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Association between CCNE1 variants and bladder cancer

Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01–1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01–1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00–1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis. [Cancer Res 2009;69(17):6857–64]

Supplementary Tables 1-8 from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

Supplementary Figure Legend from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

Supplementary Figure 1 from Polymorphisms in DNA Repair Genes, Smoking, and Bladder Cancer Risk: Findings from the International Consortium of Bladder Cancer

Supplementary Figure 1: Electrophoretic mobility shift assays (EMSA) for CCNE1 SNPs rs8102137 and rs7257330. Supplementary Figure 2: Alignment of cyclin E protein isoforms - WT1, WT2 and ES and ET. Supplementary Figure 3: Functional analysis of cyclin E isoforms.Supplementary Table 1: Description of sub-studies included in NCI-GWAS1 and GWAS2 of bladder cancer. Supplementary Table 2: Characteristics of bladder tissue samples used for mRNA expression analysis. Supplementary Table 3: PCR primers, genotyping and gene expression assays, EMSA probes and antibodies. Supplementary Table 4: Bladder cancer stage and grade information for patients in the combined GWAS1+2 set. Supplementary Table 6: Association with bladder cancer risk with mutual adjustment for CCNE1 variants. Supplementary Table 7: Association with bladder cancer risk for CCNE1 variants previously associated with other cancers and for two non-synonymous coding variants. Supplementary Table 8: Association between cyclin E protein expression (IHC scores), bladder cancer patient characteristics and CCNE1 variants.

Contains fulltext : 293880.pdf (Publisher’s version ) (Closed access) BACKGROUND: Genomic regions identified by genome-wide association studies (GWAS) for bladder cancer risk provide new insights into etiology. OBJECTIVE: To identify new susceptibility variants for bladder cancer in a meta-analysis of new and existing genome-wide genotype data. DESIGN, SETTING, AND PARTICIPANTS: Data from 32 studies that includes 13,790 bladder cancer cases and 343,502 controls of European ancestry were used for meta-analysis. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: Log-additive associations of genetic variants were assessed using logistic regression models. A fixed-effects model was used for meta-analysis of the results. Stratified analyses were conducted to evaluate effect modification by sex and smoking status. A polygenic risk score (PRS) was generated on the basis of known and novel susceptibility variants and tested for interaction with smoking. RESULTS AND LIMITATIONS: Multiple novel bladder cancer susceptibility loci (6p.22.3, 7q36.3, 8q21.13, 9p21.3, 10q22.1, 19q13.33) as well as improved signals in three known regions (4p16.3, 5p15.33, 11p15.5) were identified, bringing the number of independent markers at genome-wide significance (p

Respirable Crystalline Silica (RCS) is a hazardous substance with known effects that can be well correlated with exposure levels that still persist in many traditional sectors, such as construction or stone processing. In the past decade, exposure scenarios for RCS have been found in the sector of artificial stone processing. The aim of this study is to evaluate the levels of RCS in facilities specialized in the production of artificial stone countertops and other accessories for the furnishing of kitchens, bathrooms, and offices after the introduction of some preventive technical measures such as wet processing or local exhaust ventilation systems. The study involved 51 subjects in four facilities. Personal silica exposure assessment was carried out using GS3 cyclones positioned in the breathing zone during the work shift. Quantitative determination of silica was carried out by X-ray diffraction analysis. Respirable dust levels were in the range 0.046-1.154 mg/m3 with RCS levels within the range

Purpose Microbial secondary infections can contribute to an increase in the risk of mortality in COVID-19 patients, particularly in case of severe diseases. In this study, we collected and evaluated the clinical, laboratory and microbiological data of COVID-19 critical ill patients requiring intensive care (ICU) to evaluate the significance and the prognostic value of these parameters. Methods One hundred seventy-eight ICU patients with severe COVID-19, hospitalized at the S. Francesco Hospital of Nuoro (Italy) in the period from March 2020 to May 2021, were enrolled in this study. Clinical data and microbiological results were collected. Blood chemistry parameters, relative to three different time points, were analyzed through multivariate and univariate statistical approaches. Results Seventy-four percent of the ICU COVID-19 patients had a negative outcome, while 26% had a favorable prognosis. A correlation between the laboratory parameters and days of hospitalization of the patients was observed with significant differences between the two groups. Moreover, Staphylococcus aureus, Enterococcus faecalis, Candida spp, Pseudomonas aeruginosa and Klebsiella pneumonia were the most frequently isolated microorganisms from all clinical specimens. Conclusions Secondary infections play an important role in the clinical outcome. The analysis of the blood chemistry tests was found useful in monitoring the progression of COVID-19.

Microbial secondary infections can contribute to an increase in the risk of mortality in COVID-19 patients, particularly in case of severe diseases. In this study, we collected and evaluated the clinical, laboratory and microbiological data of COVID-19 critical ill patients requiring intensive care (ICU) to evaluate the significance and the prognostic value of these parameters. One hundred seventy-eight ICU patients with severe COVID-19, hospitalized at the S. Francesco Hospital of Nuoro (Italy) in the period from March 2020 to May 2021, were enrolled in this study. Clinical data and microbiological results were collected. Blood chemistry parameters, relative to three different time points, were analyzed through multivariate and univariate statistical approaches. Seventy-four percent of the ICU COVID-19 patients had a negative outcome, while 26% had a favorable prognosis. A correlation between the laboratory parameters and days of hospitalization of the patients was observed with significant differences between the two groups. Moreover, Staphylococcus aureus, Enterococcus faecalis, Candida spp, Pseudomonas aeruginosa and Klebsiella pneumoniae were the most frequently isolated microorganisms from all clinical specimens. Secondary infections play an important role in the clinical outcome. The analysis of the blood chemistry tests was found useful in monitoring the progression of COVID-19.

Background Recent studies have shown that nurses have been more affected by the COVID-19 pandemic than any other group of hospital workers in terms of anxiety, depression, and burnout. Several clinical studies had previously demonstrated the effectiveness of mindfulness and compassion interventions in reducing burnout and emotional distress amongst healthcare professionals. Methods and analysis A parallel-group randomized controlled trial will assess the feasibility, acceptability, and efficacy of a mindfulness and compassion-focused programme on frontline nurses who had been working during the COVID-19 pandemic. Seventy-two participants will be recruited from Verona University Hospital Trust (Veneto Region, north-east Italy) and will be divided equally into an intervention group and a control group. Primary outcome will be assessed using the Emotional Exhaustion subscale of the Maslach Burnout Inventory General Survey (MBI-GS). Secondary outcomes will be measured by the Cynicism and Professional Efficacy subscales of the MBI-GS, the Patient Health Questionnaire (PHQ-9), the Generalized Anxiety Disorder (GAD-7), the Insomnia Severity Index (ISI), the Impact of Stressful Events (IES-R), the Perceived Stress Scale (PSS), the Five Facet Mindfulness Questionnaire (FFMQ), and the Forms of Self-Criticising/attacking and Self-Reassuring Scale (FSCRS). Discussion The study aims to fill a gap in the literature and present a scientifically validated intervention for those healthcare professionals most exposed to the stressful conditions of working during the COVID-19 pandemic. Trial registration ClinicalTrials.gov; Identifier: NCT05308537

Excessive salt consumption is one of the leading causes of high blood pressure. Worldwide salt intake largely exceeds the WHO recommended amount. This study aimed to evaluate the prevalence of high salt consumers and the effectiveness of a short-term workplace educational intervention among health workers. An online survey, assessing daily salt consumption through the MINISAL-SIIA questionnaire, was sent to the 4911 health workers employed by the University Hospital of Verona, Italy. Health workers who had a high (total score ≥ 10) or moderate (total score = 8/9) salt consumption associated with obesity or arterial hypertension were invited to undergo a medical examination and a short individual counselling session. A total of 1665 health workers (34.0%) completed the online questionnaire; 40.9% and 12.6% had moderate and high salt intake, respectively. High salt intake was more prevalent in men, current and past smokers, and obese and overweight subjects. In 95 participants completing the clinical phase, median daily salt consumption decreased from 10 (p25–p75 8–11) to 7 g (6–8) (p < 0.001), systolic blood pressure from 130 (120–140) to 120 (120–130) mmHg and weight from 78 (62–87) to 75 (62–86) kg. More than half of health workers had an excessive salt intake. However, a brief educational intervention in the healthcare working setting can substantially reduce unhealthy dietary habits, fostering weight loss and blood pressure control. Studies with a longer follow-up are needed to evaluate the persistence over time of these effects.

