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.

The incidence and risk factors of selected drug prescriptions and outpatient care after SARS-CoV-2 infection in low-risk subjects: a multicenter population-based cohort study.

Background: Knowledge about the dynamics of transmission of SARS-CoV-2 and the clinical aspects of COVID-19 has steadily increased over time, although evidence of the determinants of disease severity and duration is still limited and mainly focused on older adult and fragile populations. Methods: The present study was conceived and carried out in the Emilia-Romagna (E-R) and Veneto Regions, Italy, within the context of the EU's Horizon 2020 research project called ORCHESTRA (Connecting European Cohorts to increase common and effective response to SARS-CoV-2 pandemic) (www.orchestra-cohort.eu). The study has a multicenter retrospective population-based cohort design and aimed to investigate the incidence and risk factors of access to specific healthcare services (outpatient visits and diagnostics, drug prescriptions) during the post-acute phase from day-31 to day-365 after SARS-CoV-2 infection, in a healthy population at low risk of severe acute COVID-19. The study made use of previously recorded large-scale healthcare data available in the administrative databases of the two Italian Regions. The statistical analysis made use of methods for competing risks. Risk factors were assessed separately in the two Regions and results were pooled using random effects meta-analysis. Results: There were 35,128 subjects in E-R and 88,881 in Veneto who were included in the data analysis. The outcome (access to selected health services) occurred in a high percentage of subjects in the post-acute phase (25% in E-R and 21% in Veneto). Outpatient care was observed more frequently than drug prescriptions (18% vs. 12% in E-R and 15% vs. 10% in Veneto). Risk factors associated with the outcome were female sex, age greater than 40 years, baseline risk of hospitalization and death, moderate to severe acute COVID-19, and acute extrapulmonary complications. Conclusion: The outcome of interest may be considered as a proxy for long-term effects of COVID-19 needing clinical attention. Our data suggest that this outcome occurs in a substantial percentage of cases, even among a previously healthy population with low or mild severity of acute COVID-19. The study results provide useful insights into planning COVID-19-related services.

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.

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.

Adult first-generation immigrants and cardiovascular risk factors in the Veneto Region, Northeast Italy.

Introduction: The health condition of immigrants traditionally follows a transition from a low disease occurrence to the epidemiological profile of the deprived groups in the host country. In the Europe, studies examining differences in biochemical and clinical outcomes among immigrants and natives are lacking. We examined differences in cardiovascular risk factors between first-generation immigrants and Italians, and how migration pattern variables could affect health outcomes. Material and methods: We included participants between 20 and 69 years recruited from a Health Surveillance Program of the Veneto Region. Blood pressure (BP), total cholesterol (TC) and LDL cholesterol levels were measured. Immigrant status was defined by being born in a high migratory pressure country (HMPC) and subdivided by geographical macro-areas. We used generalized linear regression models to investigate differences between these outcomes among immigrants compared to native-born, adjusting for age, sex, education, BMI, alcohol consumption, smoking status, food consumption, salt consumption in the BP analysis and the laboratory in charge for cholesterol analysis. Within immigrant subjects, the results were stratified by variables of the migration pattern: age at immigration and length of residence in Italy. Results: Thirty seven thousand three hundred and eighty subjects were included in the analysis, 8.6% were born in an HMPC. Heterogeneous results were seen by the macro-areas of origin and sex, with male immigrants from CE Europe (ß = 8.77 mg/dl) and Asia (ß = 6.56 mg/dl) showing higher levels of TC than native-born, while female immigrants from Northern Africa showed lower levels of TC (ß = -8.64 mg/dl). BP levels were generally lower among immigrants. Immigrants residing in Italy for more than 20 years had lower levels of TC (ß = -2.9 mg/dl) than native-born. In contrast, immigrants who arrived <20 years ago or arrived older than 18 years had higher levels of TC. This trend was confirmed for CE Europeans and was inverted for Northern Africans. Conclusions: The large heterogeneity in the results depending on sex and macro-area of origin indicates the need for targeted intervention in each specific immigrant group. The results confirm that acculturation leads to a convergence toward the epidemiological profile of the host population that depends on the starting condition of the immigrant group.

Associations between Mixture of Perfluoroalkyl Substances and Lipid Profile in a Highly Exposed Adult Community in the Veneto Region.

