality compared to regional rates (SMR = 1.48; 95% CI 0.82-2.68). In the cohort analyses, a doubled risk of lung cancer mortality among PVC baggers was confirmed after adjustment for smoking and time-dependent covariates (MRR = 1.99, 95% CI 1.04-3.81). Exposure to PVC dust resulting from activity as bagger in a polymerization PVC plant was associated with an increase in lung cancer mortality risk after adjustment for smoking habits.

The p-value has been widely criticized in the scientific literature for its naive use in classifying results as 'significant' and 'non significant'. Much has been written about it; for example, see the American Statistical Association position statement of march 2016. To date, few alternative measures have been suggested and few changes were observed in the scientific practice regarding the use of p-value despite general agreement on the critics raised on it. In this paper, we use an alternative measure to p-value. It consists in the probability of the direction of the effect, that is the strength of empirical evidence in favour of the alternative directional hypothesis. In the context of scientific research, reporting the probability of the direction of the effect is easier to understand. Moreover, it focuses on the effect in the study rather than on the value under the null hypothesis, which sometimes has little meaning or has been used opportunistically. The proposal is not intended as an alternative to using the confidence interval, but as a probabilistic metric to be used instead of the p-value when we refer to particular hypotheses to be tested.

The methodology of health impact assessment (HIA), originally proposed by WHO, is widely used to predict the potential health effects in a community living in a place in which a new project (e.g., an industrial plant) will be implemented. One of the key quantities to calculate the impact (i.e., the number of attributable cases) is the baseline (i.e., before the project implementation) rate of selected diseases in the community. In a recent paper on this journal, this methodology has been challenged. Specifically, the use of baseline rate has been questioned, proposing to use only the fraction of the baseline rate due to the exposures related to the project, and not the rate due to all risk factors for the disease. In this commentary, we argue that the proposal is logically and epidemiologically unsound, and devoid of scientific motivation. The conclusion that the traditional approach overestimates the health impact should be rejected as based on flawed assumptions. On the contrary, the proposal may produce a (seriously biased) underestimation of attributable cases.

Background: Asbestos exposure is a recognized risk factor for ovarian cancer and malignant mesothelioma. There are reports in the literature of geographical ecological associations between the occurrence of these two diseases. Our aim was to further explore this association by applying advanced Bayesian techniques to a large population (10 million people)., Methods: We specified a series of Bayesian hierarchical shared models to the bivariate spatial distribution of ovarian and pleural cancer mortality by municipality in the Lombardy Region (Italy) in 2000-2018., Results: Pleural cancer showed a strongly clustered spatial distribution, while ovarian cancer showed a less structured spatial pattern. The most supported Bayesian models by predictive accuracy (widely applicable or Watanabe-Akaike information criterion, WAIC ) provided evidence of a shared component between the two diseases. Among five municipalities with significant high standardized mortality ratios of ovarian cancer, three also had high pleural cancer rates. Wide uncertainty was present when addressing the risk of ovarian cancer associated with pleural cancer in areas at low background risk of ovarian cancer., Conclusions: We found evidence of a shared risk factor between ovarian and pleural cancer at the small geographical level. The impact of the shared risk factor can be relevant and can go unnoticed when the prevalence of other risk factors for ovarian cancer is low. Bayesian modelling provides useful information to tailor epidemiological surveillance.

Currently, there are more and more requests for a characterization of the health profile by populations living in areas affected by several types of environmental contaminations, notably for the presence of previously unknown and accidentally discovered landfills. The aim of the present paper is to describe the mortality profile of the residents of Piazzola sul Brenta (Veneto Region, Northern Italy). In this area, it was discovered an environmental contamination of the soil in the nearby of a large school building, where was formerly located a phosphate fertiliser plant. Using cause of death data provided by the Italian National Institute of Health, 10th International Classification 2013-2018, standardised mortality ratios (SMRs) and 90% confidence intervals (CIs) were calculated by gender and specific causes of death. Compared to the provincial reference population, no excess was found, for both genders, for all-causes mortality and for circulatory diseases. However, an excess for malignant tumours was found, 523 observed deaths over 498 expected deaths, an SMR of 105 (IC90% 98-113), and 85% probability of excess cancer mortality; lung cancer (SMR 117; IC90% 100-135) and lympho-hematopoietic tumours (in men only, SMR 134; IC90% 101-178).In light of these results and of the potential human exposure to carcinogenic substances, present results support further epidemiological investigations and environmental remediation.