This study aimed to evaluate the mental health outcomes of health care workers (HCWs) of the Verona academic hospital trust (Italy) one year after the outbreak of COVID-19 and to identify predicted risk factors. A web-based survey was conducted from mid-April to mid-May 2021 on hospital workers one year after the first evaluation performed during the lock-down phase of the COVID-19 pandemic. Post-traumatic stress, general anxiety, depression, and burnout were assessed by using, respectively, the impact of event scale (IES-R), the self-rating anxiety scale (SAS), the patient health questionnaire (PHQ-9) and the Maslach burnout inventory-general survey (MBI-GS). Multivariate logistic regression analysis was performed to identify factors associated with each of the four mental health outcomes one year after the COVID-19 outbreak. A total of 1033 HCWs participated. The percentage of HCWs scoring above the cut-off increased from 2020 to 2021 in all of the outcome domains (anxiety, 50.1% vs. 55.7, p < 0.05; depression, 26.6% vs. 40.6%, p < 0.001; burnout, 28.6% vs. 40.6%, p < 0.001; chi-square test), with the exception of post-traumatic distress. There was also an increase when stratifying by occupation and workplace, with a greater increase for depression and burnout. Multivariate analysis revealed that, one year after the COVID-19 outbreak, nurses were at the greatest risk of anxiety and depression, whereas residents were at the greatest risk of burnout (in terms of low professional efficacy). Working in intensive care units was associated with an increased risk of developing severe emotional exhaustion and a cynical attitude towards work.

BackgroundSince universal vaccination is a pillar against coronavirus disease 2019 (COVID-19), monitoring anti-SARS-CoV-2 neutralizing antibodies is essential for deciphering post-vaccination immune response.MethodsThree healthcare workers received 30 μg BNT162b2 mRNA Covid-19 Vaccine, followed by a second identical dose, 21 days afterwards. Venous blood was drawn at baseline and at serial intervals, up to 63 days afterwards, for assessing total immunoglobulins (Ig) anti-RBD (receptor binding domain), IgG anti-S1/S2, IgG anti-RBD, IgM anti-RBD, IgM anti-N/S1 and IgA anti-S1.ResultsAll subjects were SARS-CoV-2 seronegative at baseline. Total Ig anti-RBD, IgG anti-S1/S2 and IgG anti-RBD levels increased between 91-368 folds until 21 days after the first vaccine dose, then reached a plateau. The levels raised further after the second dose (by ∼30-, ∼8- and ∼8-fold, respectively), peaking at day 35, but then slightly declining and stabilizing ∼50 days after the first dose. IgA anti-S1 levels increased between 7-11 days after the first dose, slightly declined before the second dose, after which levels augmented by ∼24-fold from baseline. The anti-RBD and anti-N/S1 IgM kinetics were similar to that of anti-S1 IgA, though displaying substantially weaker increases and modest peaks, only 4 to 7-fold higher than baseline. Highly significant inter-correlation was noted between total Ig anti-RBD, anti-S1/S2 and anti-RBD IgG (all r=0.99), whilst other anti-SARS-CoV-2 antibodies displayed lower, though still significant, correlations. Serum spike protein concentration was undetectable at all time points.ConclusionsBNT162b2 mRNA vaccination generates a robust humoral immune response, especially involving IgG and IgA, magnified by the second vaccine dose.

Objectives Since universal vaccination is a pillar against coronavirus disease 2019 (COVID-19), monitoring anti-SARS-CoV-2 neutralizing antibodies is essential for deciphering post-vaccination immune response. Methods Three healthcare workers received 30 μg BNT162b2 mRNA Covid-19 Pfizer Vaccine, followed by a second identical dose, 21 days afterwards. Venous blood was drawn at baseline and at serial intervals, up to 63 days afterwards, for assessing total immunoglobulins (Ig) anti-RBD (receptor binding domain), anti-S1/S2 and anti-RBD IgG, anti-RBD and anti-N/S1 IgM, and anti-S1 IgA. Results All subjects were SARS-CoV-2 seronegative at baseline. Total Ig anti-RBD, anti-S1/S2 and anti-RBD IgG levels increased between 91 and 368 folds until 21 days after the first vaccine dose, then reached a plateau. The levels raised further after the second dose (by ∼30-, ∼8- and ∼8-fold, respectively), peaking at day 35, but then slightly declining and stabilizing ∼50 days after the first vaccine dose. Anti-S1 IgA levels increased between 7 and 11 days after the first dose, slightly declined before the second dose, after which levels augmented by ∼24-fold from baseline. The anti-RBD and anti-N/S1 IgM kinetics were similar to that of anti-S1 IgA, though displaying substantially weaker increases and modest peaks, only 4- to 7-fold higher than baseline. Highly significant inter-correlation was noted between total Ig anti-RBD, anti-S1/S2 and anti-RBD IgG (all r=0.99), whilst other anti-SARS-CoV-2 antibodies displayed lower, though still significant, correlations. Serum spike protein concentration was undetectable at all-time points. Conclusions BNT162b2 mRNA vaccination generates a robust humoral immune response, especially involving anti-SARS-Cov-2 IgG and IgA, magnified by the second vaccine dose.

BACKGROUND During the COVID-19 pandemic, swab tests proved to be effective in containing the infection and served as a means for early diagnosis and contact tracing. However, little evidence exists regarding the correct timing for the execution of the swab test, especially for asymptomatic individuals and health care workers. OBJECTIVE The objective of this study was to analyze changes in the positive findings over time in individual SARS-CoV-2 swab tests during a health surveillance program. METHODS The study was conducted with 2071 health care workers at the University Hospital of Verona, with a known date of close contact with a patient with COVID-19, between February 29 and April 17, 2020. The health care workers underwent a health surveillance program with repeated swab tests to track their virological status. A generalized additive mixed model was used to investigate how the probability of a positive test result changes over time since the last known date of close contact, in an overall sample of individuals who tested positive for COVID-19 and in a subset of individuals with an initial negative swab test finding before being proven positive, to assess different surveillance time intervals. RESULTS Among the 2071 health care workers in this study, 191 (9.2%) tested positive for COVID-19, and 103 (54%) were asymptomatic with no differences based on sex or age. Among 49 (25.7%) cases, the initial swab test yielded negative findings after close contact with a patient with COVID-19. Sex, age, symptoms, and the time of sampling were not different between individuals with an initial negative swab test finding and those who initially tested positive after close contact. In the overall sample, the estimated probability of testing positive was 0.74 on day 1 after close contact, which increased to 0.77 between days 5 and 8. In the 3 different scenarios for scheduled repeated testing intervals (3, 5, and 7 days) in the subgroup of individuals with an initially negative swab test finding, the probability peaked on the sixth, ninth and tenth, and 13th and 14th days, respectively. CONCLUSIONS Swab tests can initially yield false-negative outcomes. The probability of testing positive increases from day 1, peaking between days 5 and 8 after close contact with a patient with COVID-19. Early testing, especially in this final time window, is recommended together with a health surveillance program scheduled in close intervals.