BACKGROUND: Residents of a large area in the Veneto Region (Northeastern Italy) were exposed to drinking water contaminated by perfluoroalkyl substances (PFAS) for decades. While exposure to PFAS has been consistently associated with elevated serum lipids, combined exposures to multiple PFASs have been poorly investigated. Utilising different statistical approaches, we examine the association between chemical mixtures and lipid parameters. METHODS: Cross-sectional data from the regional health surveillance program (34,633 individuals aged 20-64 years) were used to examine the combined effects of PFAS mixture (Perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorononanoic acid (PFNA) and perfluorohexane sulfonate (PFHxS)) on total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Weighted Quantile Sum (WQS) regression, Quantile-based G-computation (Q-Gcomp) and Bayesian Kernel Machine Regression (BKMR) were used based on their ability to handle highly correlated chemicals. RESULTS: We observed that each quartile increase in the WQS index was associated with an increase in the levels of TC (ß: 4.09, 95% CI: 3.47-4.71), HDL-C (ß: 1.13, 95% CI: 0.92-1.33) and LDL-C (ß: 3.14, 95% CI: 2.65-3.63). Q-Gcomp estimated that a quartile increase in the PFAS mixture was associated with increased TC (ψ: 4.04, 95% CI 3.5-4.58), HDL-C (ψ: 1.07, 95% CI 20.87-1.27) and LDL-C (ψ: 2.71, 95% CI 2.23-3.19). In the BKMR analysis, the effect of PFAS mixture on serum lipids increased significantly when their concentrations were at their 75th percentiles or above, compared to those at their 50th percentile. All methods revealed a major contribution of PFOS and PFNA, although the main exposure was due to PFOA. We found suggestive evidence that associations varied when stratified by gender. CONCLUSIONS: The PFAS mixture was positively associated with lipid parameters, regardless of the applied method. Very similar results obtained from the three methods may be attributed to the linear positive association with the outcomes and no interaction between each PFAS.

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.

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.

To which extent are per-and poly-fluorinated substances associated to metabolic syndrome?

Exposure to per- and polyfluoroalkyl substances (PFAS), ubiquitous persistent environmental contaminants, has led to substantial global concern due to their potential environmental and human health effects. Several epidemiological studies have assessed the possible association between PFAS exposure and risk of metabolic syndrome (MetS), however, the results are ambiguous. The aim of this study was to assess the current human epidemiologic evidence on the association between exposure to PFAS and MetS. We performed a systematic search strategy using three electronic databases (PubMed, Scopus, and Web of Science) for relevant studies concerning the associations of PFAS with MetS and its clinical relevance from inception until January 2021. We undertook meta-analyses where there were five or more studies with exposure and outcomes assessments that were reasonably comparable. The pooled odd ratios (ORs) were calculated using random effects models and heterogeneity among studies was assessed by I2 index and Q test. A total of 12 cross-sectional studies (10 studies on the general population and two studies in the occupational settings) investigated the association between PFAS exposure and MetS. We pooled data from seven studies on the general population for perfluorooctanoic acid (PFOA) and perfluorooctanesulfonate (PFOS) and five studies for perfluorohexanesulfonate (PFHxS) and perfluorononanoic acid (PFNA). Predominately, most studies reported no statistically significant association between concentrations of PFAS and MetS. In the meta-analysis, the overall measure of effect was not statistically significant, showing no evidence of an association between concentrations of PFOA, PFOS, PFNA, and PFHxS and the risk of MetS. Based on the results of the meta-analysis, current small body of evidence does not support association between PFAS and MetS. However, due to limited number of studies and substantial heterogeneity, results should be interpreted with caution. Further scrutinizing cohort studies are needed to evaluate the association between various and less well-known PFAS substances and their mixture with MetS and its components in both adults and children in different settings.

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.

PFAS Concentrations and Cardiometabolic Traits in Highly Exposed Children and Adolescents.