In a wide area among the provinces of Vicenza, Verona, and Padua (Veneto Region, Northern Italy), one of the larger known massive contamination of the environment by per- and polyfluoroalkyl substances (PFASs) occurred since the year 1965. The most important source of human exposure was through aquiferous and contaminated water supplies (the regional authorities distinguished red zone A - aquiferous - and red zone B - water supply) for a total of slightly less than two hundred thousand exposed people. Food contamination and food contribution to total human exposure were assessed by a food monitoring campaign on the years 2016-2017 by the National Health Institute sponsored by Veneto Region.Thanks to the availability of the individual records of the monitoring campaign, we evaluated the spatial distribution of PFAS contamination by food matrix. Generally speaking, PFAS contamination was widespread over the entire red zone (either A or B). Some zones appeared to be higher contaminated consistently with the water plume. Other higher contaminated zones were less consistent and such result raises questions about routes of environmental pollution.

Politics is facing the need to make important decisions about anti-COVID-19 vaccination campaign in uncertain and changing contexts. With reference to the time frame between the administration of the first and second dose, the scientific evidence is still weak and comes from different contexts. New ways to collect and synthesize expert knowledge and opinions are needed with the direct involvement of the citizens in order to explain the uncertainties and maintain trust in institutions and their decisions.

Background: Diagnosis of endometriosis and evaluation of incidence data are complex tasks because the disease is identified laparoscopically and confirmed histologically. Incidence estimates reported in literature are widely inconsistent, presumably reflecting geographical variability of risk and the difficulty of obtaining reliable data., Methods: We retrieved incident cases of endometriosis in women aged 15-50 years using hospital discharge records and pathology databases of the Friuli Venezia Giulia region in the calendar period 2004-2017. We studied the spatial pattern of endometriosis incidence applying Bayesian approaches to Disease Mapping, and profiled municipalities at higher risk controlling for multiple comparisons using both q-values and a fully Bayesian approach., Results: 4125 new cases of endometriosis were identified in the age range 15 to 50 years in the period 2004-2017. The incidence rate (x100 000) is 111 (95% CI 110-112), with a maximum of 160 in the age group 31-35 years. The geographical distribution of endometriosis incidence showed a very strong north-south spatial gradient. We consistently identified a group of five neighboring municipalities at higher risk (RR 1.31 95% CI 1.13; 1.52), even accounting for ascertainment bias., Conclusions: The cluster of 5 municipalities in the industrialized and polluted south-east part of the region is suggestive. However, due to the ecologic nature of the present study, information on the patients' characteristics and exposure histories are limited. Individual studies, including biomonitoring, and life-course studies are necessary to better evaluate our findings.

Several citizen science (CS) initiatives have been adopted in environmental science to monitor air and noise pollution, and water quality related to civic concerns. Nevertheless, CS projects in environmental epidemiology remain scarce. This is because little attention has been paid to evaluate associations of environmental exposures with health effects directly. This narrative review aims to promote the understanding and application of CS in environmental epidemiology. There are many commonalities between CS and other participatory approaches in environmental epidemiology. Yet, CS can foster the democratization of scientific governance and enhance the sustainability of research projects more effectively than other existing participatory approaches. This is especially the case in projects where citizens are invited to participate, engage and become involved throughout all the phases of a research project (co-created projects). This paper identifies various challenges and opportunities specific to the implementation of co-created CS projects in environmental epidemiology. The development of more locally relevant research designs, using local knowledge, obtaining medical ethical clearance, and co-analysing the association between exposure and health, are examples of opportunities and challenges that require epidemiologists to go beyond the traditional research framework and include more outreach activities. Continued efforts, particularly the sharing of information about projects' collaborative processes, are needed to make CS a more concrete and cohesive approach in environmental epidemiology., (Copyright © 2021. Published by Elsevier Ltd.)

