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Background Most patients with hereditary hemochromatosis in the Caucasian population are homozygous for the p.C282Y mutation in the HFE gene. The penetrance and expression of hereditary hemochromatosis differ largely among cases of homozygous p.C282Y. Genetic factors might be involved in addition to environmental factors. Design and Methods In the present study, we analyzed 50 candidate genes involved in iron metabolism and evaluated the association between 214 single nucleotide polymorphisms in these genes and three phenotypic outcomes of iron overload (serum ferritin, iron removed and transferrin saturation) in a large group of 296 p.C282Y homozygous Italians. Polymorphisms were tested for genetic association with each single outcome using linear regression models adjusted for age, sex and alcohol consumption. Results We found a series of 17 genetic variants located in different genes with possible additive effects on the studied outcomes. In order to evaluate whether the selected polymorphisms could provide a predictive signature for adverse phenotype, we re-evaluated data by dividing patients in two extreme phenotype classes based on the three phenotypic outcomes. We found that only a small improvement in prediction could be achieved by adding genetic information to clinical data. Among the selected polymorphisms, a significant association was observed between rs3806562, located in the 5'UTR of CYBRD1, and transferrin saturation. This variant belongs to the same haplotype block that contains the CYBRD1 polymorphism rs884409, found to be associated with serum ferritin in another population of p.C282Y homozygotes, and able to modulate promoter activity. A luciferase assay indicated that rs3806562 does not have a significant functional role, suggesting that it is a genetic marker linked to the putative genetic modifier rs884409. Conclusions While our results support the hypothesis that polymorphisms in genes regulating iron metabolism may modulate penetrance of HFE-hereditary hemochromatosis, with emphasis on CYBRD1, they strengthen the notion that none of these polymorphisms alone is a major modifier of the phenotype of hereditary hemochromatosis

Introduction: Gender, age, physiology (GAP) system have proven to be an easy tool for predicting disease stages and survival in idiopathic pulmonary fibrosis (IPF) patients. Objective: To validate mortality risk as determined by the GAP system in a real-life multicentre IPF population treated with pirfenidone. Methods: The study included patients who received pirfenidone for at least 6 months. The GAP calculator and the GAP index were determined. The primary outcome was all-cause mortality. The prognostic accuracy of the GAP system was evaluated with respect to calibration and discrimination. Results and Conclusion: Sixty-eight IPF patients were enrolled in the study. The median follow-up was 2.4 years (range 0.1-7.4 years). A total of 22 deaths as first event (32%) and of 10 lung transplantation (15%) were recorded. The cumulative incidence of mortality at 1, 2 and 3 years was 10.4%, 22.4% and 38.4%, respectively. The differences between the predicted and observed mortality were not significant for the GAP index while the observed mortality become comparable to that predicted by the GAP calculator only in the third year of follow-up. The C-index for the GAP index was 0.74 (95% CI 0.57-0.93) while the C-statistic value for the GAP calculator was 0.77 (95% CI 0.59-0.95).

Purpose We aim to provide the most accurate and updated quantification of the effect of cigarette smoking on kidney cancer risk focusing on dose-response relationships. Methods We conducted a meta-analysis, using an innovative approach combining an umbrella review and a traditional literature search. Results Fifty-six original studies were included, providing pooled relative risks (RR) of kidney cancer of 1.39 (95% confidence interval, CI: 1.28–1.51) for current and 1.20 (95% CI: 1.14–1.27) for former compared with never smokers. Kidney cancer risk increased non-linearly with smoking intensity, the RR compared with never smokers being 1.18 (95% CI: 1.11–1.26) for five and 1.72 (95% CI: 1.52–1.95) for 30 cigarettes/day, and increased linearly with smoking duration, the RR being 1.70 (95% CI: 1.10–2.64) after 25 years. The risk linearly decreased with time-since-quitting. Conclusions Even smoking few cigarettes per day significantly increases kidney cancer risk. Quitting smoking reduces the risk, the earlier the better.

Introduction: To date we have available specific instruments assessing health-related quality of life (HRQL) in rhinoconjunctivitis or in asthma, but not instruments evaluating rhinitis and asthma together, although they often coexist. The aim of our study was to develop and validate a specific quality of life (QoL) questionnaire for adult patients with rhinoconjunctivitis, asthma or both. Materials and methods: A pool of 42 items covering the main symptoms and problems related to respiratory allergy, was generated based on literature review and clinical experience. The items were randomly listed and presented to 148 consecutive outpatients 46 suffering from asthma (age 32.9 ± 14.3 years), 53 suffering from rhinoconjunctivitis (age 32.6 ± 11.5 years) and 49 from asthma and rhinoconjunctivitis (age 35.6 ± 12.2 years). The patients were asked to indicate which item they had directly experienced and for each of them, its importance on a four-point scale (1 = not important; 4 = very important). Twelve items were cancelled from the list, because of low importance or redundance. In the instrument validation phase, 104 patients (42 with rhinoconjunctivitis alone and 62 with asthma and rhinoconjunctivitis) were evaluated with the generic instrument SF-36 and the new questionnaire (RHINASTHMA). Results: RHINASTHMA was able to differentiate patients with rhinitis from those with both rhinitis and asthma. In stable condition, RHINASTHMA showed good reliability. The factor analysis extracted three factors with a good reliability (0.93, 0.87, 0.76). Discussion: RHINASTHMA is the first tool aimed at evaluating HRQL impairment in patients with rhinitis and/or asthma. It provides a short and simple assessment, and has overall psychometric properties. This is of relevance because of the frequent asthma–rhinitis comorbidity.