The Mutographs biorepository: A unique genomic resource to study cancer around the world.

Large-scale biorepositories and databases are essential to generate equitable, effective, and sustainable advances in cancer prevention, early detection, cancer therapy, cancer care, and surveillance. The Mutographs project has created a large genomic dataset and biorepository of over 7,800 cancer cases from 30 countries across five continents with extensive demographic, lifestyle, environmental, and clinical information. Whole-genome sequencing is being finalized for over 4,000 cases, with the primary goal of understanding the causes of cancer at eight anatomic sites. Genomic, exposure, and clinical data will be publicly available through the International Cancer Genome Consortium Accelerating Research in Genomic Oncology platform. The Mutographs sample and metadata biorepository constitutes a legacy resource for new projects and collaborations aiming to increase our current research efforts in cancer genomic epidemiology globally.

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.

Estimation of per- and polyfluoroalkyl substances (PFAS) half-lives in human studies: a systematic review and meta-analysis.

BACKGROUND: Per- and polyfluoroalkyl substances (PFAS) constitute a heterogeneous group of synthetic compounds widely used in industrial applications. The estimation of PFAS half-life (t1/2) is essential to quantify their persistence, their toxicity and mechanism of action in humans. OBJECTIVES: The purpose of this review is to summarize the evidence on PFAS half-lives in humans from the available literature, and to investigate the limitations and uncertainties characterizing half-life estimation. METHODS: The search was conducted on PubMed, Scopus, and Embase databases up to July 03, 2023 and was aimed at identifying all papers that estimated PFAS half-life in human populations. We excluded studies on temporal trends or providing estimates of half-life based solely on renal clearance. As persistent and ongoing exposures can influence half-life estimation, we decided to include only studies that were conducted after the main source of exposure to PFAS had ceased. A random-effects meta-analysis was conducted on studies that reported perfluorooctanoic acid (PFOA), perfluorooctane sulfonic acid (PFOS) or perfluorohexanesulfonic acid (PFHxS) half-life estimation. Risk of bias was evaluated using the OHAT tool. RESULTS: A total of 13 articles were included in the review, with 5 studies conducted in exposed general populations and 8 studies conducted in exposed workers; the estimated mean half-life ranged from 1.48 to 5.1 years for PFOA, from 3.4 to 5.7 years for total PFOS, and from 2.84 to 8.5 years for PFHxS. High heterogeneity among studies was observed; potential reasons include the variability among the investigated populations, discrepancies in considering ongoing exposures, variability in PFAS isomeric compositions, accounting for background exposure, time since exposure stopped and methods used for half-life estimation. DISCUSSION: Despite the efforts made to better understand PFAS toxicokinetics, further studies are needed to identify important characteristics of these persistent chemicals. Biomonitoring studies should focus on persistent and unaccounted sources of exposure to PFAS and on individual characteristics potentially determining half-life, to ensure accurate estimates.

Poor oral health influences head and neck cancer patient survival: an International Head and Neck Cancer Epidemiology Consortium pooled analysis.

BACKGROUND: Poor oral health has been identified as a prognostic factor potentially affecting the survival of patients with head and neck squamous cell carcinoma. However, evidence to date supporting this association has emanated from studies based on single cohorts with small-to-modest sample sizes. METHODS: Pooled analysis of 2449 head and neck squamous cell carcinoma participants from 4 studies of the International Head and Neck Cancer Epidemiology Consortium included data on periodontal disease, tooth brushing frequency, mouthwash use, numbers of natural teeth, and dental visits over the 10 years prior to diagnosis. Multivariable generalized linear regression models were used and adjusted for age, sex, race, geographic region, tumor site, tumor-node-metastasis stage, treatment modality, education, and smoking to estimate risk ratios (RR) of associations between measures of oral health and overall survival. RESULTS: Remaining natural teeth (10-19 teeth: RR = 0.81, 95% confidence interval [CI] = 0.69 to 0.95; ≥20 teeth: RR = 0.88, 95% CI = 0.78 to 0.99) and frequent dental visits (>5 visits: RR = 0.77, 95% CI = 0.66 to 0.91) were associated with better overall survival. The inverse association with natural teeth was most pronounced among patients with hypopharyngeal and/or laryngeal, and not otherwise specified head and neck squamous cell carcinoma. The association with dental visits was most pronounced among patients with oropharyngeal head and neck squamous cell carcinoma. Patient-reported gingival bleeding, tooth brushing, and report of ever use of mouthwash were not associated with overall survival. CONCLUSIONS: Good oral health as defined by maintenance of the natural dentition and frequent dental visits appears to be associated with improved overall survival among head and neck squamous cell carcinoma patients.

