Perfluoroalkyl substance mixtures and cardio-metabolic outcomes in highly exposed male workers in the Veneto Region: A mixture-based approach.

BACKGROUND: Perfluoroalkyl substances (PFAS) have been consistently associated with cardio-metabolic traits. Occupational exposures to multiple PFAS with health outcomes have been poorly investigated. The aim of the present study was to examine these associations among former workers involved in PFAS production. METHODS: We considered 232 male ex-employees who had worked in a factory (Trissino, Veneto Region, Italy), which produced PFAS and other chemicals during 1968-2018. Out of twelve serum PFAS, only four (PFOA, PFOS, PFHxS, and PFNA) were quantifiable in at least 50% of samples. Non-fasting serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured. The associations between serum PFAS mixture and considered outcomes were assessed through linear regression mixed models and Weighted Quantile Sum (WQS) regression, adjusting for potential confounders. RESULTS: PFOA was detected at the highest level, with a median concentration (in ng/mL) of 80.8 (min-max: 0.35-13,033), followed by PFOS (median: 8.55, min-max: 0.35-343), PFHxS (median: 6.8, min-max: 0.35-597) and PFNA (median: 0.8, min-max: 0.35-5). We observed that each A quartile increase in the WQS index was positively associated with the levels of TC (ß: 8.41, 95% IC: 0.78-16.0), LDL-C (ß: 8.02, 95% IC: 1-15.0) and SBP (ß: 3.21, 95% IC: 0.82-5.60). No association of serum PFAS concentration on HDL cholesterol and DBP emerged. WQS analyses revealed a major contribution of PFNA and PFHxS for the cholesterol levels, although PFOA reported the highest concentration. PFOA and PFOS emerged as chemicals of concern regarding the association with SBP. CONCLUSIONS: The results showed a clear association between serum PFAS levels and markers of cardiovascular risk and support the importance of clinical surveillance of cardiovascular risk factors in population with a high exposure to PFAS, especially in the occupational setting.

How to investigate human health effects related to exposure to mixtures of per- and polyfluoroalkyl substances: A systematic review of statistical methods.

BACKGROUND: Humans are exposed to several per- and polyfluoroalkyl substances (PFAS) daily; however, most previous studies have focused on individual PFAS. Although attention to effects of exposure to mixtures of PFAS has grown in recent years, there is no consensus on the appropriate statistical methods that can be used to assess their combined effect on human health. OBJECTIVES: We aim to perform a comprehensive review of the statistical methods used in the existing studies which evaluate the association between exposure to mixtures of PFAS and any adverse human health effect. METHODS: The online databases PubMed, Embase and Scopus were searched for eligible studies, published during the last ten years (last search performed on April 08, 2021). Covidence software was used by two different reviewers to perform a title/abstract screening, followed by a full text revision of the selected papers. RESULTS: A total of 3640 papers were identified, and after the screening process, 53 papers were included in the current review. Most of the studies were published between 2019 and 2021 and were conducted mainly in North America and Europe; more than half of the studies (28 out of 53) were conducted on mother and child pairs. WQS (Weighted Quantile Sum) Regression and BKMR (Bayesian Kernel Machine Regression) were used in 36 out of 53 papers to model mixtures' effects. Health outcomes included in the studies are immunotoxicity (n = 8), fetal development (n = 7), neurodevelopment (n = 9), reproductive hormones (n = 6), thyroid hormones (n = 7), outcomes related to metabolic pathways (n = 16). CONCLUSION: Studies on human exposure to PFAS as complex mixtures and health consequences have substantially increased in the last few years. Based on our findings, we propose that addressing risk from PFAS mixtures will likely require combinations of approaches and implementation of constantly evolving statistical methods. Specific guidelines and tools for quality assessment and publication of mixture observational studies are warranted.

Perfluoroalkyl substances and thyroid stimulating hormone levels in a highly exposed population in the Veneto Region.

BACKGROUND: Per- and poly-fluoroalkyl substances (PFAS) are persistent and widespread environmental pollutants. People living in Veneto Region (Italy) have been exposed from the late 1970s to 2013 to elevated concentrations of PFAS through drinking water. The effect of PFAS on thyroid function is still controversial and studies focusing on thyroid stimulating hormone (TSH) have shown inconsistent results. The aim of this study was to evaluate the association between serum PFAS and TSH levels and its dose-response relationship in a large population of highly exposed individuals. METHODS: A cross-sectional study was conducted on 21,424 individuals aged 14-39 living in the contaminated area. In the main analysis, participants with prevalent thyroid disease and pregnant women were excluded. Serum levels of perfluorooctanoic acid (PFOA), perfluorooctanesulfonic acid (PFOS), perfluorohexanesulfonic acid (PFHxS) and perfluorononanoic acid (PFNA) were measured. Generalized Additive Models were used to evaluate the association between TSH levels and serum PFAS, using thin plate spline smooth terms to model the potential non-linear relationship. Models were stratified by sex and age group and adjusted for potential confounders. A secondary analysis was conducted to evaluate the association between PFAS with prevalent self-reported thyroid disorders. RESULTS: We found no association between TSH and any type of PFAS among adolescents or women. A decrease in TSH concentration was observed in association with an IQR increase in PFHxS and a mild decrease in TSH at low levels of PFOA, PFOS and PFHxS among male adults. Self-reported thyroid disease was more common among women with higher levels of PFNA concentrations, whereas all other PFAS were not associated with thyroid diseases regardless of sex or age. CONCLUSIONS: Overall there is no evidence of an association between TSH and PFAS. However, some results are suggestive of a possible inverse association of TSH with PFOA, PFOS and PFHxS among adult males.

