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Rationale: The identification of novel molecules associated with asthma may provide insights into the mechanisms of disease and their potential clinical implications. Objectives: To conduct a screening of circulating proteins in childhood asthma and to study proteins that emerged from human studies in a mouse model of asthma. Methods: We included 2,264 children from eight birth cohorts from the Mechanisms of the Development of ALLergy project and the Tucson Children's Respiratory Study. In cross-sectional analyses, we tested 46 circulating proteins for association with asthma in the selection stage and carried significant signals forward to a validation and replication stage. As CK (creatine kinase) was the only protein consistently associated with asthma, we also compared whole blood CK gene expression between subjects with and without asthma ( n  = 249) and used a house dust mite (HDM)-challenged mouse model to gain insights into CK lung expression and its role in the resolution of asthma phenotypes. Measurements and Main Results: As compared with the lowest CK tertile, children in the highest tertile had significantly lower odds for asthma in selection (adjusted odds ratio, 95% confidence interval: 0.31; 0.15-0.65; P  = 0.002), validation (0.63; 0.42-0.95; P  = 0.03), and replication (0.40; 0.16-0.97; P  = 0.04) stages. Both cytosolic CK forms ( CKM and CKB ) were underexpressed in blood from asthmatics compared with control subjects ( P  = 0.01 and 0.006, respectively). In the lungs of HDM-challenged mice, Ckb expression was reduced, and after the HDM challenge, a CKB inhibitor blocked the resolution of airway hyperresponsiveness and reduction of airway mucin. Conclusions: Circulating concentrations and gene expression of CK are inversely associated with childhood asthma. Mouse models support a possible direct involvement of CK in asthma protection via inhibition of airway hyperresponsiveness and reduction of airway mucin.

Background: Involuntary weight loss may occur during systemic anti-cancer therapy (SACT), causing treatment disruption and poorer prognoses. There remain gaps in clinical awareness as to which patients may benefit from nutritional interventions that aim to prevent unintended weight loss during SACT.We utilised England's population-level cancer registry data, conducting a pan-cancer assessment of patient weight loss during SACT. We aimed to identify cancers with weight loss-associated treatment modifications, potential beneficiaries of nutritional intervention., Methods: This cross-sectional study used England's Cancer Analysis System database, including SACT-treated adults with one tumour and ⩾2 weight recordings between 2014 and 2018. Binary weight loss (threshold: 2.5%) was derived from patients' most negative weight change from first SACT weight recording. The Martin et al. body mass index-adjusted weight loss grading system (BMI-WLG) was assigned. We describe binary weight loss, BMI-WLG and treatment modification status by cancer. Multivariate logistic regression models of weight loss (binary and BMI-WLG) and a composite outcome of patient treatment-modification status by cancer were produced., Results: Our study population contained 200,536 patients across 18 cancers; 28% experienced binary weight loss during SACT. Weight loss patients were more likely to have multiple types of treatment modifications recorded across all cancers. Regression analyses included 86,991 patients. Binary weight loss was associated ( p  < 0.05) with higher likelihood of treatment modification in; colon [Odds Ratio (OR) = 1.72, 95% confidence interval (CI): 1.42, 2.07]; gynaecologic (excl. ovarian) (OR = 1.48, 95% CI: 1.08, 2.01); stomach (OR = 1.6, 95% CI: 1.04, 2.06); lung (OR = 1.38, 95% CI: 1.21, 1.58); leukaemia (OR = 1.30, 95% CI: 1.09, 1.55); head and neck (OR = 1.30, 95% CI: 1.02, 1.65) and oesophageal (OR = 1.29, 95% CI: 1.01, 1.64) cancers. In lung, colon, and grouped gastro-intestinal cancers, association between BMI-WLG and treatment modification increased by WLG., Discussion: Our study is a wide assessment of weight loss during SACT using England's cancer registry data. Across different cancers we found patients have weight loss-associated treatment modifications during SACT, a precursor to poorer prognoses. Our findings highlight cancers that may benefit from improved nutritional intervention during SACT., Competing Interests: Conflict of interest statement: AR, EW and SN are employees of IQVIA who performed the study and received sponsorship from Baxter Healthcare Ltd. RW and JS are employees of Baxter Healthcare Ltd. These authors report no other conflict of interest. NS and CS received no sponsorship for their participation in this study and report no conflict of interest in relation to this study., (© The Author(s), 2020.)