Diagnostic accuracy of HPV16 early antigen serology for HPV-driven oropharyngeal cancer is independent of age and sex.

A growing proportion of head and neck cancer (HNC), especially oropharyngeal cancer (OPC), is caused by human papillomavirus (HPV). There are several markers for HPV-driven HNC, one being HPV early antigen serology. We aimed to investigate the diagnostic accuracy of HPV serology and its performance across patient characteristics. Data from the VOYAGER consortium was used, which comprises five studies on HNC from North America and Europe. Diagnostic accuracy, that is, sensitivity, specificity, Cohen's kappa and correctly classified proportions of HPV16 E6 serology, was assessed for OPC and other HNC using p16INK4a immunohistochemistry (p16), HPV in situ hybridization (ISH) and HPV PCR as reference methods. Stratified analyses were performed for variables including age, sex, smoking and alcohol use, to test the robustness of diagnostic accuracy. A risk-factor analysis based on serology was conducted, comparing HPV-driven to non-HPV-driven OPC. Overall, HPV serology had a sensitivity of 86.8% (95% CI 85.1-88.3) and specificity of 91.2% (95% CI 88.6-93.4) for HPV-driven OPC using p16 as a reference method. In stratified analyses, diagnostic accuracy remained consistent across sex and different age groups. Sensitivity was lower for heavy smokers (77.7%), OPC without lymph node involvement (74.4%) and the ARCAGE study (66.7%), while specificity decreased for cases with <10 pack-years (72.1%). The risk-factor model included study, year of diagnosis, age, sex, BMI, alcohol use, pack-years, TNM-T and TNM-N stage. HPV serology is a robust biomarker for HPV-driven OPC, and its diagnostic accuracy is independent of age and sex. Future research is suggested on the influence of smoking on HPV antibody levels.

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.

FAIR environmental and health registry (FAIREHR)- supporting the science to policy interface and life science research, development and innovation.

The environmental impact on health is an inevitable by-product of human activity. Environmental health sciences is a multidisciplinary field addressing complex issues on how people are exposed to hazardous chemicals that can potentially affect adversely the health of present and future generations. Exposure sciences and environmental epidemiology are becoming increasingly data-driven and their efficiency and effectiveness can significantly improve by implementing the FAIR (findable, accessible, interoperable, reusable) principles for scientific data management and stewardship. This will enable data integration, interoperability and (re)use while also facilitating the use of new and powerful analytical tools such as artificial intelligence and machine learning in the benefit of public health policy, and research, development and innovation (RDI). Early research planning is critical to ensuring data is FAIR at the outset. This entails a well-informed and planned strategy concerning the identification of appropriate data and metadata to be gathered, along with established procedures for their collection, documentation, and management. Furthermore, suitable approaches must be implemented to evaluate and ensure the quality of the data. Therefore, the 'Europe Regional Chapter of the International Society of Exposure Science' (ISES Europe) human biomonitoring working group (ISES Europe HBM WG) proposes the development of a FAIR Environment and health registry (FAIREHR) (hereafter FAIREHR). FAIR Environment and health registry offers preregistration of studies on exposure sciences and environmental epidemiology using HBM (as a starting point) across all areas of environmental and occupational health globally. The registry is proposed to receive a dedicated web-based interface, to be electronically searchable and to be available to all relevant data providers, users and stakeholders. Planned Human biomonitoring studies would ideally be registered before formal recruitment of study participants. The resulting FAIREHR would contain public records of metadata such as study design, data management, an audit trail of major changes to planned methods, details of when the study will be completed, and links to resulting publications and data repositories when provided by the authors. The FAIREHR would function as an integrated platform designed to cater to the needs of scientists, companies, publishers, and policymakers by providing user-friendly features. The implementation of FAIREHR is expected to yield significant benefits in terms of enabling more effective utilization of human biomonitoring (HBM) data.

An Updated Pooled Analysis of Off-Label Under and Over-Dosed Direct Oral Anticoagulants in Patients with Atrial Fibrillation.