Objectives The COVID-19 pandemic is putting a huge strain on the provision and continuity of care. The length of sickness absence of the healthcare workers as a result of SARS-CoV-2 infection plays a pivotal role in hospital staff management. Therefore, the aim of this study was to explore the timing of COVID-19 recovery and viral clearance, and its predictive factors, in a large sample of healthcare workers. Study design Retrospective cohort study. Methods The analysis was conducted on data collected during the hospital health surveillance programme for healthcare staff at the University Hospital of Verona; healthcare workers were tested for SARS-CoV-2 through RT-PCR with oro-nasopharyngeal swab samples. The health surveillance programme targeted healthcare workers who either had close contact with SARS-CoV-2 infected patients or were tested as part of the screening-based strategy implemented according to national and regional requirements. Recovery time was estimated from the first positive swab to two consecutive negative swabs, collected 24 hours apart, using survival analysis for both right-censored and interval-censored data. Cox proportional hazard was used for multivariate analysis. Results During the health surveillance programme, 6455 healthcare workers were tested for SARS-CoV-2 and 248 (3.8%, 95% confidence interval [CI] 3.4–4.3) reported positive results; among those who tested positive, 49% were asymptomatic, with a median age of 39.8 years, which is significantly younger than symptomatic healthcare workers (48.2 years, p < 0.001). Screening tests as part of the health surveillance programme identified 31 (12.5%) of the positive cases. Median recovery time was 24 days (95% CI 23–26) and 21.5 days (95% CI 15.5–30.5) in right- and interval-censoring analysis, respectively, with no association with age, sex or presence of symptoms. Overall, 63% of participants required >20 days to test negative on two consecutive swabs. Hospitalised healthcare workers (4.8%) were older and had a significantly longer recovery time compared with non-hospitalised healthcare workers in both analyses (33.5 vs 24 days, p = 0.005). Conclusions Recovery from COVID-19 and viral clearance may take a long time, especially in individuals who are hospitalised. To detect asymptomatic cases, screening programmes for healthcare workers is recommended.

Objectives The ongoing outbreak of coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses formidable challenges to all health care systems. Serological assays may be used for improving disease management when appropriately applied, for investigating the antibody responses mounted against SARS-CoV-2 infection and for assessing its real prevalence. Although testing the whole population is impractical, well-designed serosurveys in selected subpopulations in specific risk groups may provide valuable information. We evaluated the prevalence of SARS-CoV-2 infection in health care workers (HCW) who underwent molecular testing with reverse transcription real-time polymerase chain reaction (rRT-PCR) in the main hospitals of the Veneto Region of Italy by measuring specific antibodies (Abs). Methods Both immunoglobulin (Ig)M and IgG antibodies against SARS-Cov-2 S-antigen and N-protein were measured using a validated chemiluminescent analytical system (CLIA) called Maglumi™ 2000 Plus (New Industries Biomedical Engineering Co., Ltd [Snibe], Shenzhen, China). Results A total of 8,285 HCW were tested. SARS-CoV-2 specific antibodies (IgM, IgG or both) were detectable in 378 cases (4.6%, 95% CI 4.1–5.0%). Seroconversion was observed in 4.4% of women vs. 5.0% of men, but this difference was not significant. Although detectable antibodies were found in all HCW who developed severe COVID-19 infection (100%), lower seropositivity was found in mild disease (83%) and the lowest prevalence (58%) was observed in asymptomatic subjects. Conclusions Seroprevalence surveys are of utmost importance for understanding the rate of population that has already developed antibodies against SARS-CoV-2. The present study defined precisely the circulation of SARS-CoV-2 in a cohort of HCW in the Veneto Region, with its prevalence (4.6%) reflecting a relatively low circulation. Symptomatic individuals or those hospitalized for medical care were 100% antibody positive, whilst Abs were only detectable in 58% of asymptomatic carriers.

Glyphosate is a non-selective systemic herbicide used in agriculture. For almost half a century, the International Agency for Research on Cancer has run a Monographs program, the conclusion in March 2015 that glyphosate is “probably carcinogenic to humans” in addition to being genotoxic and carcinogenic in animals, while the regulatory European Food Safety Authority have asserted that glyphosate poses no public risk. The scientific debate is still lively. We collected detailed socio-demographic, occupational exposures and health surveillance information for 26 winegrowers as aim to investigate exposure to glyphosate and other pesticide. Exposure was assessed through biological monitoring (24-hour urine collection), immune function (IL-4, IL-5, IL-8, IL-12, IL- 17, IL-33, IFN- γ), transcriptional and post transcriptional alterations (miRNA) and genotoxic effects (Comet assay). The exposure conditions in our winegrowers, as referred to the parameters so far analyzed, did not reveal a significant glyphosate absorption nor significant health concerns.

Background: The SARS-CoV-2 vaccination campaign began on 27 December 2020 in Europe, primarily involving health workers. This study aimed to assess the SARS-CoV-2 vaccination effectiveness, as assessed by reductions in incidence, symptom severity, and further infection spreading. Methods: A retrospective cohort study was conducted on 9811 health workers operating at the Verona University Hospital, Italy, from 27 December 2020 to 3 May 2021. All health workers were offered vaccination with Comirnaty (BNT162b2, BioNTech/Pfizer, Mainz, Germany/New York, United States), and a health surveillance program was implemented with periodical swab testing. Vaccination status and clinical data were collected using an ad hoc semi-structured questionnaire and health surveillance charts. Results: As of 3rd of May, 82.5% of health workers had been vaccinated against SAR-CoV-2, and 177 (1.8%) had tested positive for SARS-CoV-2. Vaccination more than halved the cumulative incidence of SARS-CoV-2 infection and reduced by two-thirds the cumulative incidence of symptomatic subjects. In detail, most unvaccinated HWs were symptomatic; 50% reported fever, 45% reported ageusia/anosmia, and nearly 20% reported dyspnea. These percentages were much lower in HWs who had been vaccinated for at least 14 days (18% for fever and anosmia, 6% for dyspnea and ageusia). Moreover, cases of vaccine breakthrough were sixfold less likely to further spread the infection than unvaccinated HWs. Conclusions: SARS-CoV-2 vaccination reduced the infection frequency among HWs, further spreading of the infection, and the presence, severity, and duration of COVID-19-related symptoms.