Background: In the context of the COVID-19 pandemic, there is interest in assessing if per- and polyfluoroalkyl substances (PFAS) exposures are associated with any increased risk of COVID-19 or its severity, given the evidence of immunosuppression by some PFAS. The objective of this paper is to evaluate at the ecological level if a large area (Red Zone) of the Veneto Region, where residents were exposed for decades to drinking water contaminated by PFAS, showed higher mortality for COVID-19 than the rest of the region., Methods: We fitted a Bayesian ecological regression model with spatially and not spatially structured random components on COVID-19 mortality at the municipality level (period between 21 February and 15 April 2020). The model included education score, background all-cause mortality (for the years 2015-2019), and an indicator for the Red Zone. The two random components are intended to adjust for potential hidden confounders., Results: The COVID-19 crude mortality rate ratio for the Red Zone was 1.55 (90% Confidence Interval 1.25; 1.92). From the Bayesian ecological regression model adjusted for education level and baseline all-cause mortality, the rate ratio for the Red Zone was 1.60 (90% Credibility Interval 0.94; 2.51)., Conclusion: In conclusion, we observed a higher mortality risk for COVID-19 in a population heavily exposed to PFAS, which was possibly explained by PFAS immunosuppression, bioaccumulation in lung tissue, or pre-existing disease being related to PFAS.

Objectives: to examine the factors that, in the context of the current pandemic, have influenced the conduct of a randomized clinical trial on hydroxychloroquine in Italy., Design: the trend of enrolment in the PROTECT study, "A randomized study with Hydroxychloroquine versus observational support for prevention or early phase treatment of Coronavirus disease (COVID-19)" (Eudract number: 2020-001501-24, NCT04363827), conducted in the period from May to September 2020, was analysed to evaluate the possible association of the enrolment rate with the amount of information published in the national and local press on hydroxychloroquine., Setting and Participants: the PROTECT clinical study is an Italian interventional superiority study, open label, with cluster randomization, aimed at evaluating whether treatment with hydroxychloroquine can reduce the percentage of symptomatic subjects compared to observation only in a population of subjects exposed to SARS-CoV-2 virus consisting of cohabitants/contacts of COVID-19 patients and asymptomatic or paucisymptomatic subjects diagnosed with COVID-19., Main Outcome Measures: the number of asymptomatic or paucisymptomatic COVID-19 patients and the number of contacts/cohabitants of COVID-19 patients enrolled in the Protect study from May to September 2020., Results: from May to September 2020, the number of patients diagnosed with COVID-19 enrolled in the PROTECT clinical trial showed a decrease consistent with the number of news on hydroxychloroquine appearing in the national and local press, starting from the time when the first criticisms of the efficacy of hydroxychloroquine were made known; the number of contacts/cohabitants of COVID-19 patients showed a more marked and more timely decrease., Conclusions: in the context determined by the current COVID-19 pandemic, conducting a controlled clinical trial is strongly influenced by public opinion on scientific issues. Adherence to a clinical study can become highly problematic and invalidate the possibility of answering a scientific question and the validity of a project. In the current pandemic situation, randomized controlled trials may not always be the optimal tool to reach the expected scientific evidence, due to a number of problems. It is preferable to use a sequential or adaptive design. Furthermore, study protocols should implement innovative approaches that also include the involvement of participants in the decision-making process. In any case, the influence of public information on scientific issues is an extremely important factor to consider in the design of clinical trials in exceptional situations such as a pandemic., Competing Interests: None declared

Hypertensive disorders are common complications during pregnancy (HDP) with substantial public health impact. Acute and chronic particulate matter (PM) exposure during pregnancy increases the risk of HDP, although the underlying molecular mechanisms remain unclear. Extracellular vesicles (EVs) may be the ideal candidates for mediating the effects of PM exposure in pregnancy as they are released in response to environmental stimuli. The INSIDE project aims to investigate this mechanism in pregnancy outcomes. The study population is enrolled at the Fetal Medicine Unit of Fondazione IRCCS Ca'Granda-Ospedale Maggiore Policlinico at 10-14 weeks of gestation. Exposure to PM 10 and PM 2.5 is assessed using the flexible air quality regional model (FARM) and Bayesian geostatistical models. Each woman provides a blood sample for EV analysis and circulating biomarker assessment. Moreover, a subgroup of recruited women (n = 85) is asked to participate in a cardiovascular screening program including a standard clinical evaluation, a non-invasive assessment of right ventricular function, and pulmonary circulation at rest and during exercise. These subjects are also asked to wear a personal particulate sampler, to measure PM 10 , PM 2.5 , and PM 1 . The INSIDE study is expected to identify the health impacts of PM exposure on pregnancy outcomes.

