BACKGROUND:Shift work can disrupt circadian rhythms and is postulated to play a role in cardiovascular diseases (CVD). In the German prospective population-based Heinz Nixdorf Recall Study, we analyzed longitudinal associations between shift work and night-shift work with CVD. METHODS:CVD was defined as a fatal or non-fatal cardiac or cerebrovascular event or interventional coronary revascularization during an average follow-up of 15 years. Retrospective shift-work information was assessed as binary and as lifetime duration in years. Adjusted log-linear Poisson regression models were applied to estimate incidence rate ratios (IRR) and 95% confidence intervals (CI) for the effect of shift and night-shift work on incident events. Stratified analyses by sex, diurnal preference, and blue-collar status were also performed. RESULTS:Incident CVD was not associated with shift work (N = 3024; shift work for at least 1 year: IRR = 0.87, 95% CI = 0.68-1.10; night-shift work for at least 1 year: IRR = 0.87, 95% CI = 0.66-1.14). However, we observed sex differences with reduced incidence of CVD for long duration of night-shift work among men (N = 1369 with 380 night-shift workers; model for duration of night-shift work: 1- < 10 years: IRR = 1.08, 95% CI = 0.74-1.57; 10+ years: IRR = 0.64, 95% CI = 0.42-0.96). For women, we found slightly elevated IRRs (N = 1438 with 91 night-shift workers; model for duration of night-shift work: 1- < 10 years: IRR = 1.11, 95% CI = 0.35-3.50; 10+ years: IRR = 2.05, 95% CI = 0.75-5.61). These estimates were stronger in women that never worked in blue-collar jobs (10+ years night-shift work: IRR = 3.22, 95% CI = 1.17-8.92). CONCLUSIONS:We did not observe consistently increased risks of CVD with shift and night workers. However, stratified analyses pointed toward sex- and job-specific vulnerable subgroups.

The reliable assessment of characteristics of shift-work exposure remains a critical methodological issue in epidemiological studies. A working group of the International Agency for Research on Cancer developed recommendations for the assessment of shift-work. These were translated into a detailed interview for the 10-year follow-up of the Heinz Nixdorf Recall (HNR) cohort. This study investigated the agreement of shift-work characteristics between three different assessments that were administered in interviews at two time points. At the study baseline (2000-2003), 4,814 participants were enrolled, and brief shift-work information was collected for 2,121 working participants (1,244 men and 877 women aged 45-75 years). Of 2,613 cohort members in the prospective 10-year follow-up between 2011 and 2013, 2,444 (also non-working) individuals participated in detailed shift-work interviews that consisted of (a) key summary questions and (b) period-based shift-work histories. participants' shift-work exposures up to the study baseline were compared in 1,217 subjects who were interviewed during both the baseline and the follow-up. Within the follow-up, participant responses to key summary questions were compared with calculated parameters from period-based histories. Agreement was measured by simple agreement (%), Gwet's agreement coefficient 1 (Gwet's AC1), and intraclass correlation coefficients (ICC) with 95% confidence intervals (CI). Beta-regression models were applied to investigate potential associations between age and sex with the reliability of shift-work characteristics. A high level of agreement was found between ever having worked shift-work (ever shift-work) and duration that each participant worked shift-work (duration of shift-work) reported during baseline and at follow-up (ever shift-work until study baseline in men: Gwet's AC1 = 0.77 (CI 0.72-0.82)). When comparing key summary questions and detailed shift-work histories, the duration of shift-work showed a high level of reliability that marginally decreased with age (in women ICC = 0.96 (CI 0.95-0.97), linear effect of age groups on µ: p = 0.08). Participants had problems remembering more detailed shift-work information. Ever shift-work and duration of shift-work can be assessed with key summary questions but reliability slightly decreases with age.