Background: In Italy, direct oral anticoagulant drugs (DOACs) were authorized for stroke prevention in patients with non-valvular atrial fibrillation (NVAF) in 2013. There is conflicting evidence on their benefit-risk profile under real world conditions., Methods: The Italian Medicines Agency funded this study to investigate effectiveness and safety of DOACs compared to vitamin K antagonists (VKAs) in three Italian regions. An observational study was conducted with a sequential propensity-score-matched new user parallel-cohort design in the period July 2013-December 2015 using administrative health data. DOAC users with NVAF diagnosis were 1:1 matched to VKA users based on a PS which accounted for over 90 potential confounders at baseline. Applying an as-treated approach with a 90-day renewal grace time, patients were followed from the day after the first prescription of the study drug until occurrence of the outcome, death, discontinuation, switch, end of health plan enrolment, or study end. Outcomes were total and cardiovascular mortality, acute myocardial infarction, ischemic and haemorrhagic stroke, and gastrointestinal bleeding. Analyses were performed, using Cox proportional hazard models stratified by matched set. The results of the regional analyses were combined through a random-effects meta-analysis., Results: During the first 30 months of authorisation for NVAF, DOACs were increasingly prescribed. Overall, 72,434 new anticoagulant users were enrolled, 34% of whom received a DOAC. After PS matching, 37,266 patients contributed to the analysis. No differences between the study groups were found for total and cardiovascular mortality, myocardial infarction and ischemic stroke. DOAC users were at higher risk of gastrointestinal bleeding (HR 1.41, 95%CI 1.07-1.86) and at a not significant lower risk of haemorrhagic stroke (HR 0.36, 95%CI 0.10-1.33)., Conclusions: The present study confirms findings from previous research regarding bleeding events, whereas we did not find a reduced risk of mortality in DOAC users. Further research on single active agents and specific populations is warranted.

The numbers of international collaborations among birth cohort studies designed to better understand asthma and allergies have increased in the last several years. However, differences in definitions and methods preclude direct pooling of original data on individual participants. As part of the Mechanisms of the Development of Allergy (MeDALL) Project, we harmonized data from 14 birth cohort studies (each with 3-20 follow-up periods) carried out in 9 European countries during 1990-1998 or 2003-2009. The harmonization process followed 6 steps: 1) organization of the harmonization panel; 2) identification of variables relevant to MeDALL objectives (candidate variables); 3) proposal of a definition for each candidate variable (reference definition); 4) assessment of the compatibility of each cohort variable with its reference definition (inferential equivalence) and classification of this inferential equivalence as complete, partial, or impossible; 5) convocation of a workshop to agree on the reference definitions and classifications of inferential equivalence; and 6) preparation and delivery of data through a knowledge management portal. We agreed on 137 reference definitions. The inferential equivalence of 3,551 cohort variables to their corresponding reference definitions was classified as complete, partial, and impossible for 70%, 15%, and 15% of the variables, respectively. A harmonized database was delivered to MeDALL investigators. In asthma and allergy birth cohorts, the harmonization of data for pooled analyses is feasible, and high inferential comparability may be achieved. The MeDALL harmonization approach can be used in other collaborative projects.