The association between perfluoroalkyl substances and lipid profile in exposed pregnant women in the Veneto region, Italy.

BACKGROUND: Residents of a large area of North-Eastern Italy were exposed for decades to high concentrations of perfluoroalkyl and polyfluoroalkyl substances (PFAS) via drinking water. Serum PFAS levels have been consistently associated with elevated serum lipids, but few studies have been conducted among pregnant women, and none has stratified analyses by trimester of gestation. Elevated serum lipid levels during pregnancy can have both immediate and long-lasting effects on pregnant women and the developing fetus. We evaluated the association between perfluorooctane sulfonate (PFOS), perfluorooctanoic acid (PFOA), and perfluoro-hexanesulfonate (PFHxS) levels in relation to lipid profiles in highly-exposed pregnant women. METHODS: A cross-sectional analysis was conducted in 319 pregnant women (age 14-48 years) enrolled in the Regional health surveillance program. Non-fasting blood samples were obtained in any trimester of pregnancy and analyzed for PFOA, PFOS and PFHxS, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C). Low-density lipoprotein cholesterol (LDL-C) was calculated. The associations between ln-transformed PFAS (and categorized into quartiles) and lipids were assessed using generalized additive models. Analyses were adjusted for potential confounders and stratified according to pregnancy trimester. RESULTS: The geometric means of PFOA, PFOS and PFHxS were 14.78 ng/mL, 2.67 ng/mL and 1.89 ng/mL, respectively. The plasma levels of TC, HDL-C and LDL-C increased steadily throughout the trimesters. In the 1st trimester, PFOS was positively associated with TC and PFHxS with HDL-C. In the 3rd trimester, instead, an inverse relationship was seen between PFOA and PFHxS and both TC and LDL-C. CONCLUSIONS: Results suggest the associations between PFAS concentrations and lipid profiles in pregnant women might differ by trimesters of pregnancy. In the first trimester, patterns are similar to those of non-pregnant women, while they differ late in pregnancy. Different independent behavior of PFAS and lipid levels throughout the pregnancy might explain our observations. These findings support the ubiquitous exposure to PFAS and possible influence on lipid metabolisms during pregnancy and suggest a careful evaluation of the timing of PFAS measurement, when examining effects of PFAS during pregnancy on gestational outcomes related to serum lipids amounts.

Perfluoroalkyl substances are associated with elevated blood pressure and hypertension in highly exposed young adults.

BACKGROUND: Residents in a large area of North-Eastern Italy were exposed to perfluoroalkyl substances (PFAS) via drinking water. Studies on the association between PFAS and blood pressure levels are limited, and results are inconsistent. Using cross-sectional data from the Regional health surveillance program, we aimed to quantify the associations between PFAS serum concentrations and blood pressure and hypertension prevalence. METHODS: The study comprised 16,224 individuals aged 20-39 years. Pregnant women (n = 327), or individuals with missing information on the selected covariates (n = 111) were excluded, leaving 15,786 subjects for the analyses. Hypertension was defined as any self-reported diagnosis, use of antihypertensive drugs, or elevated systolic blood pressure (SBP ≥ 140 mmHg)/diastolic blood pressure (DBP ≥ 90 mmHg). Generalized additive models were used to investigate the relation between perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA)) natural log (ln) transformed and by decile, and SBP, DBP, hypertension, adjusted for potential confounders. RESULTS: Both SBP and DBP increased significantly with an increase in the ln-transformed serum PFAS concentrations in a monotonic way. The predicted increase in SBP and DBP were 1.54 mmHg (95%CI 0.61-2.47), 1.60 mmHg (95%CI 0.92-2.27) from lowest to highest decile of PFOA. The associations were stronger for SBP in men and for DBP in women. One unit increase in each In-transformed PFAS was positively associated with an increased odd of hypertension in men: PFOA OR = 1.06 (1.01-1.11), PFOS OR = 1.13 (1.03-1.23), PFHxS OR = 1.08 (1.02-1.15), PFNA OR = 1.20 (1.02-1.40). CONCLUSIONS: Our findings suggest that serum PFAS concentrations were associated with increased systolic and diastolic blood pressure in a large highly exposed young adult population. Although the magnitude of the observed effect was relatively small, if confirmed it would be of public health relevance since even small increases in blood pressure levels at the population level may be associated to a raised risk of adverse outcomes such as cardiovascular disease and target organ damage.