Analyses of adverse events (AEs) are an important aspect of the evaluation of experimental therapies. The SAVVY (Survival analysis for AdVerse events with Varying follow-up times) project aims to improve the analyses of AE data in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times, censoring, and competing events (CE). An empirical study including 17 randomized clinical trials investigates the impact on comparisons of two treatment arms with respect to AE risks. The comparisons of relative risks (RR) of standard probability-based estimators to the gold-standard Aalen-Johansen estimator or hazard-based estimators to an estimated hazard ratio (HR) from Cox regression are done descriptively, with graphical displays, and using a random effects meta-analysis on AE level. The influence of different factors on the size of the bias is investigated in a meta-regression. We find that for both, avoiding bias and categorization of evidence with respect to treatment effect on AE risk into categories, the choice of the estimator is key and more important than features of the underlying data such as percentage of censoring, CEs, amount of follow-up, or value of the gold-standard RR. There is an urgent need to improve the guidelines of reporting AEs.

BACKGROUND:To reduce the risk of invasive aspergillosis (IA), air purification by high-efficiency particulate air filtration and laminar air flow (HEPA/LAF) is standard of care in allogeneic blood stem cell transplantation. Its use in non-transplant haematological patients is inconsistent. OBJECTIVES:We sought to assess the incidence and outcome of pulmonary IA in non-transplant patients with life-threatening neutropenia by comparing an ambient air hospitalisation period (2008-2011) with a subsequent HEPA/LAF hospitalisation period (2012-2014). PATIENTS AND METHODS:We compared 204 consecutive patients with acute myeloid leukaemia, acute lymphoblastic leukaemia or aplastic anaemia completing 534 neutropenia-related hospitalisations under ambient air conditions with 126 such patients completing 437 neutropenia-related hospitalisations under HEPA/LAF conditions. IA was defined using the 2008 EORTC/MSG criteria. RESULTS:Within a 7-year study period, we observed one 'proven', three 'probable' and 73 'possible' IAs, most often during acute leukaemia remission induction. Their frequency rose with increasing duration of life-threatening neutropenia (1-10 days, 1.8%; >40 days, 35.2%) and concomitant severe anaemia (0 days, 3.2%; >20 days, 31.0%). Multiple logistic regression revealed a strong correlation between IA incidence and hospitalisation under HEPA/LAF conditions (odds ratio [OR], 0.368 [95% confidence interval, 0.207-0.654]; p < .001) and duration of neutropenia (OR, 1.043 [1.023-1.062] per day; p < .001) and anaemia (OR, 1.044 [1.008-1.081] per day; p = .016). IA-associated fatal outcomes were non-significantly reduced under HEPA/LAF (OR, 0.077 [0.005-1.151]; p = .063). The protective effect of HEPA/LAF was not seen under posaconazole prophylaxis (OR, 0.856 [0.376-1.950]; p = .711). CONCLUSIONS:Implementation of HEPA/LAF was associated with a significant reduction in neutropenia-related IA in non-transplant haematological patients.

We studied the association between shift work and depressive symptoms in the prospective Heinz Nixdorf Recall Study, considering various demographic, lifestyle and work-related factors. Depressive symptoms were assessed using the Center for Epidemiologic Studies-Depression (CES-D)-Scale (>= 17 points defined as high symptoms) and the Patient Health Questionnaire (PHQ) with a cutoff >= 9, or prescription of an anti-depressant. The definition of shift work included work hours outside 7:00 to 18:00, whereas night work was defined as a shift including work between 0:00 and 5:00. Poisson regression with robust error variances was calculated to estimate relative risks (RR) and 95% confidence intervals (CI), adjusted for age at follow-up, diurnal preference, monthly household income and education. Analyses were stratified by sex. We performed various sensitivity and stratified analyses to test the robustness of our results. At baseline, 1,500 gainfully employed subjects, 45-73 years of age and without a history of depression, were included. Until the 5-year follow-up, 896 participants were observed, and 486 participants survived through the 10-year follow-up. Although most analyses did not reach the level of formal statistical significance, women working night shifts tended to show increased relative risks for depressive symptoms according to the PHQ (RR = 1.78; 95% CI 0.71-4.45), in particular when working night shifts for >= 20 years (RR = 2.70; 95% CI 0.48-15.4). Stratification by age group revealed no increased risks among women above 60 years of age. Stratified analyses indicated that over-commitment was associated with higher risks for depressive symptoms among women (RR = 4.59; 95% CI 0.95-22.2 in the CES-D and RR = 12.7; 95% CI 2.89-56.1 in the PHQ). Exclusion of subgroups for the purpose of sensitivity analyses generally strengthened associations in women, whereas little evidence for an increased risk of depression remained among male shift workers. In summary, negative effects on depression were suggested among female shift workers, although results were based on small numbers. Among men, we did not identify consistently increased risks for depressive symptoms in relation to shift work.