INTRODUCTION: Off-label, under-, and overdosed direct oral anticoagulants (DOACs) are commonly prescribed to patients with atrial fibrillation (AF), but real-world evidence on their effectiveness and safety is limited. METHODS: MEDLINE, Embase, and Cochrane Library databases were systematically searched from 01 July 2020 to 28 February 2022 to update a previous systematic review with the same search strategy from the inception to 30 June 2020. Eligible studies were those that reported effectiveness (stroke/systemic embolism and myocardial infarction) or safety (gastrointestinal or major bleeding and death) outcomes of off-label doses of DOACs compared to on-label doses in AF patients. A random-effects meta-analysis was performed to estimate the pooled hazard ratio (HR) and 95% confidence interval (CI). Subgroup analyses were performed by specific DOACs and geographic regions. RESULTS: Twenty-two studies were included. Off-label, underdosed DOACs, compared to on-label doses, were not associated with an increased risk of stroke (HR 1.03, 95%CI: 0.88-1.17) but were associated with an increased risk of death (HR 1.26, 95%CI: 1.09-1.43). However, risk varied depending on the active ingredient. No other safety outcomes were associated with underdosed DOACs. No significant differences were observed by geographic regions. Compared to on-label DOACs, overdosing increased the risk of stroke (HR 1.17, 95%CI: 1.04-1.31), major bleeding (HR 1.18, 95%CI: 1.05-1.31), and death (HR 1.19, 95%CI: 1.03-1.35). Risk varied between geographical regions. CONCLUSIONS: Off-label underdoses, compared to on-label dosing of DOACs, did not increase the risk of stroke but did increase overall mortality. Overdosed DOACs, compared to on-label doses, were associated with an increased risk of stroke, major bleeding, and death. Future studies must examine these associations, focusing on specific active ingredients and geographic settings.

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.

Adherence to Cervical Cancer Screening Programs in Migrant Populations: A Systematic Review and Meta-Analysis.

Organized cervical cancer screening programs to promote the early identification of precancerous lesions have proven to be effective in decreasing the burden associated with cervical cancer, but knowledge regarding screening adherence among migrant women compared to that of native women has not been summarized. A systematic search of the literature on PubMed, Scopus and Embase led to the identification of 772 papers that were published up to July 2022 and reported population-based data regarding adherence to cervical screening. The screening participation rates among migrant women, compared to native women, were pooled using a random-effects meta-analysis. A total of 18 papers were included in the review, with most of them being conducted in Europe (83.3%). Overall, migrants showed a significantly lower participation rate compared to native women (OR for screening adherence: 0.54, 95% CI = 0.42-0.70). This discrepancy was especially evident for migrant women from North Africa and Sub-Saharan Africa (OR = 0.47, 95% CI = 0.35-0.63, and OR = 0.35, 95% CI = 0.24-0.49, respectively). The results of this systematic review emphasize the importance of increasing cervical cancer screening adherence among migrant women. A significant heterogeneity in screening adherence was observed based on the country of origin. Interventions aimed at reducing the disparities in screening participation should specifically consider how to improve the recruitment of migrant women.

A risk prediction model for head and neck cancers incorporating lifestyle factors, HPV serology and genetic markers.

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.

The Association Between Pediatric COVID-19 Vaccination and Socioeconomic Position: Nested Case-Control Study From the Pedianet Veneto Cohort.

BACKGROUND: The success of pediatric COVID-19 vaccination strongly depends on parents' willingness to vaccinate their children. To date, the role of socioeconomic position (SEP) in pediatric COVID-19 vaccination has not been thoroughly examined. OBJECTIVE: We evaluated the association between COVID-19 vaccination and SEP in a large pediatric cohort. METHODS: A case-control study design nested into a pediatric cohort of children born between 2007 and 2017, living in the Veneto Region and followed up to at least January 1, 2022, was adopted. Data on children were collected from the Pedianet database and linked with the regional COVID-19 registry. Each child vaccinated with at least one dose of any COVID-19 vaccine between July 1, 2021, and March 31, 2022, was matched by sex, year of birth, and family pediatrician to up to 5 unvaccinated children. Unvaccinated children with a positive outcome on the swab test within 180 days before the index date were excluded from the analyses. Children were geo-referenced to determine their area deprivation index (ADI)-a social and material deprivation measure calculated at the census block level and consisting of 5 socioeconomic items. The index was then categorized in quintiles based on the regional ADI level. The association between ADI quintiles and vaccination status was measured using conditioned logistic regression models to estimate odds ratios and the corresponding 95% CIs. Quantile-g-computation regression models were applied to develop a weighted combination of the individual items to estimate how much each component influenced the likelihood of vaccination. All analyses were stratified by age at vaccination (5-11 and 12-14 years). RESULTS: The study population consisted of 6475 vaccinated children, who were matched with 32,124 unvaccinated children. Increasing area deprivation was associated with a lower probability of being vaccinated, with approximately a linear dose-response relationship. Children in the highest deprivation quintile were 36% less likely to receive a COVID-19 vaccine than those with the lowest area deprivation (95% CI 0.59-0.70). The results were similar in the 2 age groups, with a slightly stronger association in 5-11-year-old children. When assessing the effects of the weighted combination of the individual items, a quintile increase was associated with a 17% decrease in the probability of being vaccinated (95% CI 0.80-0.86). The conditions that influenced the probability of vaccination the most were living on rent, being unemployed, and being born in single-parent families. CONCLUSIONS: This study has shown a significant reduction in the likelihood of receiving a COVID-19 vaccine among children living in areas characterized by a lower SEP. Findings were robust among multiple analyses and definitions of the deprivation index. These findings suggest that SEP plays an important role in vaccination coverage, emphasizing the need to promote targeted public health efforts to ensure global vaccine equity.