Epidemiology and public health response in early phase of COVID-19 pandemic, Veneto Region, Italy, 21 February to 2 April 2020.

BackgroundVeneto was one of the Italian regions hit hardest by the early phase of the coronavirus disease (COVID-19) pandemic.AimThis paper describes the public health response and epidemiology of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in the Veneto Region from 21 February to 2 April 2020.MethodsInformation on the public health response was collected from regional health authorities' official sources. Epidemiological data were extracted from a web-based regional surveillance system. The epidemic curve was represented by date of testing. Characteristics of hospitalised COVID-19 cases were described and compared to those never admitted to hospital. Age- and sex-stratified case-fatality ratios (CFRs) were calculated.ResultsKey elements of the regional public health response were thorough case-finding and contact tracing, home care for non-severe cases, creation of dedicated COVID-19 healthcare facilities and activation of sub-intensive care units for non-invasive ventilation. As at 2 April 2020, 91,345 individuals were tested for SARS-CoV-2 and 10,457 (11.4%) were positive. Testing and attack rates were 18.6 per 1,000 and 213.2 per 100,000 population, respectively. The epidemic peaked around 20 to 24 March, with case numbers declining thereafter. Hospitalised cases (n = 3,623; 34.6%) were older and more frequently male compared with never-hospitalised cases. The CFR was 5.6% overall, and was higher among males and people > 60 years of age.ConclusionIn the Veneto Region, the strict social distancing measures imposed by the Italian government were supported by thorough case finding and contact tracing, as well as well-defined roles for different levels of care.

A Systematic Review of Case-Identification Algorithms Based on Italian Healthcare Administrative Databases for Two Relevant Diseases of the Endocrine System: Diabetes Mellitus and Thyroid Disorders.

BACKGROUND: diabetes mellitus (DM) and thyroid disorders (TDs) are two of the most prevalent and relevant endocrine disorders worldwide, and determining their occurrence and their follow-up pathways is essential. In Italy, due to the presence of a universal health care system, administrative data can be effectively used to determine these measurements. DM is an ideal model for surveillance with administrative data, due to its specific pharmacologic treatment, high rate of hospitalization, and specific care units. The identification of TDs, conversely, is more challenging: they are less frequently managed in a hospital setting, and even if the treatment is highly specific, subclinical forms often do not need any pharmacological treatment. OBJECTIVES: to identify and to describe all DM and TD caseidentification algorithms by means of Italian Healthcare Administrative Databases (HADs), through the review of papers published in the past 10 years. METHODS: this study is part of a project that systematically reviewed case-identification algorithms for 18 acute and chronic conditions by means of HADs in Italy. PubMed was searched for original articles, published between 2007 and 2017, in Italian or English. The search string consisted of a combination of free text and MeSH terms with a common part that focused on HADs and a disease-specific part. All identified papers were screened by two independent reviewers. Pertinent papers were classified according to the objective for which the algorithm had been used, and only articles that used algorithms for "primary objectives" (I disease occurrence; II population/cohort selection; III outcome identification) were considered for algorithm extraction. The HADs used (hospital discharge records, drug prescriptions, etc.), ICD-9 and ICD-10 codes, ATC classification of drugs, follow-back periods, and age ranges applied by the algorithms have been reported. Further information on specific objective(s), accuracy measures, sensitivity analyses and the contribution of each HAD, have also been recorded. Algorithms were divided between those identifying type 2/not specified DM and type 1 DM, and those created to identify hypo- and hyperthyroidism. RESULTS: of the 780 articles identified for DM, 77 were included and a further 14 papers were added by screening the references. For TD, 65 articles were identified through the search string and 5 of them were included. Of the selected articles, 64% and 80% were published after 2014 for DM and TD, respectively, and 33% (for DM) and 20% (for TD) used multicentric national or international data. Forty original algorithms for DM (29 for type 2 DM/not-specified DM, and 11 for type 1 DM) and 9 for TD (6 for hypo- and 3 for hyperthyroidism) were extracted. In 6 algorithms, specific selections were made so as not to include gestational diabetes. With regard to type 2 DM, the most commonly used sources were the drug prescription database (DPD, 27 cases), hospital discharge record database (HDD, 23 cases), and exemption from healthcare co-payment database (ECD, 19 cases). Other sources were the ambulatory care services database (ACD), birth register, and mortality record database (MRD). Among the 11 algorithms to identify type 1 DM, 9 used DPD, 7 ECD, and 6 HDD; in one case ACD codes were added, and all 11 algorithms but one was applied to a population of young people (always <35 years old). With regard to TDs, 2 algorithms from one paper for hypo and hyperthyroidism relied on DPD as the only source, the other 7 original algorithms combined DPD with HDD (5 cases), ECD (3 cases), and ACD (1 case). One paper identified autoimmune/iodine deficiency hypothyroidism by subtracting iatrogenic hypothyroidism cases (identified through records of previous procedures from HDD and ACD) from the whole hypothyroid population (identified through DPD). External validation was performed for two algorithms for DM and none for TD. The first algorithm for DM was obtained through HDD only and its sensitivity ranged from 61% to 70%, the second had a sensitivity of 71%. CONCLUSION: Italian literature on the use of administrative healthcare data for case identification of diabetes is vast; the proposed algorithms are quite similar to one another, and the differences between them are rarely accompanied by clinical justification. On the contrary, the literature concerning thyroid disorders is relatively poor. Further validations of the proposed algorithms, as well as their further implementation, are needed.