Background: Genomic regions that confer susceptibility for bladder cancer have provided important insights into the mechanisms of this disease. Sixteen genomic regions harboring bladder cancer susceptibility loci have been reported to date. To identify additional loci associated with bladder cancer risk, we conducted a meta-analysis including data from previously published genome-wide association studies as well as unpublished data. Methods: Data from 32 studies including 13,790 bladder cancer cases and 343,502 controls of European ancestry were included. Stratified analyses by sex and smoking status, as well as heterogeneity in risk by muscle-invasiveness, were also conducted. We tested for multiplicative and additive interactions between cigarette smoking and susceptibility loci that achieved genome-wide significance. After genotyping, quality control, and imputation log-additive effects were calculated by study/array group using regression models adjusting for age and significant eigenvectors. Results were combined by meta-analysis using a fixed-effects model. Results: We report strengthened or independent signals in several previously published regions at 4p16.3 (TACC3, FGFR3), 5p15.33 (CLPTM1L, TERT) and 11p15.5 (TNNT3, LSP1), as well as nine novel loci. In addition, we observed the first evidence of effect modification by sex at the FGFR3 locus, with a stronger risk observed in women (pmultiplicative-interaction=0.002). Further, we confirmed an interaction between smoking and a susceptibility locus at 8p22 (NAT2), indicating an increased risk of bladder cancer among smokers with the NAT2 slow acetylation genotype/phenotype (pmultiplicative-interaction=0.001). We also identified additional multiplicative, as well as additive, interactions between several novel loci and cigarette smoking status. In addition, we are currently building a risk stratification model using the combined effects of smoking and genetic susceptibility to identify subgroups of individuals at higher and lower absolute risk of bladder cancer. Conclusions: This meta-analysis identified 3 novel loci in previously reported regions and 9 novel bladder cancer susceptibility loci in new regions. These results add to our knowledge of the genetic architecture of bladder cancer. In addition, observed gene-smoking interactions suggest that risk stratification models may have translational implications, informing future disease screening efforts. Citation Format: Stella Koutros, Lambertus A. Kiemeney, Roger L. Milne, Yuanqing Ye, Vijai Joseph, Jonine Figueroa, Nilanjan Chatterjee, Graham G. Giles, Michelle A. Hildebrandt, Lars Dyrskjot, Kenneth Offit, Manolis Kogevinas, Elisabete Weiderpass, Marjorie L. McCullough, Neal D. Freedman, Demetrius Albanes, Charles Kooperberg, Victoria Cortessis, Margaret R. Karagas, Dalsu Baris, Alison Johnson, Molly R. Schwenn, Helena Furberg, Dean F. Bajorin, Parichoy Pal Choudhury, Oscar Florez-Vargas, Olivier Cussenot, Geraldine Cancel-Tassin, Simone Benhamou, Peter Kraft, Stefano Porru, Mark P. Purdue, Katherine A. McGlynn, Cari M. Kitahara, Christopher A. Haiman, Mark H. Greene, Thorunn Rafnar, Stephen J. Chanock, Xifeng Wu, Francisco X. Real, Debra T. Silverman, Montserrat Garcia-Closas, Kari Stefansson, Ludmila Prokunina-Olsson, Nuria Malats, Nathaniel Rothman. Large-scale genome-wide association study identifies multiple novel germline susceptibility variants associated with bladder cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 826.

Background During the COVID-19 pandemic, swab tests proved to be effective in containing the infection and served as a means for early diagnosis and contact tracing. However, little evidence exists regarding the correct timing for the execution of the swab test, especially for asymptomatic individuals and health care workers. Objective The objective of this study was to analyze changes in the positive findings over time in individual SARS-CoV-2 swab tests during a health surveillance program. Methods The study was conducted with 2071 health care workers at the University Hospital of Verona, with a known date of close contact with a patient with COVID-19, between February 29 and April 17, 2020. The health care workers underwent a health surveillance program with repeated swab tests to track their virological status. A generalized additive mixed model was used to investigate how the probability of a positive test result changes over time since the last known date of close contact, in an overall sample of individuals who tested positive for COVID-19 and in a subset of individuals with an initial negative swab test finding before being proven positive, to assess different surveillance time intervals. Results Among the 2071 health care workers in this study, 191 (9.2%) tested positive for COVID-19, and 103 (54%) were asymptomatic with no differences based on sex or age. Among 49 (25.7%) cases, the initial swab test yielded negative findings after close contact with a patient with COVID-19. Sex, age, symptoms, and the time of sampling were not different between individuals with an initial negative swab test finding and those who initially tested positive after close contact. In the overall sample, the estimated probability of testing positive was 0.74 on day 1 after close contact, which increased to 0.77 between days 5 and 8. In the 3 different scenarios for scheduled repeated testing intervals (3, 5, and 7 days) in the subgroup of individuals with an initially negative swab test finding, the probability peaked on the sixth, ninth and tenth, and 13th and 14th days, respectively. Conclusions Swab tests can initially yield false-negative outcomes. The probability of testing positive increases from day 1, peaking between days 5 and 8 after close contact with a patient with COVID-19. Early testing, especially in this final time window, is recommended together with a health surveillance program scheduled in close intervals.

Objectives. To deal with biohazards in research laboratories (RL), identify exposure features, types and incidence of laboratory-acquired infections/diseases (LAI), and prevention strategies. Methods. Literature search and appraisal, non-systematic, last 40 years; legislation, guidelines and good practices evaluation. Results. Biohazards are relevant in RL, in various biomedical, agri-food and industrials sectors, with a variety of LAI (especially viruses and bacteria), modes of exposure and transmission; LAI decrease after preventive measures, vaccinations and clinical treatments; LAI underestimation, due to underreporting and subclinical LAI; need to implement and comply with well-known and available technical and scientific guidelines, good medical and laboratory practices; need for specific health education and training; lack of reporting and epidemiologic surveillance systems, with consequent limited data on risk assessment and effectiveness of preventive interventions. Conclusions. The roles of the occupational physician must be underlined, especially for risk assessment, health and clinicepidemiologic surveillance, with the need to monitor seconeffectiveness of preventive interventions, particularly for biosafety and biosecurity levels in RL. It should be useful to increase capacity of epidemiologic surveillance for LAI, through networking or dedicated websites, in order to collect and analyze accidents, injuries, infections, or adverse events occurred to workers in RL.Obiettivi. Trattare del rischio biologico (RB) nei laboratori di ricerca (LR), identificarne peculiarità per caratteristiche di esposizione, incidenza e tipologia di infezioni/malattie correlate (LAI) e per strategie preventive. Metodi. Ricerca e valutazione bibliografica non sistematica, ultimi 40 anni; valutazione legislazione, linee guida, buone prassi. Risultati. Emerge un RB nei LR in vari settori produttivi biomedici, agroalimentari, industriali, con varietà di LAI (soprattutto virus e batteri), di modalità di esposizione e trasmissione; riduzione delle LAI per misure preventive, efficacia trattamenti clinici e vaccinazioni, ma anche sottostima, per inadeguato reporting e LAI subcliniche; necessità di implementazione ed adesione a note linee guida tecnico-scientifiche e buone prassi già disponibili; necessità di informazione, formazione e addestramento specifici; assenza di sistemi di reporting e sorveglianza epidemiologica strutturati, con conseguente limitazione di dati su valutazione del rischio ed efficacia dei sistemi preventivi. Conclusioni. Si ribadisce il ruolo del medico del lavoro in particolare per valutazione del rischio, sorveglianza sanitaria e clinico-epidemiologica, con necessità di monitorare l’efficacia degli interventi di prevenzione, in particolare dei livelli di biosicurezza. Utile migliorare la capacità di sorveglianza epidemiologica delle LAI, ad esempio attraverso networking o portali dedicati a segnalazioni di infortuni, malattie ed eventi avversi occorsi ai lavoratori dei LR.

Introduction Exposure to biological agents occurs in many workplaces. Immunisation is a safe, cost-effective intervention for Vaccine Preventable Diseases (VPD). Although updated, evidence-based vaccination policies are available for the general population, overall there are few consensus recommendations for working populations apart from health care workers (HCWs). Methods To evaluate current trends and evidence-based options, we performed a literature review of main online databases from 1997 to 2017, websites of various public health organisations, and professional societies, focusing on vaccination policies and practices in occupational settings. Result Many vaccines are available for workers exposed to certain biological agents, while others are imminent. However, systematic, representative data on occupational immunisation policies, practices and coverage are lacking. Most pertain to HCWs, Influenza and HBV and coverage is sub-optimal. Variations exist by country and region for legislation, policies, schedules, groups requiring vaccination, implementation. Relevant issues include: access to vaccines; cost-effectiveness; immunisation coverage; identification susceptible of workers at-risk; fitness for work; involvement of all stakeholders. Discussion Immunisation is an additional preventive tool to conventional workplace interventions, very effective for biohazard containment. A specific immunisation policy and practice is a strategic priority for individual workers, different workforces and the public health system. The main Occupational Health Professionals’ (OHP) responsibilities are: individual, activity and area risk assessment; evaluation and provision of cost-effective vaccines; obtaining consent (or refusal) following counselling; managing non-responders and those who refuse vaccinations; career guidance; remaining updated. Mandatory immunisation should be explored in selected circumstances. OHP, employers and workers share the responsibility to implement the WHO Global Vaccine Action Plan to expand access to immunisation to all susceptible workers and strengthen routine immunisation. Policies and services should reside in the realm of Corporate Social Responsibility and be harmonised across industries, regions and countries with the ultimate goal to control and eradicate VPD in workplaces.