Despite a 15-year long effort to define the "safety" of fish intake during pregnancy, there remains still uncertainty on this important public health issue. The evaluation of the toxic effects of contaminants, particularly mercury (Hg) in fish-eating populations is complicated by the fact that sea-food is also rich in beneficial nutrients, such as selenium (Se). There is toxicological plausibility of an antagonistic effects between Se and Hg, and some theoretical support for the inclusion of the Se-Hg interaction to better assess the risk linked with fish intake. To assess the effects of exposure to low-level Hg through fish consumption on the developing brain and the interaction between Hg and Se, we conducted an analysis at age 40 months in Italian children, enrolled in a prospective mother-child cohort, comparing additive and multiplicative models. Participant subjects were the 470 children born within the Northern Adriatic Cohort II (NAC-II) cohort who were tested by using the Bayley Scales of Infant and Toddler Development third edition (Bayley-III) (BSID-III) at age 40. Family demographic and socioeconomic information, pregnancy and delivery history, parental and child medical history and food consumption were assessed through questionnaires. Maternal blood samples were collected during pregnancy, cord blood at birth and maternal milk 1 month after delivery. As other exposures of interest, we considered the level of Se in maternal and cord blood and in breast milk and the potential Se-Hg antagonism. Se and inverse of THg (1:THg) concentrations were categorized according to the tertiles of their distributions, in low, medium and high levels of exposure. The lower end of the composite cognitive score distribution closest to 20% was defined as suboptimal development. Multiple logistic regression were applied to assess the association between the dichotomized composite cognitive score and the categorized exposure to Se and 1:THg, and the antagonism between Se and 1:THg. In the recruiting period, 900 pregnant women were enrolled in the cohort; 767 of these remained in the study at delivery and 470 children at 40 months. After excluding preterm births, 456 children were used in the final analyses. The larger difference in risk for suboptimal neurodevelopment was observed for the category with High THg and Low Se with OR = 2.55 (90% CI 1.02; 6.41) under the multiplicative and OR = 1.33 (90% CI 0.80; 1.87) under the additive model. The category High THg and High Se showed a very slightly better fit of the additive model (OR = 1.07, 90% CI 0.65; 1.50) versus the multiplicative (OR = 1.66, 90% CI 0.73; 1.77). A negative - antagonistic - interaction term for this category was estimated under the multiplicative model giving an OR = 1.17 (90% CI 0.42; 3.28). Although this evidence of the effects of the Se-Hg antagonism on the children neuro-development needs to be confirmed, if Se can counterbalance Hg toxicity, the evaluation of the effect on human health of fish consumption, should also consider the diverse ratios between Se and Hg concentration in different fish species., (Copyright © 2020 The Authors. Published by Elsevier GmbH.. All rights reserved.)

Background: the first confirmed cases of COVID-19 in WHO European Region was reported at the end of January 2020 and, from that moment, the epidemic has been speeding up and rapidly spreading across Europe. The health, social, and economic consequences of the pandemic are difficult to evaluate, since there are many scientific uncertainties and unknowns., Objectives: the main focus of this paper is on statistical methods for profiling municipalities by excess mortality, directly or indirectly caused by COVID-19., Methods: the use of excess mortality for all causes has been advocated as a measure of impact less vulnerable to biases. In this paper, observed mortality for all causes at municipality level in Italy in the period January-April 2020 was compared to the mortality observed in the corresponding period in the previous 5 years (2015-2019). Mortality data were made available by the Ministry of Internal Affairs Italian National Resident Population Demographic Archive and the Italian National Institute of Statistics (Istat). For each municipality, the posterior predictive distribution under a hierarchical null model was obtained. From the posterior predictive distribution, we obtained excess death counts, attributable community rates and q-values. Full Bayesian models implemented via MCMC simulations were used., Results: absolute number of excess deaths highlights the burden paid by major cities to the pandemic. The Attributable Community Rate provides a detailed picture of the spread of the pandemic among the municipalities of Lombardy, Piedmont, and Emilia-Romagna Regions. Using Q-values, it is clearly recognizable evidence of an excess of mortality from late February to April 2020 in a very geographically scattered number of municipalities. A trade-off between false discoveries and false non-discoveries shows the different values of public health actions., Conclusions: despite the variety of approaches to calculate excess mortality, this study provides an original methodological approach to profile municipalities with excess deaths accounting for spatial and temporal uncertainty.