A Systematic Review of Case-Identification Algorithms Based on Italian Healthcare Administrative Databases for Three Relevant Diseases of the Digestive and Genitourinary System: Inflammatory Bowel Diseases, Celiac Disease, and Chronic Kidney Disease.

OBJECTIVES: to identify and describe all Inflammatory Bowel Disease (IBD), Celiac Disease (CD), and Chronic Kidney Disease (CKD) case-identification algorithms by means of Italian Healthcare Administrative Databases (HADs), through a review of papers published in the past 10 years. METHODS: this study is part of a project that systematically reviewed case-identification algorithms for 18 acute and chronic conditions by means of HADs in Italy. PubMed was searched for original articles, published between 2007 and 2017, in Italian or English. The search string consisted of a combination of free text and MeSH terms with a common part that focused on HADs and a disease-specific part. All identified papers were screened by two independent reviewers; exclusion criteria were the following: no details of algorithms reported, algorithm not developed in the Italian context, exclusive use of data from the death certificate register, or from general practitioner or pediatrician databases. Pertinent papers were classified according to the objective for which the algorithm had been used, and only articles that used algorithms for primary objectives (I disease occurrence, II population/cohort selection, III outcome identification) were considered for algorithm extraction. The HADs used (hospital discharge records, drug prescriptions, etc.), ICD-9 and ICD-10 codes, ATC classification of drugs, followback periods, and age ranges applied by the algorithms have been reported. Further information on specific objective(s), accuracy measures, sensitivity analyses and the contribution of each HAD, have also been recorded. RESULTS: the search string led to the identification of 98 articles for IBD, 42 articles for CD, and 390 for CKD. By screening the references, one paper for IBD was added. Finally, this led to 5, 9, and 8 pertinent papers respectively for IBD, CD, and CKD. Considering the papers on IBD and CD, specific age selections were applied to focus on children and young adult populations. When a selection on age was applied for CKD, instead, it mostly considered individuals aged more than 18 years. Three algorithms for IBD, 4 for CD, and 5 for CKD were extracted from papers and characterized. Drug prescription databases were used for both IBD and CKD algorithms, whereas the hospital discharge database and co-payment exemption database were used for IBD and CD. Pathology records and specialist visit databases were also used for CD and CKD, respectively. For each disease only one algorithm applied criteria for the exclusion of prevalent cases. External validation was performed only for Crohn's disease among IBDs, in one algorithm. CONCLUSIONS: the results of this review indicate that case identification for IBD and CD from routinely collected data can be considered feasible and can be used to perform different kinds of epidemiological studies. The same is not true for CKD, which requires further efforts, mainly to improve the detection of early stage patients.

A Systematic Review of Case-Identification Algorithms for 18 Conditions Based on Italian Healthcare Administrative Databases: A Study Protocol.

BACKGROUND: there has been a long-standing, consistent use worldwide of Healthcare Administrative Databases (HADs) for epidemiological purposes, especially to identify acute and chronic health conditions. These databases are able to reflect health-related conditions at a population level through disease-specific case-identification algorithms that combine information coded in multiple HADs. In Italy, in the past 10 years, HAD-based case-identification algorithms have experienced a constant increase, with a significant extension of the spectrum of identifiable diseases. Besides estimating incidence and/or prevalence of diseases, these algorithms have been used to enroll cohorts, monitor quality of care, assess the effect of environmental exposure, and identify health outcomes in analytic studies. Despite the rapid increase in the use of case-identification algorithms, information on their accuracy and misclassification rate is currently unavailable for most conditions. OBJECTIVES: to define a protocol to systematically review algorithms used in Italy in the past 10 years for the identification of several chronic and acute diseases, providing an accessible overview to future users in the Italian and international context. METHODS: PubMed will be searched for original research articles, published between 2007 and 2017, in Italian or English. The search string consists of a combination of free text and MeSH terms with a common part on HADs and a disease-specific part. All identified papers will be screened for eligibility by two independent reviewers. All articles that used/defined an algorithm for the identification of each disease of interest using Italian HADs will be included. Algorithms with exclusive use of death certificates, pathology register, general practitioner or pediatrician data will be excluded. Pertinent papers will be classified according to the objective for which the algorithm was used, and only articles that used algorithms with "primary objectives" (I disease occurrence; II population/cohort selection; III outcome identification) will be considered for algorithm extraction. The HADs used (hospital discharge records, drug prescriptions, etc.), ICD-9 and ICD-10 codes, ATC classification of drugs, follow-back periods, and age ranges applied by the algorithms will be collected. Further information on specific accuracy measures from external validations, sensitivity analyses, and the contribution of each source will be recorded. This protocol will be applied for 16 different systematic reviews concerning eighteen diseases (Hypothyroidism, Hyperthyroidism, Diabetes mellitus, Type 1 diabetes mellitus, Acute myocardial infarction, Ischemic heart disease, Stroke, Hypertension, Heart failure, Congenital heart anomalies, Parkinson's disease, Multiple sclerosis, Epilepsy, Chronic obstructive pulmonary disease, Asthma, Inflammatory bowel disease, Celiac disease, Chronic kidney failure). CONCLUSION: this protocol defines a standardized approach to extensively examine and compare all experiences of case identification algorithms in Italy, on the 18 abovementioned diseases. The methodology proposed may be applied to other systematic reviews concerning diseases not included in this project, as well as other settings, including international ones. Considering the increasing availability of healthcare data, developing standard criteria to describe and update characteristics of published algorithms would be of great use to enhance awareness in the choice of algorithms and provide a greater comparability of results.

