Ovarian cancer deaths attributable to asbestos exposure in Lombardy (Italy) in 2000-2018.

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.

Implementing co-created citizen science in five environmental epidemiological studies in the CitieS-Health project.

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.

All-cause, cardiovascular disease and cancer mortality in the population of a large Italian area contaminated by perfluoroalkyl and polyfluoroalkyl substances (1980-2018).

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.

[Risk appraisal of dietary intake of per- and polyfluoroalkyl substances by the Veneto population living in the area with water contamination. Update based on EFSA 2020 limits. Food surveillance campaign 2016-2017]. / Valutazione del rischio legato all'assunzione di sostanze per- e polifluoroalchiliche per via alimentare da parte della popolazione veneta residente nella zona con contaminazione delle acque. Aggiornamento sulla base dei limiti EFSA 2020. Campagna di so.

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.

[Endometriosis, a participatory study in the Serchio Valley (Tuscany Region, Central Italy): state of the art and perspectives]. / Endometriosi, uno studio partecipato nella Valle del Serchio: stato dell'arte e prospettive.

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.

Epidemiologic transition of lung cancer mortality in Italy by sex, province of residence and birth cohort (1920-1929 to 1960-1969).

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.

Patient presentation, skin biopsy utilization and cutaneous malignant melanoma incidence and mortality in northern Italy: Trends and correlations.

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.

[Methodological approaches to evaluate the over-time mortality in SENTIERI epidemiological surveillance system: a focus on cohort analyses]. / Approcci metodologici per valutare l'andamento della mortalità nel lungo periodo nel sistema di sorveglianza SENTIERI: focus sull'analisi di coorte.

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.

Applying competing risks analysis to recurrences of primary breast cancer.

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.

How a faecal immunochemical test screening programme changes annual colorectal cancer incidence rates: an Italian intention-to-screen study.

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.

The relative contribution of the decreasing trend in tumour thickness to the 2010s increase in net survival from cutaneous malignant melanoma in Italy: a population-based investigation.

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.

Role of meteorological factors on SARS-CoV-2 infection incidence in Italy and Spain before the vaccination campaign. A multi-city time series study.

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.

[P-value and the probability of direction of effect]. / P-value e probabilità di direzione dell'effetto.

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.

[Mortality study of residents of the municipality of Piazzola sul Brenta (Veneto Region, Northern Italy), 2003-2018]. / Profilo di mortalità per causa nel Comune di Piazzola sul Brenta (Padova), anni 2003-2018.

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.

Health impact assessment should be based on correct methods.

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.

Strategia vaccinale in un contesto incerto e in costante evoluzione.

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.

[Perfluoroalchilic food contamination in the PFAS high-risk area of the Veneto Region (Northern Italy)]. / Sostanze perfluoroalchiliche (PFAS) negli alimenti dell'area rossa del Veneto.

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.

Is it possible to conduct clinical trials during a pandemic? The example of a trial of hydroxychloroquine.

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.

Spatial Epidemiology of Sporadic Creutzfeldt-Jakob Disease in Apulia, Italy.

BACKGROUND: Sporadic Creutzfeldt-Jakob disease (CJD) is a rare neurodegenerative disease caused by prions that is randomly distributed in all countries, with an overall yearly mortality rate of about 1-2 cases per million people. On a few occasions, however, sporadic CJD occurred with higher than expected rates, but further investigations failed to recognize any convincing causal link. In Italy, cluster analyses of sporadic CJD cases have not been performed previously. OBJECTIVE: To investigate the geographical distribution of sporadic CJD using municipality geographical data of Apulia with the aim of detecting spatial clusters of disease. PATIENTS AND METHODS: Patients included in this study were diagnosed as probable or definite sporadic CJD and were residents of the Apulia Region (Italy). Bayesian hierarchical models with spatially structured and unstructured random components were used to describe the spatial pattern of the disease and to assess the extent of heterogeneity among municipalities. The Kulldorff-Nagarwalla scan test and the flexible spatial scan statistic were used for detecting spatial clusters. RESULTS: Smoothed Bayesian relative risks above the null value were observed in a few adjacent municipalities in the north and middle areas of Apulia. However, both the circular scanning method and the flexible spatial scan statistic identified only a single cluster in the central part of the region. CONCLUSION: Geographical analyses and tests for spatial randomness identified a restricted area with an unusually high number of sporadic CJD cases in the Apulia region of Italy. Environmental and genetic risk factors other than mutations in the prion protein gene however, need to be investigated.

Incidence trends of vulvar squamous cell carcinoma in Italy from 1990 to 2015.

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.