Introduction: Measuring and mapping the occurrence of malignant mesothelioma (MM) is a useful means to monitor the impact of past asbestos exposure and possibly identify previously unknown sources of asbestos exposure., Objective: Our goal is to decompose the observed spatial pattern of incidence of MM in the Lombardy region (Italy) in gender-specific components linked to occupational exposure and a shared component linked to environmental exposure., Materials and Methods: We selected from the Lombardy Region Mesothelioma Registry (RML) all incident cases of MM (pleura, peritoneum, pericardium, and tunica vaginalis testis) with first diagnosis in the period 2000-2016. We mapped at municipality level crude incidence rates and smoothed rates using the Besag York and Mollié model separately for men and women. We then decomposed the spatial pattern of MM in gender-specific occupational components and a shared environmental component using a multivariate hierarchical Bayesian model., Results: We globally analyzed 6226 MM cases, 4048 (2897 classified as occupational asbestos exposure at interview) in men and 2178 (780 classified as occupational asbestos exposure at interview) in women. The geographical analysis showed a strong spatial pattern in the distribution of incidence rates in both genders. The multivariate hierarchical Bayesian model decomposed the spatial pattern in occupational and environmental components and consistently identified some known occupational and environmental hot spots. Other areas at high risk for MM occurrence were highlighted, contributing to better characterize environmental exposures from industrial sources and suggesting a role of natural sources in the Alpine region., Conclusion: The spatial pattern highlights areas at higher risk which are characterized by the presence of industrial sources - asbestos-cement, metallurgic, engineering, textile industries - and of natural sources in the Alpine region. The multivariate hierarchical Bayesian model was able to disentangle the geographical distribution of MM cases in two components interpreted as occupational and environmental., (Copyright © 2020 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: since the beginning of the COVID-19 pandemic, the importance of developing a serological test has emerged and a debate on test accuracy and reliability become an issue widely discussed in the media. The importance of communication during this pandemic has been strongly underlined by public health experts, epidemiologists, media expert, psychologists, sociologists. In the case of serological tests, there are several aspects that have to be considered: why we perform the test, what population is tested, which are the parameters conditioning the results and their interpretation., Objectives: to show how to quantify the uncertainty related to the validity of the serological test with respect to its predictive value and in particular the positive predictive value., Methods: the evaluation of a qualitative diagnostic test includes four distinct assessments: accuracy, empirical evidence, practical importance, and prevalence of the pathology. Accuracy is measured by the sensitivity and specificity of the test; empirical evidence is quantified by the likelihood ratio, respectively for a positive and negative test result; the practical importance of the result of a diagnostic test is assessed by the positive or negative predictive value. Prevalence of COVID-19 is substantial uncertainty and it is possible to estimate the apparent prevalence starting from the results obtained with a diagnostic test., Results: at the moment, the knowledge about the accuracy of serological tests is limited and little attention is paid to confidence interval on point estimates. In terms of practical importance of testing at individual level, while negative predictive values are high whatever the level of sensitivity of the test, the interpretation of a positive results is very cumbersome. Positive predictive values above 90% can be reached only by tests with specificity above 99% at the expected prevalence rate of 5%. There is a linear relationship between apparent - testing positive - prevalence and real prevalence. The apparent prevalence in the context of serological test for COVID-19 is always larger than real prevalence. The level of specificity is crucial., Conclusions: the main applications of the serological test in the epidemic contest are: to study the seroprevalence of the virus antibodies in the general population; to screen the healthcare workers for the early identification of contagious subjects' health care settings and to screen the general population in order to identify new incident cases. In the first two cases, seroprevalence study and screening of a high-risk population, the consequences of the uncertainty associated to the statistics are already accounted for in the first situation, or are overcome by repeating the screening on the healthcare workers, and using the molecular test to verify the presence of the virus in those tested positive. The case of screening of general population is more complex and of major interest for the implication it may have on individual behaviours and on the implementation of public health interventions by the political decision makers. A positive result has, per se, no practical value for individuals since the probability of being really infected by the virus is low. The uncertainty associated with the different estimates (sensitivity, specificity and disease prevalence) play a double role: it is a key factor in defining the informative content of the test result and it might guide the individual actions and the public policy decisions.