Risk of Fractures in Youths with Celiac Disease-A Population-Based Study.

OBJECTIVE: To assess the risk of any fracture requiring hospital care in a cohort of individuals with celiac disease diagnosed in childhood/adolescence compared with reference individuals matched by age and sex. STUDY DESIGN: Our study cohort consisted of 213 635 people born and residing in Friuli-Venezia Giulia Region, Italy, in 1989-2011. We selected, through pathology reports, hospital discharge records, or co-payment exemptions, 1233 individuals with celiac disease (aged 0-17 years at diagnosis) and compared them with 6167 reference individuals matched by sex and year of birth. Fractures were identified through hospital discharge records. We calculated hazard ratios (HRs) for any fracture after celiac disease diagnosis (or index date for reference individuals) with Cox regression and ORs for any fracture before celiac disease diagnosis with conditional logistic regression. RESULTS: During the follow-up period (maximum 23 years), 22 individuals with celiac disease (9394 person-years) and 128 reference individuals (47 308 person-years) experienced a fracture, giving an overall HR of 0.87 (95% CI 0.55-1.37). The risk was not modified by sex, age at diagnosis, or calendar period of diagnosis. We obtained similar HRs when excluding fractures occurring after the age of 18 years and adjusting for maternal education or vitamin D supplementation. The odds of previous fracture also did not differ between subjects with celiac disease and reference individuals (22 and 96 cases, respectively: OR 1.15; 95% CI 0.72-1.84). CONCLUSIONS: We did not find any evidence of an increased risk of fractures during childhood and youth among patients with celiac disease.

[Assessment of an algorithm to identify paediatric-onset celiac disease cases through administrative healthcare databases]. / Valutazione di un algoritmo per l'identificazione dei casi di celiachia a insorgenza pediatrica utilizzando fonti sanitarie correnti.

OBJECTIVES: to assess the role of four administrative healthcare databases (pathology reports, copayment exemptions, hospital discharge records, gluten-free food prescriptions) for the identification of possible paediatric cases of celiac disease. DESIGN: population-based observational study with record linkage of administrative healthcare databases. SETTING AND PARTICIPANT S: children born alive in the Friuli Venezia Giulia Region (Northern Italy) to resident mothers in the years 1989-2012, identified using the regional Medical Birth Register. MAIN OUTCOME MEASURES: we defined possible celiac disease as having at least one of the following, from 2002 onward: 1. a pathology report of intestinal villous atrophy; 2. a copayment exemption for celiac disease; 3. a hospital discharge record with ICD-9-CM code of celiac disease; 4. a gluten-free food prescription. We evaluated the proportion of subjects identified by each archive and by combinations of archives, and examined the temporal relationship of the different sources in cases identified by more than one source. RESULT S: out of 962 possible cases of celiac disease, 660 (68.6%) had a pathology report, 714 (74.2%) a copayment exemption, 667 (69.3%) a hospital discharge record, and 636 (66.1%) a gluten-free food prescription. The four sources coexisted in 42.2% of subjects, whereas 30.2% were identified by two or three sources and 27.6% by a single source (16.9% by pathology reports, 4.2% by hospital discharge records, 3.9% by copayment exemptions, and 2.6% by gluten-free food prescriptions). Excluding pathology reports, 70.6% of cases were identified by at least two sources. A definition based on copayment exemptions and discharge records traced 80.5% of the 962 possible cases of celiac disease; whereas a definition based on copayment exemptions, discharge records, and gluten-free food prescriptions traced 83.1% of those cases. The temporal relationship of the different sources was compatible with the typical diagnostic pathway of subjects with celiac disease. CONCLUSIONS: the four sources were only partially consistent. A relevant proportion of all possible cases of paediatric celiac disease were identified exclusively by pathology reports.