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. Despite the large amount of evidence in adults of a positive association between serum PFAS and metabolic outcomes, studies focusing on children and adolescents are limited. We evaluated the associations between serum PFAS concentrations that were quantifiable in at least 40% of samples and lipid profile, blood pressure (BP) and body mass index (BMI) in highly exposed adolescents and children. METHODS: A cross-sectional analysis was conducted in 6669 adolescents (14-19 years) and 2693 children (8-11 years) enrolled in the health surveillance program of the Veneto Region. Non-fasting blood samples were obtained and analyzed for perfluorooctanoic acid (PFOA), perfluorooctane sulfonate (PFOS), perfluorohexanesulfonic acid (PFHxS), perfluorononanoic acid (PFNA), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and triglycerides. Low-density lipoprotein cholesterol (LDL-C) was calculated. Systolic and diastolic BP were measured, and BMI z-score accounting for age and sex was estimated. The associations between ln-transformed PFAS (and categorized into quartiles) and continuous outcomes were assessed using generalized additive models. The weighted quantile sum regression approach was used to assess PFAS-mixture effects for each outcome. Analyses were stratified by gender and adjusted for potential confounders. RESULTS: Among adolescents, significant associations were detected between all investigated PFAS and TC, LDL-C, and to a lesser extent HDL-C. Among children, PFOS and PFNA had significant associations with TC, LDL-C and HDL-C, while PFOA and PFHxS had significant associations with HDL-C only. Higher serum concentrations of PFAS, particularly PFOS, were associated with lower BMI z-score. No statistically significant associations were observed between PFAS concentrations and BP. These results were confirmed by the multi-pollutant analysis. CONCLUSIONS: Our study supports a consistent association between PFAS concentration and serum lipids, stronger for PFOS and PFNA and with a greater magnitude among children compared to adolescents, and a negative association of PFAS with BMI.

Exposure to Perfluoroalkyl Substances and Mortality for COVID-19: A Spatial Ecological Analysis in the Veneto Region (Italy).

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.

Associations of Perfluoroalkyl Substances with Prevalence of Metabolic Syndrome in Highly Exposed Young Adult Community Residents-A Cross-Sectional Study in Veneto Region, Italy.

BACKGROUND: Studies on the association between perfluoroalkyl substances (PFAS) and metabolic syndrome (MetS) are limited, and results are inconsistent. We aimed to examine the associations between PFAS serum levels and the prevalence of MetS among highly exposed young adults (ages 20-39) residents of a large area of the Veneto Region (North-Eastern Italy) primarily stemming from PFAS water contamination before September 2013. A total of 15,876 eligible young adult residents living in the investigated municipalities were enrolled in the study from January 2017 to July 2019. METHODS: MetS was defined by using a modified harmonized definition requiring the presence of 3 of the following: obesity (body mass index ≥30), elevated triglyceride (TG), reduced high-density lipoprotein cholesterol, elevated blood pressure, and hemoglobin A1c ≥ 6.1% or self-reported diabetes mellitus or drug treatment for hyperglycemia. Multivariable generalized additive models were performed to identify the associations between four serum PFAS, including perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorohexane sulfonic acid (PFHxS), and perfluorononanoic acid (PFNA), and risk of MetS controlling for potential confounders. RESULTS: A total of 1282 participants (8.1%) met the criteria of MetS with a higher prevalence among men. PFOA, PFHxS, and PFNA were not associated with the risk of MetS, whereas PFOS showed a consistent protective effect against the risk of MetS (OR 0.76, (95% CI: 0.69, 0.85) per ln-PFOS). However, we found statistically significant positive associations between PFAS serum levels and individual components of MetS, mainly elevated blood pressure and elevated TG. CONCLUSION: Our results did not support a consistent association between PFAS and MetS and conflicting findings were observed for individual components of MetS.

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.

Survival of Hospitalized COVID-19 Patients in Northern Italy: A Population-Based Cohort Study by the ITA-COVID-19 Network.

INTRODUCTION: COVID-19 case fatality rate in hospitalized patients varies across countries and studies. Reliable estimates, specific for age, sex, and comorbidities, are needed to monitor the epidemic, to compare the outcome in different settings, and to correctly design trials for COVID-19 interventions. The aim of this study was to provide population-based survival curves of hospitalized COVID-19 patients. MATERIALS AND METHODS: A cohort study was conducted in three areas of Northern Italy, heavily affected by SARS-CoV-2 infection (Lombardy and Veneto Regions, and Reggio Emilia province), using a loco-regional COVID-19 surveillance system, linked to hospital discharge databases. We included all patients testing positive for SARS-CoV-2 RNA by RT-PCR on nasopharyngeal/throat swab samples who were hospitalized from 21 February to 21 April 2020. Kaplan-Meier survival estimates were calculated at 14 and 30 days for death in any setting, stratifying by age, sex, and the Charlson Index. RESULTS: Overall, 42,926 hospitalized COVID-19 patients were identified. Patients' median age was 69 years (IQR: 57-79), 62.6% were males, and 6.0% had a Charlson Index ≥3. Survival curves showed that 22.0% (95% CI 21.6-22.4) of patients died within 14 days and 27.6% (95% CI 27.2-28.1) within 30 days from hospitalization. Survival was higher in younger patients and in females. The negative impact of comorbidities on survival was more pronounced in younger age groups. CONCLUSION: The high fatality rate observed in the study (28% at 30 days) suggests that studies should focus on death as primary endpoint during a follow-up of at least one month.