Objective: Thirty-four geothermal power plants for the production of electricity are currently active in the geothermal areas in Tuscany. The present study aimed to investigate the association between short-term exposure to hydrogen sulfide (H 2 S) and acute health outcomes., Methods: This study used individual data on non-accidental, cardiovascular and respiratory mortality, urgent hospital admissions (HA) and emergency department (ED) visits for cardiorespiratory diseases occurring from 2000 to 2017. All cases were georeferenced and matched to daily H 2 S data, derived from 18 monitoring sites. A case-crossover design following the matched pair interval approach was applied and conditional logistic regression models were fitted to estimate odds ratios and their 90% confidence intervals, adjusting for a set of time-dependent variables, such as influenza epidemics, holidays and temperature., Results: A total of 8054 deaths, 30,527 HA and 15,263 ED visits occurred. Mortality for non-accidental (OR = 1.11, 90% CI 1.02-1.22) and cardiovascular causes (OR = 1.22, 90% CI 1.03-1.44) were associated with an increase of 10 µg/m 3 of H 2 S daily levels only among men. Hospital admissions for respiratory diseases were positively associated with H 2 S exposure: OR = 1.11 (90% CI 1.00-1.22) among women. No associations were observed in ED visits analyses., Conclusions: In this case-crossover study in the Tuscan geothermal areas, short-term exposure to H 2 S was weakly associated with some mortality and morbidity outcomes. Our findings did not show a clear pattern as the results were not homogeneous between mortality and morbidity data or between men and women.