Celiac Disease and Risk of Autoimmune Disorders: A Population-Based Matched Birth Cohort Study.

OBJECTIVES: To estimate the relative risk of developing type 1 diabetes mellitus (T1DM) and autoimmune thyroid disease in children with celiac disease (CD). STUDY DESIGN: A matched cohort design with linkage of administrative data was adopted. A total of 1215 cases of CD and 6075 references matched by sex and year of birth born in Friuli Venezia Giulia Region (Italy) between 1989 and 2011 were included. Cox regression models were used to estimate hazard ratios (HRs) for autoimmune diseases in patients with CD compared with references, stratified by sex and age at diagnosis. RESULTS: Individuals with CD had an increased risk of subsequent hypothyroidism (HR 4.64 [95% CI 2.88-7.46]) and T1DM (HR 2.50 [95% CI 0.94-6.66]), the latter not statistically significant. Risk of hypothyroidism was higher in males (HR 20.00; 95% CI 5.64-70.87) than females (HR 3.21; 95% CI 1.85-5.57) (P value <.01). No differences were observed between males and females risks for diabetes or age at CD diagnosis. The small number of hyperthyroidism cases identified precluded any statistical analysis. CONCLUSIONS: Children and youth with CD are at increased risk of developing autoimmune hypothyroidism and to some extent T1DM. This suggests the need for surveillance of children with CD in order to timely detect the onset of such comorbidities.

Risks of hospitalization and drug consumption in children and young adults with diagnosed celiac disease and the role of maternal education: a population-based matched birth cohort study.

BACKGROUND: Celiac disease (CD) may affect healthcare use in children and young adults. Socio-economic factors may act as a confounder or effect modifier. We assessed such hypotheses in a population-based birth cohort of young celiac subjects and references matched by maternal education. METHODS: The cohort included all newborns recorded in the Medical Birth Register of Friuli-Venezia Giulia Region (Italy) between 1989 and 2011. CD incident cases were identified through pathology reports, hospital discharges and copayment exemptions and matched with up to five references by sex, year of birth and maternal education. Cox regression models were used to estimate Hazard Ratios (HRs) for major causes of inpatient diagnosis and drug prescription occurring after diagnosis in CD patients compared to references, stratifying by time of first event and maternal education. RESULTS: We identified 1294 CD cases and 5681 references. CD cases had a higher risk of hospital admission for any cause (HR: 2.34; 95 % CI 2.08-2.63) and for all major ICD9-CM categories except obstetric complications, skin and musculoskeletal diseases, and injuries and poisoning. Prescription of all major ATC drug categories, except dermatologicals and genito-urinary medications, was significantly increased in CD subjects. For most outcomes, HRs were highest in the first year after CD diagnosis but remained significant after five or more years. HRs were similar across different categories of maternal education. CONCLUSIONS: Diagnosed CD subjects had a higher risk of hospitalization and medication use compared to the general population, even five or more years after diagnosis, with no effect modification of maternal education.

Antibiotic exposure in the first year of life and later treated asthma, a population based birth cohort study of 143,000 children.

Several epidemiological studies reported an association between antibiotic consumption in the first year of life and later asthma, but results are conflicting and affected by potential biases. We examined this controversial issue in a population-based birth cohort. Using administrative data, we identified 143,163 children born in 1995-2011 in Friuli-Venezia Giulia (Italy) (median follow-up 5.25 years, 927,350 person-years). Antibiotic prescriptions in the first year of life and subsequent treated asthma (defined as ≥2 anti-asthmatic drug prescriptions within a 12-month period) were retrieved from drug prescription records. We estimated incidence rate ratios (IRR) using Poisson regression models, adjusted for perinatal variables and for hospitalizations for infections in the first year of life. We identified 34,957 new-onset asthma cases. Antibiotic consumption in the first year of life increased the risk of new-onset asthma [IRR 1.51, 95% confidence interval (CI) 1.48-1.54] with a dose-response relationship (p-trend <0.001). The risk was highest for asthma identified at 13-35 months of life (IRR 2.07, 95% CI 2.00-2.14), but remained statistically significant for asthma identified at 36-71 months (IRR 1.17, 95% CI 1.14-1.21) and at ≥72 months (IRR 1.15, 95% CI 1.08-1.22). Antibiotics increased the risk of current asthma at ≥6 years (IRR 1.35, 95% CI 1.30-1.41) and at ≥13 years of age (IRR 1.19, 95% CI 1.08-1.33). Antibiotic exposure in infancy is associated with an increased risk of asthma up to adolescence. The association detected at older ages is not explained by reverse causation; however, confounding by respiratory infections not leading to hospital admission cannot be excluded.

[A systematic review of epidemiological cohort studies based on the Italian Medical Birth Register. Is it time to think of a multicentric birth cohort?] / Una revisione sistematica degli studi epidemiologici basati su coorti CeDAP in Italia. Possibile pensare a una coorte di nascita multicentrica?