Background: Residential exposure to air pollution (AP) has been shown to activate the immune system (IS). Although innate immune responses to AP have been studied extensively, investigations on the adaptive IS are scarce. Objectives: The aim of this study was to investigate the association between short- to long-term AP exposure and polyclonal free light chains (FLC) produced by plasma cells. Methods: We used repeated data from three examinations (t0: 2000–2003; t1: 2006–2008; and t2: 2011–2015) of the population-based German Heinz Nixdorf Recall cohort of initially 4,814 participants (45–75 y old). Residential exposure to total and source-specific particulate matter (PM) with an aerodynamic diameter of 10 or 2.5μm (PM10 and PM2.5 respectively), nitrogen dioxide (NO2), and particle number concentrations (accumulation mode; PNAM) was estimated using a chemistry transport model with different time windows (1- to 365-d mean ± standard deviation) before blood draw. We applied linear mixed models with a random participant intercept to estimate associations between total, traffic- and industry-related AP exposures and log-transformed FLC, controlling for examination time, sociodemographic and lifestyle variables, estimated glomerular filtration rate and season. Results: Analyzing 9,933 observations from 4,455 participants, we observed generally positive associations between AP exposures and FLC. We observed strongest associations with middle-term exposures, e.g., 3.0% increase in FLC (95% confidence interval: 1.8%, 4.3%) per interquartile range increase in 91-d mean of NO2 (14.1μg/m³). Across the different pollutants, NO2 showed strongest associations with FLC, followed by PM10 and PNAM. Effect estimates for traffic-related exposures were mostly higher compared with total exposures. Although NO2 and PNAM estimates remained stable upon adjustment for PM, PM estimates decreased considerably upon adjustment for NO2 and PNAM. Discussion: Our results suggest that middle-term AP exposures in particular might be positively associated with activation of the adaptive IS. Traffic-related PM, PNAM, and NO2 showed strongest associations. https://doi.org/10.1289/EHP7164

BackgroundThe SAVVY project aims to improve the analyses of adverse events (AEs), whether prespecified or emerging, in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times and competing events (CEs). Although statistical methodologies have advanced, in AE analyses, often the incidence proportion, the incidence density, or a non-parametric Kaplan-Meier estimator are used, which ignore either censoring or CEs. In an empirical study including randomized clinical trials from several sponsor organizations, these potential sources of bias are investigated. The main purpose is to compare the estimators that are typically used to quantify AE risk within trial arms to the non-parametric Aalen-Johansen estimator as the gold-standard for estimating cumulative AE probabilities. A follow-up paper will consider consequences when comparing safety between treatment groups.MethodsEstimators are compared with descriptive statistics, graphical displays, and a more formal assessment using a random effects meta-analysis. The influence of different factors on the size of deviations from the gold-standard is investigated in a meta-regression. Comparisons are conducted at the maximum follow-up time and at earlier evaluation times. CEs definition does not only include death before AE but also end of follow-up for AEs due to events related to the disease course or safety of the treatment.ResultsTen sponsor organizations provided 17 clinical trials including 186 types of investigated AEs. The one minus Kaplan-Meier estimator was on average about 1.2-fold larger than the Aalen-Johansen estimator and the probability transform of the incidence density ignoring CEs was even 2-fold larger. The average bias using the incidence proportion was less than 5%. Assuming constant hazards using incidence densities was hardly an issue provided that CEs were accounted for. The meta-regression showed that the bias depended mainly on the amount of censoring and on the amount of CEs.ConclusionsThe choice of the estimator of the cumulative AE probability and the definition of CEs are crucial. We recommend using the Aalen-Johansen estimator with an appropriate definition of CEs whenever the risk for AEs is to be quantified and to change the guidelines accordingly.