Objectives: to test the validity of algorithms to identify diabetes, chronic obstructive pulmonary disease (COPD), hypertension, and hypothyroidism from routinely collected health data using information from self-reported diagnosis and laboratory or functional test., Setting and Participants: clinical or self-reported diagnosis from three surveys conducted in Lazio Region (Central Italy) between year 2010 and 2014 were assumed as gold standard and compared to the results of the algorithms application to administrative data., Main Outcome Measures: prevalence resulted from administrative data and from information available in the surveys were compared. Sensitivity, specificity, positive predictive value, and positive likelihood ratio of algorithms with respect to self-reported diagnosis, laboratory or functional test, assumed as gold standards, were calculated., Results: we analyzed data of 7,318 subjects (1,545 for diabetes, 1,783 for COPD, 2,448 for hypertension, and 1,542 for hypothyroidism). For hypertension and hypothyroidism, we observed a higher prevalence from laboratory or functional test compared to self-reported diagnosis (54.5% vs. 44.9% and 7.5% vs. 1.5%). Sensitivity of administrative data with respect to self-reported diagnosis resulted 90.9%, 38.5%, 88.3%, and 47.8%, respectively, for diabetes, COPD, hypertension, and hypothyroidism. Respectively, specificity was 97.4%, 91.7%, 84.8% and 91.8%; positive predictive value was 70,9%, 38.1%, 82.6% and 8.1%. All values of positive likelihood ratio resulted moderate (about 5), with exception of the diabetes algorithm and the disease-specific payment exemptions register for hypertension (respectively 35.5 and 17.4)., Conclusion: hypertension and hypothyroidism resulted markedly underdiagnosed from self-reported data. Case identification algorithms are highly specific, allowing their utilization for selection of cohort of subject affected by chronic diseases. The sub-optimal sensitivity observed for COPD and hypothyroidism could limit the utilization of the algorithms for prevalence estimation.

While there is evidence for variations in prevalence rates of childhood wheeze and asthma between countries, longitudinal, individual-level data are needed to understand these differences. The aim of this study was to examine variations in prevalence rates of childhood asthma, wheeze and wheeze with asthma in Europe. We analysed datasets from 10 MeDALL (Mechanisms of the Development of ALLergy) cohorts in eight countries, representing 26 663 children, to calculate prevalence rates of wheeze and asthma by child age and wheeze with asthma at age 4 years. Harmonised variables included outcomes parent-reported wheeze and parent-reported doctor-diagnosed asthma, and covariates maternal education, parental smoking, pets, parental asthma, doctor-diagnosed allergic rhinitis, doctor-diagnosed eczema and wheeze severity. At age 4 years, asthma prevalence varied from 1.72% in Germany to 13.48% in England and the prevalence of wheeze varied from 9.82% in Greece to 55.37% in Spain. Adjusted estimates of the proportion of 4-year-old children with wheeze diagnosed with asthma remained highest in England (38.14%, 95% CI 31.38-44.90%) and lowest in Spain (15.94%, 95% CI 6.16-25.71%). The large differences in prevalence rates of asthma, wheeze and wheeze with asthma at age 4 years between European cohorts may indicate that childhood asthma is more readily diagnosed in some countries while going unrecognised elsewhere., Competing Interests: Conflict of interest: Disclosures can be found alongside this article at openres.ersjournals.com

Background: Early life exposure to air pollution has been linked with cognitive impairment in children, but the results have not been conclusive. We analyzed the association between traffic-related air pollution and cognitive function in a prospective birth cohort in Rome., Methods: A cohort of 719 newborns was enrolled in 2003-2004 as part of the GASPII project. At age 7 years, 474 children took the Wechsler Intelligence Scale for Children-III to assess their cognitive development in terms of IQ composite scores. Exposure to air pollutants (NO2, PMcoarse, PM2.5, PM2.5 absorbance) at birth was assessed using land use regression models. We also considered variables indicating traffic intensity. The effect of environmental pollution on IQ was evaluated performing a linear regression model for each outcome, adjusting for gender, child age at cognitive test, maternal age at delivery, parental educational level, siblings, socio-economic status, maternal smoking during pregnancy, and tester. To account for selection bias at enrollment and during follow-up, the regression models were weighted for the inverse probabilities of participation and follow-up., Results: A 10 μg/m³ higher NO2 exposure during pregnancy was associated with 1.4 fewer points (95% confidence interval = -2.6, -0.20) of verbal IQ, and 1.4 fewer points (95% confidence interval = -2.7, -0.20) of verbal comprehension IQ. Similar associations were found for traffic intensity in a 100 m buffer around home. Other pollutants showed negative associations with larger confidence intervals., Conclusions: Consistent with previous evidence, this study suggests an association of exposure to NO2 and traffic intensity with the verbal area of cognitive development.See Video Abstract at http://links.lww.com/EDE/B12.

