The genetic architecture of Plakophilin 2 cardiomyopathy

Purpose The genetic architecture of Plakophilin 2 (PKP2) cardiomyopathy can inform our understanding of its variant pathogenicity and protein function. Methods We assess the gene-wide and regional association of truncating and missense variants in PKP2 with arrhythmogenic cardiomyopathy (ACM), and arrhythmogenic right ventricular cardiomyopathy (ARVC) specifically. A discovery data set compares genetic testing requisitions to gnomAD. Validation is performed in a rigorously phenotyped definite ARVC cohort and non-ACM individuals in the Geisinger MyCode cohort. Results The etiologic fraction (EF) of ACM-related diagnoses from truncating variants in PKP2 is significant (0.85 [0.80,0.88], p < 2 × 10−16), increases for ARVC specifically (EF = 0.96 [0.94,0.97], p < 2 × 10−16), and is highest in definite ARVC versus non-ACM individuals (EF = 1.00 [1.00,1.00], p < 2 × 10−16). Regions of missense variation enriched for ACM probands include known functional domains and the C-terminus, which was not previously known to contain a functional domain. No regional enrichment was identified for truncating variants. Conclusion This multicohort evaluation of the genetic architecture of PKP2 demonstrates the specificity of PKP2 truncating variants for ARVC within the ACM disease spectrum. We identify the PKP2 C-terminus as a potential functional domain and find that truncating variants likely cause disease irrespective of transcript position.

Estimation of Occupational Exposure to Asbestos in Italy by the Linkage of Mesothelioma Registry (ReNaM) and National Insurance Archives. Methodology and Results

The identification and monitoring of occupational cancer is an important aspect of occupational health protection. The Italian law on the protection of workers (D. Leg. 81/2008) includes different cancer monitoring systems for high and low etiologic fraction tumors. Record linkage between cancer registries and administrative data is a convenient procedure for occupational cancer monitoring. We aim to: (i) Create a list of industries with asbestos exposure and (ii) identify cancer cases who worked in these industries. The Italian National Mesothelioma Registry (ReNaM) includes information on occupational asbestos exposure of malignant mesothelioma (MM) cases. We developed using data from seven Italian regions a methodology for listing the industries with potential exposure to asbestos linking ReNaM to Italian National Social Security Institute (INPS) data. The methodology is iterative and adjusts for imprecision and inaccuracy in reporting firm names at interview. The list of asbestos exposing firms was applied to the list of cancer cases (all types associated or possibly associated with asbestos according to International Agency for Research on Cancer (IARC) monograph 100C) in two Italian regions for the indication of possible asbestos exposure. Eighteen percent of the cancer cases showed at least one work period in firms potentially exposing to asbestos, 48% of which in regions different from where the cases lived at diagnosis. The methodology offers support for the preliminary screening of asbestos exposing firms in the occupational history of cancer cases.

Occupational conditionality of cardiovascular diseases in workers exposed to fibrogenic dust

Using single-factor analysis, the study covered prevalence and occupational conditionality of cardiovascular diseases in workers exposed to fibrogenic dust. The findings are higher prevalence of arterial hypertension, left ventricle myocardium hypertrophy, sinus tachycardia, obesity, hypertriglyceridemia, fasting hyperglycemia in silicosis and asbestosis patients if compared to refractory and asbestos-enrichment production workers with long length of service. Based on calculated relative risk and etiologic fraction, the authors revealed average occupational conditionality of arterial hypertension (etiologic fraction 45%), high occupational conditionality of left ventricle myocardium hypertrophy (etiologic share 59.7%), sinus tachycardia syndrome and obesity, and extremely high occupational dependence of carbohydrate metabolism (etiologic fraction 77.2%) on fibrogenic dust — that helps to assign this metabolic and cardiovascular disorders to occupationally-conditioned diseases.

THE COMBINATION OF STUDY AND LABOUR ACTIVITY IN ADOLESCENCE AS A RISK FACTOR FOR HEALTH (REGIONAL ASPECTS)

Hygienic features of the employment of teenagers living in four regions of the Russian Federation (Moscow, St. Petersburg, Omsk and Pskov) have been studied. Regional peculiarities in the prevalence and structure of employment are established. It is confirmed that work in adolescence can have a negative impact on lifestyle and health. In the group of working adolescents, there is a higher prevalence of behavioral risk factors (smoking, drinking alcohol, drugs, lack of sleep, etc.). Adolescents with work experience have lower health indicators. The analysis of relative risk (RR) and etiologic fraction (EF) showed that the higher health risks are for adolescents who work continuously throughout the year.

Incidence and Risk Factors for Agranulocytosis in Latin American Countries - The LATIN Study.

The association of agranulocytosis with the use of many different drugs has been documented. LATIN is a case-control study designed to identify risk factors for agranulocytosis and aplastic anemia, including drugs, and to estimate the incidence rates of both diseases in some Latin American countries. This report will cover just agranulocytosis. In 4 years, 52 cases of agranulocytosis were diagnosed. The overall incidence rate was 0.38 cases per 1 million inhabitant-years (0.35 for Brazil, 2.09 for Argentina, and no case verified in Monterrey, Mexico). Agranulocytosis patients more often took medications already associated with agranulocytosis than controls (76.7% of cases and 52.5% of controls; OR 3.7, 95% CI 1.3–12.5; p = 0.01), the most important being methimazole (OR 44.2, 95% CI 6.8 to infinite). The population attributable risk percent (etiologic fraction) was 56%. The use of nutrients supplements was more frequent among agranulocytosis patients than controls (p = 0.03). The agranulocytosis incidence in Latin America was lower than that of European countries and Israel. The rarity of the disease indicates that it is not a public health problem, and there is no reason for major protection measures other than improving diagnostic tools and making earlier agranulocytosis diagnosis.