Background: Telomere length (TL) maintenance plays an important role in bladder cancer (BC) and prognosis. However the manifold influence of everyday life exposures and genetic traits on leucocyte TL (LTL), is not fully elucidated. Methods: Within the framework of a hospital-based case (n = 96)/control (n = 94) study (all Caucasian males), we investigated the extent to which LTL and BC risk were modulated by genetic polymorphisms and environmental and occupational exposures. Data on lifetime smoking, alcohol and coffee drinking, dietary habits and occupational exposures, pointing to aromatic amines (AAs) and polycyclic aromatic hydrocarbons (PAHs) were collected. Structural equation modelling (SEM) analysis appraised this complex relationships. Results: The SEM analysis indicates negative direct links (p < 0.05) between LTL with age, DNA adducts, alcohol and NAT2, and positive ones with coffee, MPO and XRCC3; and between BC risk (p < 0.01) with cigarettes, cumulative exposure to AAs and coffee, while are negative with LTL and age. There was evidence of indirect effects (p < 0.05) on BC risk, probably via LTL reduction, by age and NAT2 (positive link), MPO and XRCC3 (negative link). Conclusions: Our study supports evidence that LTL attrition is a critical event in BC. The new finding that LTL erosion depends on some preventable everyday life exposures genetically modulated, opens new perspectives in BC prevention.

A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell-cycle protein. We performed genetic fine-mapping analysis of the CCNE1 region using data from two bladder cancer GWAS (5,942 cases and 10,857 controls). We found that the original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2 ≥ 0.7) associated with increased bladder cancer risk. From this group, we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWASs, rs7257330 was associated only with aggressive bladder cancer, with a combined per-allele OR = 1.18 [95% confidence interval (CI), 1.09–1.27, P = 4.67 × 10−5] versus OR = 1.01 (95% CI, 0.93–1.10, P = 0.79) for nonaggressive disease, with P = 0.0015 for case-only analysis. Cyclin E protein expression analyzed in 265 bladder tumors was increased in aggressive tumors (P = 0.013) and, independently, with each rs7257330-A risk allele (Ptrend = 0.024). Overexpression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. In conclusion, we defined the 19q12 signal as the first GWAS signal specific for aggressive bladder cancer. Molecular mechanisms of this genetic association may be related to cyclin E overexpression and alteration of cell cycle in carriers of CCNE1 risk variants. In combination with established bladder cancer risk factors and other somatic and germline genetic markers, the CCNE1 variants could be useful for inclusion into bladder cancer risk prediction models. Cancer Res; 74(20); 5808–18. ©2014 AACR.

Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 x 10(-39); Region 3: rs2853677, P = 3.30 x 10(-36) and PConditional = 2.36 x 10(-8); Region 4: rs2736098, P = 3.87 x 10(-12) and PConditional = 5.19 x 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 x 10(-6); and Region 6: rs10069690, P = 7.49 x 10(-15) and PConditional = 5.35 x 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 x 10(-18) and PConditional = 7.06 x 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.

Occupational injuries are a relevant research and practical issue. However, intervention studies evaluating the effectiveness of workplace injury prevention programs are seldom performed.The effectiveness of a multifaceted intervention aimed at reducing occupational injury rates (incidence/employment-based=IR, frequency/hours-based=FR, severity=SR) was evaluated between 2008 and 2013 in 29 Italian foundries (22 ferrous; 7 non-ferrous; 3,460 male blue collar workers/year) of varying sizes. Each foundry established an internal multidisciplinary prevention team for risk assessment, monitoring and prevention of occupational injuries, involving employers, occupational physicians, safety personnel, workers' representatives, supervisors. Targets of intervention were workers, equipment, organization, workplace, job tasks. An interrupted time series (ITS) design was applied.4,604 occupational injuries and 83,156 lost workdays were registered between 2003 and 2013. Statistical analysis showed, after intervention, a reduction of all injury rates (-26% IR, -15% FR, -18% SR) in ferrous foundries and of SR (-4%) in non-ferrous foundries. A significant (p=0.021) 'step-effect' was shown for IR in ferrous foundries, independent of secular trends (p0.001). Sector-specific benchmarks for all injury rates were developed separately for ferrous and non-ferrous foundries.Strengths of the study were: ITS design, according to standardized quality criteria (i.e., at least three data points before and three data points after intervention; clearly defined intervention point); pragmatic approach, with good external validity; promotion of effective good practices. Main limitations were the non-randomized nature and a medium length post-intervention period. In conclusion, a multifaceted, pragmatic and accountable intervention is effective in reducing the burden of occupational injuries in small-, medium- and large-sized foundries. Practical Applications: The study poses the basis for feasible good practice guidelines to be implemented to prevent occupational injuries, by means of sector-specific numerical benchmarks, with potentially relevant impacts on workers, companies, occupational health professionals and society at large.

To access publisher full text version of this article. Please click on the hyperlink in Additional Links field. Three genome-wide association studies in Europe and the USA have reported eight urinary bladder cancer (UBC) susceptibility loci. Using extended case and control series and 1000 Genomes imputations of 5 340 737 single-nucleotide polymorphisms (SNPs), we searched for additional loci in the European GWAS. The discovery sample set consisted of 1631 cases and 3822 controls from the Netherlands and 603 cases and 37 781 controls from Iceland. For follow-up, we used 3790 cases and 7507 controls from 13 sample sets of European and Iranian ancestry. Based on the discovery analysis, we followed up signals in the urea transporter (UT) gene SLC14A. The strongest signal at this locus was represented by a SNP in intron 3, rs17674580, that reached genome-wide significance in the overall analysis of the discovery and follow-up groups: odds ratio = 1.17, P = 7.6 × 10(-11). SLC14A1 codes for UTs that define the Kidd blood group and are crucial for the maintenance of a constant urea concentration gradient in the renal medulla and, through this, the kidney's ability to concentrate urine. It is speculated that rs17674580, or other sequence variants in LD with it, indirectly modifies UBC risk by affecting urine production. If confirmed, this would support the 'urogenous contact hypothesis' that urine production and voiding frequency modify the risk of UBC. info:eu-repo/grantAgreement/EC/FP7/018827 info:eu-repo/grantAgreement/EC/FP7/218071 Radboud University Nijmegen Medical Centre (RUNMC) Prinses Beatrix Fonds VSB Fonds National Institute of Mental Health (NIH/NIMH) MH078075 Cancer Research UK Yorkshire Cancer Research European Union 513943 Compagnia di San Paolo-Human Genetics Foundation (HuGeF) Italian Association for Cancer Research, Italy Piedmont Region Progetti di Ricerca Sanitaria Finalizzata Flemish government Belgian province of Limburg Swedish Cancer Society Swedish Research Council Shiraz Institute for Cancer Research Shiraz, Iran ICR-87-502 Red Tematica de Investigacion Cooperativa en Cancer RD06/0020/1054

Contains fulltext : 81560.pdf (Publisher’s version ) (Closed access) The common sequence variants that have recently been associated with cancer risk are particular to a single cancer type or at most two. Following up on our genome-wide scan of basal cell carcinoma, we found that rs401681[C] on chromosome 5p15.33 satisfied our threshold for genome-wide significance (OR = 1.25, P = 3.7 x 10(-12)). We tested rs401681 for association with 16 additional cancer types in over 30,000 cancer cases and 45,000 controls and found association with lung cancer (OR = 1.15, P = 7.2 x 10(-8)) and urinary bladder, prostate and cervix cancer (ORs = 1.07-1.31, all P < 4 x 10(-4)). However, rs401681[C] seems to confer protection against cutaneous melanoma (OR = 0.88, P = 8.0 x 10(-4)). Notably, most of these cancer types have a strong environmental component to their risk. Investigation of the region led us to rs2736098[A], which showed stronger association with some cancer types. However, neither variant could fully account for the association of the other. rs2736098 corresponds to A305A in the telomerase reverse transcriptase (TERT) protein and rs401681 is in an intron of the CLPTM1L gene.