The association between shift work and the risk of colorectal cancer (CRC) is still unclear. Therefore, we studied the associations between exposure to shift or night work and incident CRC in two German population-based cohort studies, the Heinz Nixdorf Recall Study (HNR) and the Study of Health in Pomerania (SHIP). Including up to 6,903 participants, we analyzed the cohorts pooled and individually. We estimated incidence rate ratios (IRRs) with adjusted log-linear Poisson regression models with the natural logarithm of person-years as offset and performed subgroup analyses by sex and tumor localization in HNR. The pooled analysis revealed no increased risks for men working in night shifts (IRR: 1.03, 95% CI: 0.62; 1.71). In male HNR participants, we found an increased risk estimate for cancer of the distal colon in shift workers (IRR: 1.60, 95% CI: 0.53; 4.87) and in shift workers who did not perform night work (IRR: 3.93, 95% CI: 0.98; 15.70), but not in night workers. In SHIP, we observed elevated CRC risk estimates for rotating shift work including night work (IRR: 1.45, 95% CI: 0.72; 2.92) and for long-term exposure (IRR: 1.79, 95% CI: 0.81; 3.92) for men. In conclusion, night-shift work was not associated with CRC, although an increased risk was suggested for rotating shift work including nights in SHIP. The heterogeneity of shift-work jobs and schedules and associated lifestyle factors should be taken into account to disentangle a possible relationship between shift work and the risk for CRC in future investigations.

Analyses of adverse events (AEs) are an important aspect of the evaluation of experimental therapies. The SAVVY (Survival analysis for AdVerse events with Varying follow-up times) project aims to improve the analyses of AE data in clinical trials through the use of survival techniques appropriately dealing with varying follow-up times, censoring, and competing events (CE). In an empirical study including seventeen randomized clinical trials the effect of varying follow-up times, censoring, and competing events on comparisons of two treatment arms with respect to AE risks is investigated. The comparisons of relative risks (RR) of standard probability-based estimators to the gold-standard Aalen-Johansen estimator or hazard-based estimators to an estimated hazard ratio (HR) from Cox regression are done descriptively, with graphical displays, and using a random effects meta-analysis on AE level. The influence of different factors on the size of the bias is investigated in a meta-regression. We find that for both, avoiding bias and categorization of evidence with respect to treatment effect on AE risk into categories, the choice of the estimator is key and more important than features of the underlying data such as percentage of censoring, CEs, amount of follow-up, or value of the gold-standard RR. There is an urgent need to improve the guidelines of reporting AEs so that incidence proportions are finally replaced by the Aalen-Johansen estimator - rather than by Kaplan-Meier - with appropriate definition of CEs. For RRs based on hazards, the HR based on Cox regression has better properties than the ratio of incidence densities.