INTRODUCTION: birth cohorts are a necessary tool for the study of the effects of exposures which can occur during pregnancy and early life on the development and health status in paediatric and adult life. The Italian Medical Birth Register (CeDAP), linked with other health administrative data, allows to build population based births cohorts to be followed over time. OBJECTIVES: to sistematically review all published scientific papers using data extracted from the (CeDAP) in order to give a picture of their current use for epidemiological aims; to describe advantages and limits of these data and possible future developments for epidemiological purposes. METHODS: a systematic review was conducted using PubMed, identifying all peer-reviewed research papers in English or Italian published by November 2015, by combining of free text and MeSH terms, where available. Features of included papers have been double checked and possible disagreements have been discussed to reach consensus. RESULTS: the research strategy found 720 papers, 35 of which fulfilling the required criteria. Only few Italian regions used CeDAP data for epidemiological studies, particularly Lazio and Umbria (Central Italy) and Emilia-Romagna and Friuli Venezia Giulia (Northern Italy). About half of the included papers were analytical, while the others were descriptive. Occurrence of caesarean deliveries and the prevalence of malformations were the most recurrent topics. Almost all papers used only data at delivery, whereas 5 papers used a longitudinal design with follow-up after birth. CONCLUSIONS: the Italian CeDAP registry is an important source of information for epidemiological research and its use for both aetiological aims and health services assessment should be enhanced. Furthermore, its characteristics, in particular its homogeneity among all Italian regions, might allow to create a multiregional birth cohort to be regularly followed up.

Coeliac disease and asthma association in children: the role of antibiotic consumption.

The relationship between coeliac disease and asthma has been scarcely investigated. Infant antibiotic exposure has been linked to both diseases. We evaluated the association between childhood coeliac disease and asthma and the role of antibiotics in the first year of life. We followed a cohort of children born in 1995-2011 in the Friuli-Venezia Giulia region (Italy). Prescriptions for antibiotics in the first year of life and subsequent treated asthma were retrieved from drug prescription records; coeliac disease incident cases were identified from pathology reports, hospital discharges and exemption from prescription charges for clinical tests. We estimated incidence rate ratios (IRRs) using multivariate Poisson regression models. Among the 143,144 children, we identified 717 coeliac children and 34,969 asthmatics. Children with asthma were at increased risk of coeliac disease (IRR 1.46, 95% CI 1.25-1.67). Restricting the analysis to asthma that occurred before the diagnosis of coeliac disease, the excess risk disappeared, except for coeliac disease diagnosed after 5 years of age (IRR 1.37, 95% CI 1.09-1.71). Antibiotics were not a confounding factor in these associations. Childhood treated asthma and coeliac disease are significantly associated. This association is not confounded by antibiotic exposure in the first year of life and may be explained by other shared risk factors.

Association of maternal education, early infections, and antibiotic use with celiac disease: a population-based birth cohort study in northeastern Italy.

We conducted a population-based birth cohort study of approximately 203,000 babies born in northeastern Italy (1989-2012) to investigate perinatal variables, early infections leading to hospital admission, and antibiotic use in the first 12 months of life as possible risk factors for celiac disease (CD). Incident CD cases were identified from pathology reports, hospital discharge records, and exemptions from prescription charges for clinical tests. Multivariate Poisson regression models were fitted to estimate incidence rate ratios (IRRs). A total of 1,227 children had CD; CD was histopathologically confirmed in 866 (71%). Female sex, maternal age, and high maternal educational level were found to be significantly associated with CD. Gastrointestinal infections were strongly associated with a subsequent diagnosis of CD (IRR = 2.04, 95% confidence interval (CI): 1.30, 3.22). Antibiotic use was significantly associated with CD onset (IRR = 1.24, 95% CI: 1.07, 1.43), with a dose-response relationship for number of courses (P-trend < 0.01). Cephalosporin use strongly increased the risk of CD (IRR = 1.42, 95% CI: 1.18, 1.73). Use of antibiotics (supported by the dose-response relationship) and gastrointestinal infections in the first year of life may facilitate the early onset of CD by altering intestinal microflora and the gut mucosal barrier. Perinatal factors, including cesarean section, had little influence on the risk of childhood CD.

Determinants of PFOA Serum Half-Life after End of Exposure: A Longitudinal Study on Highly Exposed Subjects in the Veneto Region.