The aim of the study was to investigate NAT1, NAT2, GSTM1, GSTT1, GSTP1, SULT1A1, XRCC1, XRCC3 and XPD genetic polymorphisms, coffee consumption and risk of bladder cancer (BC) through a hospital-based case-control study. The study population included 197 incident BC cases and 211 controls. The association between genetic polymorphisms, coffee drinking and BC risk was assessed by logistic regression taking into account age, education, tobacco smoking and occupational exposures to polycyclic aromatic hydrocarbons and aromatic amines. No association was found between the genetic polymorphisms investigated and BC risk according to coffee consumption apart of a significant increased BC risk among GSTP1 105-114 Val carriers heavy coffee drinkers (3 cups/day) (OR 3.18, 95% CI 1.06-9.55). In conclusion our findings suggest a very limited role, if any, of genetic polymorphisms investigated in modulating the BC risk in coffee drinkers.

Occupational exposure to lung carcinogens is and was common in workplaces. 5–25 % of lung cancers (LCs) could be causally attributable to occupation; however, LC underreporting and undercompensation are widespread, with remarkable tolls paid by individuals and society. This work aims to: describe an ongoing hospital-based systematic search (SS) of occupational LC; improve aetiological diagnosis; increase number and quality of LC notifications. Through a short form, physicians at a public hospital referred incident LC to the Occupational Health Unit (OHU). Only patients selected through the form were interviewed; a personal, occupational and clinical history was collected; reports were sent to the ward and Local Health Authority, with aetiological diagnosis criteria and probability of causation. From 1998 to 2013, 3274 cases of LC were notified to the OHU; prior to the system, just couple of dozens were assessed. A total of 1522 patients were fully interviewed; in 395 cases, causation was attributed to occupation (26 % of interviewed patients); all were notified to authorities, as compared to the handful reported before the system was adopted. Main aetiological agents were silica, asbestos, polycyclic aromatic hydrocarbons, truck driving, painting, multiple exposures. Compensation rate was remarkable (39 %). Through SS, many occupational LCs were found that otherwise would have been lost. Aetiological diagnosis proved to be rich of scientific advantages and practical implications, with attention to equity and social aspects. SS was easy, accountable and fostered multidisciplinary collaboration among medical specialties, significantly reducing underreporting and undercompensation of occupational LC.

We pooled the data from 6 case-control studies of bladder cancer with detailed information on fluid intake and water pollutants, particularly trihalomethanes (THM), and evaluated the bladder cancer risk associated with total and specific fluid consumption. The analysis included 2,729 cases and 5,150 controls. Odds ratios (OR) and 95% confidence intervals (CI) for fluid consumption were adjusted for age, gender, study, smoking status, occupation and education. Total fluid intake was associated with an increased risk of bladder cancer in men. The adjusted OR for 1 l/day increase in intake was 1.08, (95% CI 1.03–1.14, p-value for linear trend 3.5 l/day) as compared to those in the lowest (≤2 l/day). An increased risk was associated with intake of tap water. OR for >2 l/day vs. ≤0.5 l/day was 1.46 (1.20–1.78), with a higher risk among men (OR = 1.50, 1.21–1.88). No increased risk was observed for the same intake groups of nontap water in men (OR = 0.97, 0.77–1.22) or in women (OR = 0.85, 0.50–1.42). Increased bladder cancer risks were observed for an intake of >5 cups of coffee daily vs.

Tobacco smoking and occupational exposure are major risk factors of bladder cancer via exposure to polycyclic aromatic hydrocarbons (PAHs) and aromatic amines, which lead to oxidative stress and DNA damage. Several enzymes, which play key roles in oxidative stress are polymorphic in humans. Myeloperoxidase (MPO) produces a strong oxidant for microbicidal activity, and activates carcinogens in tobacco smoke. Catechol-O-methyltransferase (COMT) catalyzes the methylation of endo- and xenobiotics and prevents redox cycling. NAD(P)H:quinone oxidoreductase (NQO1) catalyzes the two-electron reduction of quinoid compounds, which also protects cells from redox cycling. Manganese superoxide dismutase (MnSOD) protects cells from free radical injury. To test the hypothesis that the risk of bladder cancer can be influenced by polymorphisms in the genes that modulate oxidative stress, in particular by interacting with environmental carcinogens, we conducted a hospital-based case-control study among men in Brescia, Northern Italy. We recruited and interviewed 201 incident cases and 214 controls from 1997 to 2000. Occupational exposures to PAHs and aromatic amines were coded blindly by occupational physicians. Unconditional multivariate logistic regression was applied to model the association between genetic polymorphisms and bladder cancer risk and the effect of modifications of smoking and occupational exposures were evaluated. MPO G-463A homozygous variant was associated with a reduced risk of bladder cancer with an OR of 0.31 (95% CI = 0.12-0.80). MnSOD Val/Val genotype increased the risk of bladder cancer with OR of 1.91 (95% CI = 1.20-3.04), and there was a combined effect with smoking (OR = 7.20, 95% CI = 3.23-16.1) and PAH (OR = 3.02,95% CI = 1.35-6.74). We did not observe an effect of COMT Val108Met polymorphism. These findings suggest that individual susceptibility of bladder cancer may be modulated by MPO and MnSOD polymorphisms, and that the combination of genetic factors involved in oxidative stress response with environmental carcinogens may play an important role in bladder carcinogenesis. © Oxford University Press 2004; all rights reserved.

Objectives: We examined which occupations and industries are currently at high risk for bladder cancer in men. Methods: We combined data from 11 case–control studies conducted between 1976–1996 in six European countries. The study comprised 3346 incident cases and 6840 controls, aged 30–79 years. Lifetime occupational and smoking histories were examined using common coding. Results: Odds ratios for eight a priori defined high-risk occupations were low, and with the exception of metal workers and machinists (OR = 1.16, 95% CI = 1.02–1.32), were not statistically significant. Higher risks were observed for specific categories of painters, metal, textile and electrical workers, for miners, transport operators, excavating-machine operators, and also for non-industrial workers such as concierges and janitors. Industries entailing a high risk included salt mining, manufacture of carpets, paints, plastics and industrial chemicals. An increased risk was found for exposure to PAHs (OR for highest exposure tertile = 1.23, 95% CI = 1.07–1.4). The risk attributable to occupation ranged from 4.2 to 7.4%, with an estimated 4.3% for exposure to PAHs. Conclusions: Metal workers, machinists, transport equipment operators and miners are among the major occupations contributing to occupational bladder cancer in men in Western Europe. In this population one in 10 to one in 20 cancers of the bladder can be attributed to occupation.