Objectives: Hydroxychloroquine has shown to have antiviral activity in vitro against coronaviruses, specifically SARS-CoV-2. It is believed to block virus infection by increasing endosomal pH required for virus cell fusion and glycosylation of viral surface proteins. In addition to its antiviral activity, hydroxychloroquine has an immune-modulating activity that may synergistically enhance its antiviral effect in vivo, making it a potentially promising drug for the prevention and the cure of SARS-CoV-19. However, randomized controlled trials are needed to assess whether it can be used safely to treat COVID-19 patients or to prevent infection. The main objective of the present study is to evaluate the efficacy of hydroxychloroquine for (I) the prevention of COVID-19 or related symptoms in SARS-CoV-2-exposed subjects, such as as household members/contacts of COVID-19 patients and (II) the treatment of early-phase asymptomatic or paucisymptomatic COVID-19 patients., Trial Design: This is a controlled, open label, cluster-randomized, superiority trial with parallel group design. Subjects will be randomized either to receive hydroxychloroquine or to observation (2:1)., Participants: SARS-CoV-2-exposed subjects, including household members and/or contacts of COVID-19 patients and healthcare professionals (Group 1) or patients with COVID-19 (positive PCR test on a rhinopharyngeal or oropharyngeal swab for SARS-CoV-2), asymptomatic or paucisymptomatic in home situations who are not undergoing treatment with any anti COVID-19 medication (Group 2), will be enrolled. Paucisymptomatic patients are defined as patients with a low number of mild symptoms. All subjects must be aged ≥18 years, male or female, must be willing and able to give informed consent and must not have any contraindications to take hydroxychloroquine (intolerance or previous toxicity for hydroxychloroquine/chloroquine, bradycardia or reduction in heart rhythm with arrhythmia, ischemic heart disease, retinopathy, congestive heart failure with use of diuretics, favism or glucose-6-phosphate dehydrogenase (G6PD) deficiency, diabetes type 1, major comorbidities such as advanced chronic kidney disease or dialysis therapy, known history of ventricular arrhythmia, any oncologic/hematologic malignancy, severe neurological and mental illness, current use of medications with known significant drug-drug interactions, and known prolonged QT syndrome or current use of drugs with known QT prolongation). The study is monocentric and will be conducted at Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori (IRST) IRCCS. Subjects will be enrolled from a large epidemic region (North-Central Italy). The Public Health Departments of several Italian regions will collaborate by identifying potentially eligible subjects., Intervention and Comparator: The participants will be randomized (2:1 randomization) to receive either hydroxychloroquine (Arm A) or to Observation (Arm B). Hydroxychloroquine will be administered with the following schedule: Group1: A loading dose hydroxychloroquine 400 mg twice daily on day 1, followed by a weekly dose of hydroxychloroquine 200 mg twice daily on days 8, 15 and 22, for a total of one month of treatment. Group 2: A loading dose hydroxychloroquine 400 mg twice daily on day 1 followed by 200 mg twice daily for a total of 5-7 days. The comparator in this trial is observation given that currently neither treatment is administered to asymptomatic or paucisymptomatic subjects, nor prophylaxis is available for contacts. Hydroxychloroquine will be shipped to subjects within 24 hours of randomization. Given the extraordinary nature of the COVID-19 pandemic, only telephonic interviews will be carried out and electronic Patient Reported Outcomes (ePRO) completed. During treatment, each subject will be contacted every other day for the first week and weekly thereafter (Group 2) or weekly (Group 1) by a study physician to assess early onset of any COVID-19 symptom or any adverse reaction to hydroxychloroquine and to check subject compliance. Furthermore, all subjects will receive periodic ePROs which may be completed through smartphone or tablets to record drug self-administration and onset of any symptom or adverse event. All subjects will be followed up for a total of 6 months by periodic telephonic interviews and ePROs., Main Outcomes: The primary endpoint/outcome measure for this trial is: for Group 1, the proportion of subjects who become symptomatic and/or swab-positive in each arm within one month of randomization; for Group 2, the proportion of subjects who become swab-negative in each arm within 14 days of randomization., Randomization: All household members and/or contacts of each COVID-19 index case, and the COVID-19 patient himself/herself, fulfilling all inclusion criteria will be grouped into a single cluster and this cluster will be randomized (2:1) to either arm A or arm B. Information on each subject will be recorded in specific data records. Randomization lists will be stratified according to the following factors regarding COVID-19 index cases: 1. COVID-19 risk level on the basis of province of residence (high vs. low/intermediate); 2. Index case is a healthcare professional (yes vs.no) 3. Index case with COVID-19 treatment (yes vs. no) An independent statistician not otherwise involved in the trial will generate the allocation sequence, and COVID-19 response teams will be unaware of the allocation of clusters. Randomization will be performed through an interactive web-based electronic data-capturing database. An Independent Data Monitoring Committee has been established., Blinding (masking): This study is open label., Numbers to Be Randomized (sample Size): For Group 1, a sample size of about 2000 SARS-CoV-2-exposed subjects such as household members and/or contacts of COVID-19 patients will take part in the study. Assuming around 1.5-2.0 asymptomatic household members and/or contacts for each COVID-19 patient, we expect to identify approximately 1000-1300 COVID-19 index cases to be randomized. An interim analysis on efficacy is planned using standard alpha-spending function. For Group 2, sufficient power for primary objective (negative swab within 14 days of randomization) will be reached given a sample size of 300 asymptomatic or paucisymptomatic COVID-19 subjects in home situations not treated for COVID-19 (25%-30% of about 1000-1300 expected index cases). Since up to date reduced evidence about COVID-19 infection epidemiology, the continuous update of diagnostic and therapeutic approaches, the sample size estimation could be updated after a one third of population will be recruited and eventually modified according to a substantial protocol amendment. An interim analysis at 100 enrolled COVID-19 patients is planned. We have planned a Generalized Estimating Equation analysis, which is more efficient than a cluster level analysis, to take advantage of subject-specific covariates. The above reported sample size analysis is therefore to be considered conservative., Trial Status: The current version of the PROTECT trial protocol is 'Final version, 15 April 2020'. The study started on 9 th May 2020. The first patient was enrolled on 14 th May 2020. Recruitment is expected to last through September 2020., Trial Registration: The PROTECT trial is registered in the EudraCT database (no. 2020-001501-24) and in ClinicalTrials.gov ( NCT04363827 ), date of registration 24 April 2020., Full Protocol: The full PROTECT protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interests of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol (Protocol final version, 15 th April 2020). The study protocol has been reported in accordance with Standard Protocol Items: Recommendations for Clinical Interventional Trials (SPIRIT) guidelines (Additional file 2).