Risk factors for head and neck cancer in more and less developed countries: Analysis from the INHANCE consortium.

OBJECTIVE: We analyzed the pooled case-control data from the International Head and Neck Cancer Epidemiology (INHANCE) consortium to compare cigarette smoking and alcohol consumption risk factors for head and neck cancer between less developed and more developed countries. SUBJECTS AND METHODS: The location of each study was categorized as either a less developed or more developed country. We compared the risk of overall head and neck cancer and cancer of specific anatomic subsites associated with cigarette smoking and alcohol consumption. Additionally, age and sex distribution between categories was compared. RESULTS: The odds ratios for head and neck cancer sites associated with smoking duration differed between less developed and more developed countries. Smoking greater than 20 years conferred a higher risk for oral cavity and laryngeal cancer in more developed countries, whereas the risk was greater for oropharynx and hypopharynx cancer in less developed countries. Alcohol consumed for more than 20 years conferred a higher risk for oropharynx, hypopharynx, and larynx cancer in less developed countries. The proportion of cases that were young (<45 years) or female differed by country type for some HNC subsites. CONCLUSION: These findings suggest the degree of industrialization and economic development affects the relationship between smoking and alcohol with head and neck cancer.

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.

Plasma miR-151-3p as a Candidate Diagnostic Biomarker for Head and Neck Cancer: A Cross-sectional Study within the INHANCE Consortium.

BACKGROUND: Identification of screening tests for the detection of head and neck cancer (HNC) at an early stage is an important strategy to improving prognosis. Our objective was to identify plasma circulating miRNAs for the diagnosis of HNC (oral and laryngeal subsites), within a multicenter International Head and Neck Cancer Epidemiology consortium. METHODS: A high-throughput screening phase with 754 miRNAs was performed in plasma samples of 88 cases and 88 controls, followed by a validation phase of the differentially expressed miRNAs, identified in the screening, in samples of 396 cases and 396 controls. Comparison of the fold changes (FC) was carried out using the Wilcoxon rank-sum test and the Dunn multiple comparison test. RESULTS: We identified miR-151-3p (FC = 1.73, P = 0.007) as differentially expressed miRNAs in the screening and validation phase. The miR-151-3p was the only overexpressed miRNA in validation sample of patients with HNC with early stage at diagnosis (FC = 1.81, P = 0.008) and it was confirmed upregulated both in smoker early-stage cases (FC = 3.52, P = 0.024) and in nonsmoker early-stage cases (FC = 1.60, P = 0.025) compared with controls. CONCLUSIONS: We identified miR-151-3p as an early marker of HNC. This miRNA was the only upregulated in patients at early stages of the disease, independently of the smoking status. IMPACT: The prognosis for HNC is still poor. The discovery of a new diagnostic biomarker could lead to an earlier tumor discovery and therefore to an improvement in patient prognosis.

Early-life exposure to antibiotics and subsequent development of atopic dermatitis.

BACKGROUND: Antibiotic exposure may be associated with atopic dermatitis (AD). We assessed the risk of developing AD among children early exposed to antibiotics. RESEARCH DESIGN AND METHODS: From the Italian Pedianet database, children aged 0-14 years between 2004-2017 were enrolled from birth up to at least one year. Cox proportional-hazards models were fitted to estimate Hazard Ratios (HR) and 95% Confidence Intervals (CI) for the association between antibiotic exposure during the first year of life with incident AD. Exposure was also considered as a time-varying variable. RESULTS: 73,816 children were included in the final cohort, of which 34,202 had at least one antibiotic prescription. Incident AD was present in 8% of unexposed and exposed children. Early antibiotic exposure was not associated with any excess risk of AD compared to unexposed children (HR: 1.02, 95% CI: 0.97-1.07), and no dose-response effect was observed. In the time-varying analysis, antibiotic exposure was significantly associated with AD onset (1.12, 1.07-1.17). However, when taking into account the time-lag between exposure and outcome, risks progressively decreased, suggesting possible protopathic bias. CONCLUSION: These results are not suggestive of any significant association between exposure to antibiotics and subsequent AD onset and support the possible presence of protopathic bias.

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.