Bladder cancer is a complex disease with known environmental and genetic risk factors. We performed a genome-wide interaction study (GWAS) of smoking and bladder cancer risk based on primary scan data from 3002 cases and 4411 controls from the National Cancer Institute Bladder Cancer GWAS. Alternative methods were used to evaluate both additive and multiplicative interactions between individual single nucleotide polymorphisms (SNPs) and smoking exposure. SNPs with interaction P values < 5 × 10(-) (5) were evaluated further in an independent dataset of 2422 bladder cancer cases and 5751 controls. We identified 10 SNPs that showed association in a consistent manner with the initial dataset and in the combined dataset, providing evidence of interaction with tobacco use. Further, two of these novel SNPs showed strong evidence of association with bladder cancer in tobacco use subgroups that approached genome-wide significance. Specifically, rs1711973 (FOXF2) on 6p25.3 was a susceptibility SNP for never smokers [combined odds ratio (OR) = 1.34, 95% confidence interval (CI) = 1.20-1.50, P value = 5.18 × 10(-) (7)]; and rs12216499 (RSPH3-TAGAP-EZR) on 6q25.3 was a susceptibility SNP for ever smokers (combined OR = 0.75, 95% CI = 0.67-0.84, P value = 6.35 × 10(-) (7)). In our analysis of smoking and bladder cancer, the tests for multiplicative interaction seemed to more commonly identify susceptibility loci with associations in never smokers, whereas the additive interaction analysis identified more loci with associations among smokers-including the known smoking and NAT2 acetylation interaction. Our findings provide additional evidence of gene-environment interactions for tobacco and bladder cancer.

Background: Coffee consumption has been associated with an excess bladder cancer risk, but results from epidemiological studies are inconsistent. This association has been long debated, in part due to the potential confounding by smoking. We examined the risk associated with coffee consumption in nonsmokers in a pooled analysis of ten European bladder cancer case–control studies. Methods: The pooled data set comprises 564 cases and 2929 hospital or population controls who had never smoked. They were enrolled in ten studies conducted in Denmark, Germany, Greece, France, Italy and Spain. Information on coffee consumption and occupation was re-coded following standard criteria. Unconditional logistic regression was applied adjusting for age, study center, occupation and gender. Results: Seventy-nine percent of the study population reported having drunk coffee, and 2.4% were heavy drinkers, reporting having drunk on average ten or more cups per day. There was no excess risk in ever coffee drinkers (OR = 1.0, 95% CI 0.8–1.3) compared to never drinkers. The risk did not increase monotonically with dose but a statistically significant excess risk was seen for subjects having drunk ten or more cups per day (OR = 1.8, 95% CI 1.0–3.3). This excess was seen in both men and women. There was no evidence of an association of the risk with duration or type of coffee consumption. The pooled results were not dependent on the findings of any specific study, but they depended on the type of controls with an overall excess risk observed only for studies using hospital controls. Conclusion: Nonsmokers who are heavy coffee drinkers may have a small excess risk of bladder cancer. Although these results cannot be attributed to confounding by smoking, the possibility of bias in control selection cannot be discarded. On the basis of these results, only a very small proportion of cancers of the bladder among nonsmokers could be attributed to coffee drinking.

Background: In studies in men, risk estimates on occupation and bladder cancer are distorted by about 10% when not adjusting for smoking. We examined the degree to which occupational risk estimates for bladder cancer in women are confounded by smoking, and the degree of residual confounding by inadequate control of this effect. Methods: Primary data of 11 case-control studies on occupation and bladder cancer from Denmark, France, Germany, Greece, Italy, and Spain were pooled. Information for smoking and lifetime occupational history for 700 female cases and 2,425 female controls ages 30–79 was abstracted and recoded. Logistic regression was used to calculate odds ratios (OR) by occupation, applying five models which differed in their degree of adjustment for smoking. Results: In major occupational groups, risk estimates were distorted by less than 10% when not adjusting for smoking. A statistically significant excess risk for bladder cancer was found in 13 specific occupations and industries. In most occupations, adjustment for smoking led the ORs towards the null value, but all statistically significant associations were maintained after adjustment. In three occupations (lathe operators, field crop workers, and wood manufacturers), a statistically significant excess risk was masked when not adjusting for smoking. In six occupations, estimates were distorted by more than 10% (−22% up to +40%). In occupations where smoking acted as a positive confounder, the proportion of confounding removed using a dichotomous smoking variable (ever/never) was around 60%. In one occupation (buyers), controlling for smoking status (ever, never) led to over-adjustment, because the percentage of smokers was high but the quantity smoked was low. Conclusions: Tobacco smoking was not found to be a major confounder for the association between occupation and bladder cancer in women. Most of this confounding effect could be removed by adjustment by smoking status (ever/never), without consideration of amount or duration of smoking. Am. J. Ind. Med. 36:75–82, 1999. © 1999 Wiley-Liss, Inc.

Objectives: We examined the importance of occupational exposures for bladder cancer in women. Methods: We combined data from 11 case-control studies conducted between 1976 and 1996 in six European countries. The pooled data comprised 700 incident female cases and 2425 population or hospital controls, aged 3079 years. Lifetime occupational and smoking history were examined using common coding. Results: Excess risks were found in only a few of the occupations previously identified at high risk for bladder cancer. Statistically significant excess risks were observed for metal workers, particularly blacksmiths, toolmakers and machine tool operators (OR: 2.0, 95% CI: 1.1-3.6), tobacco workers (OR: 3.1, 95% CI: 1.1-9.3), field crop and vegetable farm workers (OR: 1.8, 95% CI: 1.0-3.1), tailors and dress makers (OR: 1.4, 95% CI: 1.0-2.1), saleswomen (OR: 2.6, 95% CI: 1.0-6.9), and mail sorting clerks (OR: 4.4, 95% CI: 1.0-19.5). About 8% (95% CI: 3.1-19.9) of all bladder cancers in women could be attributed to occupation after adjusting for smoking. The attributable risk was higher in women aged less than 65 years (12%), compared to older women (4%). Conclusions: The calculation of the attributable risk on the basis of results from this analysis may have caused some overestimation of the proportion of occupational bladder cancer in women. A significant proportion, however, of bladder cancer cases among European women less than 65 years is likely to be attributed to occupation. This link between bladder cancer in women and occupational factors has received little recognition, probably because studies addressing these issues have predominantly been done in men.

A study on the reliability of information on smoking habits and coffee drinking collected via interview was conducted among 500 subjects enrolled in a case-control study on bladder cancer in Brescia, North Italy. A total of 215 cases (incident and prevalent) and 285 controls were interviewed personally in the hospital setting by a first interviewer, and then re-interviewed by telephone by either the same interviewer or another one. Agreement between the first and second interview was evaluated using the kappa statistic and the intra-class correlation coefficient and via multiple logistic regression modelling. No important differences in reliability were found according to sex, education or case/control status, while agreement was better among subjects below 65 than among older ones, and among incident than prevalent cases. A slightly better agreement was found among subjects interviewed twice by the same interviewer than those interviewed by two different individuals, which may reflect the presence of inter-observer reliability for the latter. Overall, these results show a very high reliability of data on smoking and a fairly high reliability regarding coffee drinking as collected through face-to-face interviews.