Introduction: the Inverse probability weighting (IPW) is a methodology developed to account for missingness and selection bias caused by non-randomselection of observations, or non-random lack of some information in a subgroup of the population., Objectives: to provide an overview of IPW methodology and an application in a cohort study of the association between exposure to traffic air pollution (nitrogen dioxide, NO₂) and 7-year children IQ., Method: this methodology allows to correct the analysis by weighting the observations with the probability of being selected. The IPW is based on the assumption that individual information that can predict the probability of inclusion (non-missingness) are available for the entire study population, so that, after taking account of them, we can make inferences about the entire target population starting from the nonmissing observations alone.The procedure for the calculation is the following: firstly, we consider the entire population at study and calculate the probability of non-missing information using a logistic regression model, where the response is the nonmissingness and the covariates are its possible predictors.The weight of each subject is given by the inverse of the predicted probability. Then the analysis is performed only on the non-missing observations using a weighted model., Conclusions: IPW is a technique that allows to embed the selection process in the analysis of the estimates, but its effectiveness in "correcting" the selection bias depends on the availability of enough information, for the entire population, to predict the non-missingness probability. In the example proposed, the IPW application showed that the effect of exposure to NO2 on the area of verbal intelligence quotient of children is stronger than the effect showed from the analysis performed without regard to the selection processes.

The population-based cohort study is the best design for assessing the possible health effects resulting fromliving in contaminated sites. The ERAS (Epidemiology,Waste disposal, Environment and Health) Project was established to study the health of people living in close proximity to urban solid waste treatment (RU) plants in Lazio. It was conducted using an integrated approach, which consisted in studying mortality and hospital discharges of residential cohorts surrounding urban waste treatment plants. The level of exposure of each address was assigned using pollution dispersion models and studying the effects on mortality and hospital discharges. Further studies were conducted on residents of areas adjacent to waste disposal sites (includingMalagrotta in Rome), incinerators andmechanical biological treatment plants. The final version of the ERAS Report is available at www.eraslazio.it. The residential cohort approach and the combination of environmental and health-related information proved invaluable in the assessment of the health impact of solid waste treatment in Lazio.

Background: A chemical plant manufacturing pesticides has been operating since the 1950's in the Sacco River Valley (Central Italy). In 2005, high beta-hexachlorocyclohexane (Beta-HCH) concentrations were found in milk of cows raised and fed near the river. We report the results of a biomonitoring study conducted in this region to evaluate the body burden of Beta-HCH and to identify the determinants of the human contamination., Methods: We defined four residential areas by their distance from the chemical plant and the river, and selected a stratified random sample of 626 people aged 25-64 years. We evaluated the association, in terms of the geometric mean ratio (GMR), between several potential determinants and Beta-HCH serum concentrations using multivariate linear regression analysis., Results: Two hundred forty-six serum samples were analysed to assess Beta-HCH levels (mean concentration: 99 ng/g lipid; Standard Deviation: 121; Geometric Mean: 60.6; Geometric Standard Deviation: 2.65). We found a strong association between Beta-HCH and living in the area close to the river (GMR: 2.00; 95%CI: 1.36-2.94). Beta-HCH levels were also associated with age, level of education, use of private wells and consumption of local food., Conclusions: The results suggest that people living close to the river may have been contaminated by Beta-HCH, most likely through water from private wells and privately grown food. A programme of epidemiological and clinical surveillance is on-going on this population.

Introduction: The adverse health effects associated with waste treatment processes are of great concern as large population groups and workers may be exposed to refuse-derived toxic substances. The main effects are respiratory and gastrointestinal infections, reduced lung function, irritations, allergic reactions, and injuries., Objective: To evaluate morbidity and mortality among a cohort of municipal waste workers in Rome., Methods: All 6839 workers (18.6% women) involved in waste collection, transportation and landfill disposal employed since 01/01/1994, with a minimum period of employment of five years were enrolled and with follow-up until 31/12/2009. The assessment of vital status was carried out through linkages with information systems (municipality records, mortality and hospital information systems), and through contacts with municipalities of residence. Gender specific standardized mortality (SMR) and hospitalization (SHR) ratios were calculated, using regional population mortality (and hospitalization) rates., Results: Overall, in this cohort workers had the same mortality as the population of the Region. Hospitalizations for natural causes were significantly higher than expected among workers involved in transportation (SHR = 1.25, 95% CI = 1.13-1.38) and in waste collection (SHR(men) = 1.14, 95% CI = 1.07-1.22; SHR(women) = 1.65, 95% CI = 1.47-1.84). Among women there was an excess of hospitalizations for respiratory diseases (SHR = 1.95, 95% CI = 1.33-2.77), for digestive system disorders (SHR = 1.37, 95% CI = 1.03-1.79) and for injuries and intoxications (SHR = 2.28, 95% CI = 1.69-2. 99)., Conclusions: The study did not find any increased mortality among the workers of either sexes. Female workers deserve further surveillance mainly due to an increased risk of trauma and respiratory and gastrointestinal disorders.