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.

Associations between perfluoroalkyl substances and lipid profile in a highly exposed young adult population in the Veneto Region.

BACKGROUND: Residents of a large area of the Veneto Region (North-Eastern Italy) were exposed for decades to drinking water contaminated by perfluoroalkyl substances (PFAS). PFAS have been consistently associated with raised serum lipids, mainly in cross-sectional studies and in background exposure contexts, but the shape of the dose-response relationships has been poorly investigated. The objectives of our study were to evaluate the association between serum PFAS and serum lipids and their dose-response patterns in a large exposed population. METHODS: A cross-sectional study was conducted in 16,224 individuals aged 20-39 years recruited in the regional health surveillance program. 15,720 subjects were analysed after excluding pregnant women (n = 327), participants reporting use of cholesterol lowering medications (n = 67) or with missing information on the selected covariates (n = 110). Twelve PFAS were measured by HPLC-MS in serum; three (PFOA, PFOS and PFHxS) were quantifiable in at least 50% of samples. Non-fasting serum total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C) and triglycerides were measured by enzymatic assays in automated analysers and low-density lipoprotein cholesterol (LDL-C), non-HDL cholesterol and total/HDL cholesterol ratio were calculated. The associations between natural log (ln) transformed PFAS and lipids were assessed through generalized additive models using linear regression and smoothing thin plate splines, adjusted for potential confounders. RESULTS: There were strong positive associations between the ln-transformed PFOA, PFOS, and PFHxS and TC, HDL-C, and LDL-C, and between ln PFOA and PFHxS and triglycerides. Each ln-increase in PFOA was associated with an increase of 1.94 mg/dL (95% CI 1.48-2.41) in TC, with 4.99 mg/dL (CI 4.12-5.86) for PFOS and 2.02 mg/dL (CI 1.45-2.58) for PFHxS. CONCLUSIONS: Investigation of the shape of exposure-response associations using splines showed a positive association with the largest increases per unit of PFAS in cholesterol levels occurring at the lower range of PFAS concentrations for each compound.

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.

Serum Levels of Perfluoroalkyl Substances (PFAS) in Adolescents and Young Adults Exposed to Contaminated Drinking Water in the Veneto Region, Italy: A Cross-Sectional Study Based on a Health Surveillance Program.

BACKGROUND: In spring 2013, groundwater of a vast area of the Veneto Region (northeastern Italy) was found to be contaminated by perfluoroalkyl substances (PFAS) from a PFAS manufacturing plant active since the late 1960s. Residents were exposed to high concentrations of PFAS, particularly perfluorooctanoic acid (PFOA), through drinking water until autumn 2013. A publicly funded health surveillance program is under way to aid in the prevention, early diagnosis, and treatment of chronic disorders possibly associated with PFAS exposure. OBJECTIVES: The objectives of this paper are: a) to describe the organization of the health surveillance program, b) to report serum PFAS concentrations in adolescents and young adults, and c) to identify predictors of serum PFAS concentrations in the studied population. METHODS: The health surveillance program offered to residents of municipalities supplied by contaminated waterworks includes a structured interview, routine blood and urine tests, and measurement of 12 PFAS in serum by high-performance liquid chromatography-tandem mass spectrometry. We studied 18,345 participants born between 1978 and 2002, 14-39 years of age at recruitment. Multivariable linear regression was used to identify sociodemographic, lifestyle, dietary, and reproductive predictors of serum PFAS concentrations. RESULTS: The PFAS with the highest serum concentrations were PFOA [median 44.4 ng/mL, interquartile range (IQR) 19.3-84.9], perfluorohexanesulfonic acid (PFHxS) (median 3.9 ng/mL, IQR 1.9-7.4), and perfluorooctanesulfonic acid (PFOS) (median 3.9 ng/mL, IQR 2.6-5.8). The major predictors of serum levels were gender, municipality, duration of residence in the affected area, and number of deliveries. Overall, the regression models explained 37%, 23%, and 43% of the variance of PFOA, PFOS, and PFHxS, respectively. CONCLUSIONS: Serum PFOA concentrations were high relative to concentrations in populations with background residential exposures only. Interindividual variation of serum PFAS levels was partially explained by the considered predictors. https://doi.org/10.1289/EHP5337.

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.