Background: Cancer trials involving multiple treatment lines substantially increase our understanding of therapeutic strategies. However, even when the primary end-point of these studies is progression-free survival (PFS), their statistical analysis usually focuses on each line separately, or does not consider repeated events, thus missing potentially relevant information. Consequently, the evaluation of the effectiveness of treatment strategies is highly impaired., Methods: We evaluated the potentially different effect of bevacizumab (B) administered for the first- or second-line treatment of metastatic colorectal cancer (mCRC) in the ITACa (Italian Trial in Advanced Colorectal Cancer) randomized trial. The ITACa trial consisted of two arms: first-line chemotherapy (CT)+B followed by second-line CT alone versus first-line CT alone followed by second-line CT+B or CT+B+cetuximab according to KRAS status. Cox models for repeated disease progression were performed, and potential selection bias was adjusted using the inverse probability of censoring weighting method. Hazard ratios (HR) [95% confidence interval (CI)] for PFS (primary endpoint) were reported., Results: The overall effect of B across the two lines resulted in a HR = 0.80 (95% CI 0.68-0.95, p  = 0.008). Evaluating the differential effect of B in first- and second-line, the addition of B to first-line chemotherapy (CT) produced a 10% risk reduction (HR = 0.90, 95% CI 0.72-1.12, p  = 0.340) versus CT alone; B added to second-line CT produced a 36% risk reduction (HR = 0.64, 95% CI 0.49-0.84, p  = 0.0011) versus CT alone., Conclusion: Our results seem to suggest that B confers a PFS advantage when administered in combination with second-line chemotherapy, which could help to improve current international guidelines on optimal sequential treatment strategies., Competing Interests: Conflict of interest statement: The authors declare that there is no conflict of interest., (© The Author(s), 2020.)

Objective: The incidence of vulvar squamous cell carcinoma has increased for decades in most Western countries - a trend virtually restricted to women aged <50 or 60 years. In southern Europe, conversely, the trends have been insufficiently studied. This article reports a study from Italy., Method: Thirty-eight local cancer registries, currently covering 15,274,070 women, equivalent to 49.2% of the Italian national female population, participated. Invasive cancers registered between 1990 and 2015 with an International Classification of Diseases for Oncology, 3rd revision, topography code C51 and morphology codes compatible with vulvar squamous cell carcinoma (n = 6294) were eligible. Incidence trends were analysed using joinpoint regression models, with calculation of the estimated annual percent change (EAPC), and age-period-cohort models., Results: Total incidence showed a regular and significant decreasing trend (EAPC, -0.96; 95% confidence interval (CI), -1.43 to -0.48). This was entirely accounted for by women aged ≥60 years (EAPC, -1.34; 95% CI, -1.86 to -0.81). For younger women, the EAPC between 1990 and 2012 was 1.20 (95% CI, 0.34 to 2.06) with a non-significant acceleration thereafter. This pattern did not vary substantially in a sensitivity analysis for the effect of geographic area and duration of the registry. The age-period-cohort analysis revealed a risk decrease in cohorts born between 1905 and 1940 and a new increase in cohorts born since 1945., Conclusions: The decreasing trend observed among older women and the resulting decrease in total rate are at variance with reports from most Western countries. Age-period-cohort analysis confirmed a decreasing trend for earliest birth cohorts and an opposite one for recent ones., Competing Interests: Declaration of competing interest The authors have no competing interest., (Copyright © 2020 Elsevier Inc. All rights reserved.)

In addressing pandemics, science has never seemed more needed and useful, while at the same time limited and powerless. The existing contract between science and society is falling apart. A new covenant is urgently needed to navigate the days ahead.