Unlabelled: OBIETTIVO: to analyze the health status of the population living in an area close to the Colleferro industrial plant., Setting and Participants: the area of the Sacco River Valley, Central Italy nearby Rome, has been heavily polluted over the years by industrial wastes deriving from the chemical industrial plant in Colleferro. In 2006, it was discovered that the herds of livestock were contaminated by beta-hexachlorocycloexane (β-HCH, an industrial waste belonging, as well as lindane, to the group of hexachlorocycloexane isomers)., Main Outcome Measures: the analyses of mortality and morbidity were carried out for the 1998-2007 period (calculation of standardized mortality ratios, SMR), and for the period 2003-2007 (calculation of standardized hospitalization ratios, SHR), respectively. The general population in the Lazio Region has been considered as reference. In addition, a biomonitoring study was conducted on a sample of the population living in 4 areas of the Sacco River Valley with different levels of exposure and the following persistent organic pollutants were measured in the blood (α, β and γ-HCH, HCB p,p'-DDT and p,p'- DDE, 6 NDL-PCB congeners and 12 DL-PCBs, PCDDs and PCDFs), and heavy metals (Cd, Hg, Pb)., Results: cancer mortality in men was increased in the area (SMR=1.20), especially for specific cancer sites (stomach, larynx, lungs, pleura, myeloma); in women an excess of mortality from diabetes was detected (SMR=1.44). The analysis of morbidity indicated an excess of hospitalization for various cancers (larynx, myeloma) in men, for respiratory illness and asthma in both genders and for thyroid disease in women. The biomonitoring study found high mean concentration of β-HCH (mean: 99.05 ng/g fat, SD=121.3), with higher levels in the population living along the river (mean=150 ng/g fat; SD=153.5), likely occurred through water and local food., Conclusion: the area of Colleferro has been polluted by multiple sources and the human population has been exposed to industrial chemicals, toxic substances in the workplace, and to the cumulative accumulation of organic pesticides especially through water and food.

Purpose: Define patients treated with evidence-based drugs in a cohort discharged after acute myocardial infarction (AMI) in absence of prescribed daily doses (PDD). To compare different drug use measures and analyze their impact on the effect estimate of risk factors related to drug use., Methods: AMI patients discharged in Rome during 2006-2007 were selected from the Hospital Information System. Drugs claimed during the 12 months after discharge were retrieved. Measures of drug use were defined as: 'continuity' (one prescription each follow-up quarter-year) and the 'proportion of days covered' calculated by defined daily doses (DDDs) or pill counts (PCs) (≥ 80% of individual follow-up). Poly-therapy was defined through the same drug use measure for all drug groups. Kappa index was calculated to analyze the concordance between measures. For each measure we estimated the effect of age, gender and Percutaneous Transluminal Coronary Angioplasty (PTCA) on poly-therapy., Results: Poly-therapy rates varied between 11.5 and 37.8% in the cohort and between 17.3 and 56.9% in patients with at least one prescription for all drugs. Concordance between all measures was high for antiplatelets (k=0.74) and very low for beta-blockers (k=0.22). According to measures used, gender and older age effects slightly varied, while PTCA remained a strong determinant of drug use., Conclusions: Different measures of exposure to drug treatment may affect the estimate of the proportion of treated patients and the effect estimates of risk factors. Drug dispense registries are useful, but it is necessary to develop and validate methodologies in absence of PDD., (Copyright © 2010 John Wiley & Sons, Ltd.)