The association between tobacco smoking, the consumption of coffee and alcohol and bladder cancer was investigated in a hospital-based case-control study in Brescia, northern Italy. A total of 172 incident cases (135 men and 37 women) and 578 controls (398 men and 180 women) were enrolled. As expected, cigarette smoking was strongly associated with bladder cancer. The odds ratios (OR) for coffee drinking adjusted for age, education, residence and cigarette smoking in current drinkers were 2.6 (95% confidence interval, CI: 1.1–6.1) in men and 5.2 (95% CI: 1.0–30.4) in women. A dose-response relationship was found in men, with the highest risk in the highest category of exposure: drinkers of more than 5 cups per day had an OR of 4.5 (95% CI: 1.2–16.8). The ORs for current alcohol drinkers were 2.1 (95% CI: 1.0–4.8) in men and 3.4 (95% CI: 1.2–9.7) in women; according to grams of ethanol drunk per day (grams/day, g/d) the ORs were: 1.7 (1–20 g/d), 1.6 (21–40 g/d), 4.3 (41–60 g/d) and 4.6 (61+ g/d) in men and 3.1 (1–20 g/d) and 3.9 (21+ g/d) in women. These results suggest that regular consumption of both coffee and alcohol can be independently associated with an increased bladder cancer risk.

OBJECTIVES--A hospital based case-control study was conducted between 1992 and 1993 in the province of Brescia, a highly industrialised area in northern Italy, to evaluate occupational risk factors of bladder cancer. METHODS--The study evaluated 355 histologically confirmed cases of bladder cancer (275 men, 80 women) and 579 controls affected by urological non-neoplastic diseases (397 men, 182 women). Lifetime occupational history, smoking and drinking habits, and sociodemographic characteristics were recorded by means of a structured questionnaire. Odds ratios (ORs) were computed with adjustment for age, smoking, alcohol and coffee consumption, education, and place of residence. RESULTS--A significant (P < 0.05) increase of risk of bladder cancer were found in men for labourers in the construction industry (OR 2.1, 95% confidence interval (95% CI) 1.1-3.9) and for recreational and cultural services (OR 5.0, 95% CI 1.3-18.9). Increased risks, although not significant, were found for various other occupations and industries such as machinery mechanics, metal processers and polishers, blacksmiths, gunsmiths, painters; for transport workers, an increased risk with increasing duration of employment was found. CONCLUSIONS--Occupational exposures seem to contribute to bladder cancer risk in the area under study.

Tobacco smoking is the most important and well-established bladder cancer risk factor and a rich source of chemical carcinogens and reactive oxygen species that can induce damage to DNA in urothelial cells. Therefore, common variation in DNA repair genes might modify bladder cancer risk. In this study, we present results from meta-analyses and pooled analyses conducted as part of the International Consortium of Bladder Cancer. We included data on 10 single nucleotide polymorphisms corresponding to seven DNA repair genes from 13 studies. Pooled analyses and meta-analyses included 5,282 cases and 5,954 controls of non-Latino white origin. We found evidence for weak but consistent associations with ERCC2 D312N [rs1799793; per-allele odds ratio (OR), 1.10; 95% confidence interval (95% CI), 1.01-1.19; P = 0.021], NBN E185Q (rs1805794; per-allele OR, 1.09; 95% CI, 1.01-1.18; P = 0.028), and XPC A499V (rs2228000; per-allele OR, 1.10; 95% CI, 1.00-1.21; P = 0.044). The association with NBN E185Q was limited to ever smokers (interaction P = 0.002) and was strongest for the highest levels of smoking dose and smoking duration. Overall, our study provides the strongest evidence to date for a role of common variants in DNA repair genes in bladder carcinogenesis. The TBCS was supported by a grant to ECNIS, a network of excellence operating within the European Union 6th Framework Program, Priority 5: ‘‘Food Quality and Safety’’ (contract no. 513943), by a grant of the Italian Association for Cancer Research, of the Piedmont Region Progetti di Ricerca Sanitaria Finalizzata, and of the Ministry of Health, Oncology Integrated Project ‘‘Cancer Primary Prevention in Italy: a research-based approach,’’ Italy.

BACKGROUND: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites.METHODS: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers.RESULTS: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, hl (2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (ρ = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (ρ = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (ρ = 0.51, SE =0.18), and bladder and lung (ρ = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures.CONCLUSION: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.

Objectives: To highlight the role of occupational physician (OP) in occupational injuries (OI) prevention and management. To suggest an approach beyond traditional focus on descriptive epidemiology, engineering interventions, administrative aspects of OI prevention. To promote a person- and enterprise-tailored approach, entailing greater attention to human factors and to practical problems of the specific workplace, with a call to a leading role played by OP. Methods and results: Analysis of the literature on the broader topic of OI prevention revealed thousands of publications; however, only a handful of them mention or describe the participation of OP in OI prevention. While recognizing that literature search is not the proper and only way to appreciate the current role of OP in this field, therefore, it seems necessary to call OP to a stronger effort in prevention and management of OI, through the context of a comprehensive intervention in cooperation with managers, supervisors, safety personnel and workers, focusing on specific needs of each enterprise. The following areas of OP intervention were examined: risk assessment, health surveillance, management, scientific research and health education. Within each of these topics, possible contributions, methodologies, instruments available for the OP were discussed, taking into account the relevant literature. Pathways for practical applications were illustrated, e.g., OI data generation and analyses, predictors of OI, fitness for work, case management, team work, educational issues, first aid, suggestion for OP contribution in specific research questions. Conclusions: OI continue to take a remarkable toll from individuals and society. New multidisciplinary interventions are needed to prevent OI. Focused activities at the single worksite with a central role from OP are definite options. OP is an effective interface between workforce and management and may offer, through a proactive approach, valuable practical and cultural contributions, while respecting technical and ethical guidelines of occupational health professionals.

Background: Exposure to disinfection byproducts in drinking water has been associated with an increased risk of bladder cancer. We pooled the primary data from 6 case-control studies of bladder cancer that used trihalomethanes as a marker of disinfection byproducts. Methods: Two studies were included from the United States and one each from Canada, France, Italy, and Finland. Inclusion criteria were availability of detailed data on trihalomethane exposure and individual water consumption. The analysis included 2806 cases and 5254 controls, all of whom had measures of known exposure for at least 70% of the exposure window of 40 years before the interview. Cumulative exposure to trihalomethanes was estimated by combining individual year-by-year average trihalomethane level and daily tap water consumption. Results: There was an adjusted odds ratio (OR) of 1.24 in men exposed to an average of more than 1 g/L (ppb) trihalomethanes compared with those who had lower or no exposure (95% confidence interval [CI] 1.09 ‐1.41). Estimated relative risks increased with increasing exposure, with an OR of 1.44 (1.20 ‐1.73) for exposure higher than 50 g/L (ppb). Similar results were found with other indices of trihalomethane exposure. Among women, trihalomethane exposure was not associated with bladder cancer risk (0.95; 0.76 ‐1.20). Conclusions: These findings strengthen the hypothesis that the risk of bladder cancer is increased with long-term exposure to disinfection byproducts at levels currently observed in many industrialized countries. (Epidemiology 2004;15: 357‐367)

The authors investigated the dose-effect relation between alcohol drinking and hepatocellular carcinoma (HCC) in men and women separately, also considering hepatitis B and hepatitis C virus infections. They enrolled 464 subjects (380 men) with a first diagnosis of HCC as cases and 824 subjects (686 men) unaffected by hepatic diseases as controls; all were hospitalized in Brescia, northern Italy, in 1995-2000. Spline regression models showed a steady linear increase in the odds ratio of HCC for increasing alcohol intake, for values of >60 g of ethanol per day, with no substantial differences between men and women. Duration of drinking and age at start had no effect on the odds ratio when alcohol intake was considered. Former drinkers who had stopped 1-10 years previously had a higher risk of HCC than current drinkers did. The effect of alcohol drinking was evident even in the absence of hepatitis B or hepatitis C virus infection. In addition, a synergism between alcohol drinking and either infection was found, with approximately a twofold increase in the odds ratio for each hepatitis virus infection for drinkers of >60 g per day.