BACKGROUND: Perfluoroalkyl substances (PFAS) are widely used, ubiquitous, and highly persistent man-made chemicals. Groundwater of a vast area of the Veneto Region (northeastern Italy) was found to be contaminated by PFAS from a manufacturing plant active since the late 1960s. As a result, residents were overexposed to PFAS through drinking water until 2013, mainly to perfluorooctanoic acid (PFOA). OBJECTIVES: The aim of the present study was to estimate the rates of decline in serum PFOA and their corresponding serum half-lives, while characterizing their determinants. METHODS: We investigated 5,860 subjects more than 14 years of age who enrolled in the second surveillance round of the regional health surveillance program. Two blood samples were collected between 2017 and 2022 (average time between measurements: 4 years). Serum PFOA excretion rates and half-lives were estimated based on linear mixed effect models, modeling subject-specific serum PFOA concentrations over time and correcting for background concentrations. For modeling determinants of half-life [age, sex, body mass index (BMI), smoking-habit, alcohol consumption, and estimated glomerular filtration rate (eGFR)], we added interaction terms between each covariate and the elapsed time between measurements. Perfluorooctanesulfonate (PFOS) and perfluorohexanesulfonic acid (PFHxS) apparent half-lives were also estimated. A separate analysis was conducted in children (n=480). All analyses were stratified by sex. RESULTS: Median initial serum concentrations of PFOA was 49 ng/mL (range: 0.5-1,090), with a median reduction of 62.45%. The mean estimated PFOA half-life was 2.36 years [95% confidence interval (CI): 2.33, 2.40], shorter in women (2.04; 95% CI: 2.00, 2.08) compared to men (2.83; 95% CI: 2.78, 2.89). Half-lives varied when stratified by some contributing factors, with faster excretion rates in nonsmokers and nonalcohol drinkers (especially in males). CONCLUSIONS: This study, to our knowledge the largest on PFOA half-life, provides precise estimates in young adults whose exposure via drinking water has largely ceased. For other PFAS, longer half-lives than reported in other studies can be explained by some ongoing exposure to PFAS via other routes. https://doi.org/10.1289/EHP13152.

Migrant status disparities in blood pressure: a multiple mediation analysis of modifiable factors.

BACKGROUND: We examined differences in blood pressure (BP) levels between first-generation immigrants and natives in adult residents in Northeast Italy, and investigated the role of lifestyle behaviors, body mass index (BMI), and education as potentially modifiable mediating factors. METHODS: We included 20-69-year-old participants from the Health Surveillance Program of the Veneto Region (n = 37,710). Immigrants born in a high migratory pressure country (HMPC) were further grouped into geographical macro-areas. The outcomes were systolic BP (SBP) and hypertension. Multiple mediation analyses were performed to determine the contribution of each mediator of the SBP/migrant status association. RESULTS: Of the 37,380 subjects included, 8.7% were born in an HMPC. BMI, education, alcohol, sweets and meat consumption were included as potential mediators. A small advantage in SBP was seen for immigrants compared to natives (ß = - 0.71,95%CI - 1.30; - 0.10). The direct effect (net of the covariates) of immigrant status on SBP was a reduction of 1.62 mmHg (95%CI - 2.25; - 0.98). BMI played the highest suppressive role (ß = 1.14,95%CI 0.99; 1.35), followed by education. Alcohol consumption amplified the health advantage of immigrants. The suppressing effect of BMI was particularly evident among women and North Africans compared to natives. Similar results were seen for hypertension rates. CONCLUSIONS: Although causation cannot be proven given the cross-sectional design, our findings identify BMI as the most effective target to preserve the health advantage of immigrants with respect to BP levels.

Trends in SARS-CoV-2 clinically confirmed cases and viral load in wastewater: A critical alignment for Padua city (NE Italy).

Since the beginning of the COVID-19 pandemic, wastewater-based epidemiology (WBE) has been depicted as a promising environmental surveillance tool and early warning system. Predictive models for the estimate of COVID-19 cases from wastewater viral loads also earned lot of interest and are currently under development. Hereby a pilot study that compares WBE surveillance data with confirmed cases, total hospitalizations, doses of vaccine administered and predominance of coronavirus variants. Composite 24hrs wastewater samples were collected weekly between September 2021 and July 2022 from Padua wastewater treatment plant. Samples were processed following a previously published method. One-step RT-qPCR was performed for quantification, adapting an Orf1b-nsp14 gene assay. Variant replacement was derived from the monthly bulletins of the Italian National Health Institute. Aggregate data on vaccine doses administered and on COVID-19 prevalence and hospitalizations were retrieved from official reports. Eighty-two samples were processed. Viral loads highlighted 3 major peaks in January, April and July 2022. Quantitation of SARS-CoV-2 in wastewater and clinical surveillance resulted temporally juxtaposable. However, variation of the two curves is not proportional. SARS-CoV-2 showed its highest peak in April, whereas maximum COVID-19 prevalence was achieved in January. Total hospitalizations followed the prevalence trend. Omicron BA.1 started to replace the Delta variant in December 2021. Subsequently, the shift towards Omicron BA.2 occurred between February and April 2022. Finally, BA.4/5 attested around June, somehow preceding the summer peak. Emergence of Omicron BA.1 over Delta could be a possible driver of the increase in both clinical cases and wastewater viral load in January 2022. In late March 2022, Omicron BA.2 replaced BA.1: this reflected in a steep increase of wastewater viral load, but not of COVID-19 confirmed cases. When a dramatic drop in the testing capacity of clinical surveillance occurred, WBE was possibly capable of detecting a substantial increase in viral circulation.