Objectives The GMALL-B-ALL/NHL2002 protocol is effective in Burkitt lymphoma/leukemia (BL). Its role in other aggressive lymphomas and in patients with simultaneous central nervous system (CNS) and peripheral involvement is unclear. Methods This is a retrospective outcome analysis in 76 patients with BL (n = 26), B-lymphoblastic lymphoma (B-LBL; n = 3), diffuse large B-cell lymphoma (DLBCL; n = 31), mantle cell lymphoma (MCL; n = 6), transformed B-cell non-Hodgkin lymphomas (tB-NHL; n = 7), and T-cell NHL (T-NHL; n = 3) treated with the GMALL-B-ALL/NHL2002 protocol. Results 73.1% of scheduled chemotherapy cycles were administered. Treatment was discontinued in 38 patients (50.0%) due to progression (n = 14), toxicities (n = 11), scheduled treatment change (n = 6), and unknown reasons (n = 7). All BL/B-LBL patients were treated first-line, and at a median follow-up of 124.7 months, median progression-free survival was not reached. In DLBCL, median PFS was 68.4 months in first-line treated patients and 3.7 months in relapsed/refractory patients. CNS involvement was present in 10 non-BL/B-LBL cases and did not have a negative impact on survival in first-line treated patients but was fatal in all relapsed/refractory patients. Conclusion This study confirmed the activity of the GMALL-B-ALL/NHL2002 protocol in BL/B-LBL. It was also effective in first-line treated non-BL/B-LBL lymphomas with and without simultaneous CNS-/peripheral involvement, but ineffective in relapsed/refractory disease.

Knowledge of social inequalities in monoclonal gammopathy of undetermined significance (MGUS) will contribute to understanding multiple myeloma (MM) etiology, as MGUS consistently precedes MM. The aim of the present study was to examine whether socioeconomic position (SEP) is associated with MGUS in a population-based cohort including information on potential MGUS risk factors. Overall, 4787 study participants aged 45–75 years with information on MGUS were included. SEP indicators (education, income) and potential risk factors (i.e., body mass index, diabetes, smoking, dietary factors) were assessed at baseline. Overall, 260 MGUS cases were detected at baseline and prospectively over a 10-year follow-up. In age-adjusted logistic regression models, a lower chance of having MGUS at baseline or developing MGUS during 10 years of follow-up was indicated for groups of low SEP with odds ratios (OR) of 0.39 (95% confidence interval [95%-CI] 0.19–0.76) for women and 0.48 (95% CI 0.10–1.16) for men in the lowest compared to the highest educational group. After additionally including potential mediating risk factors in the regression models, the estimated ORs changed only slightly in magnitude. Similar results were obtained for income. Current smoking and low fruit consumption were associated with MGUS independently of SEP in women, but not in men. The present study indicates a lower MGUS risk in lower SEP groups. Supporting evidence is given that smoking and diet play a role in the development of MGUS independently of SEP, while it has to be assumed that risk factors unknown to date are responsible for the observed social inequalities in MGUS.

Objective We sought to assess whether genetic risk factors for atrial fibrillation (AF) can explain cardioembolic stroke risk. Methods We evaluated genetic correlations between a previous genetic study of AF and AF in the presence of cardioembolic stroke using genome-wide genotypes from the Stroke Genetics Network (N = 3,190 AF cases, 3,000 cardioembolic stroke cases, and 28,026 referents). We tested whether a previously validated AF polygenic risk score (PRS) associated with cardioembolic and other stroke subtypes after accounting for AF clinical risk factors. Results We observed a strong correlation between previously reported genetic risk for AF, AF in the presence of stroke, and cardioembolic stroke (Pearson r = 0.77 and 0.76, respectively, across SNPs with p < 4.4 × 10−4 in the previous AF meta-analysis). An AF PRS, adjusted for clinical AF risk factors, was associated with cardioembolic stroke (odds ratio [OR] per SD = 1.40, p = 1.45 × 10−48), explaining ∼20% of the heritable component of cardioembolic stroke risk. The AF PRS was also associated with stroke of undetermined cause (OR per SD = 1.07, p = 0.004), but no other primary stroke subtypes (all p > 0.1). Conclusions Genetic risk of AF is associated with cardioembolic stroke, independent of clinical risk factors. Studies are warranted to determine whether AF genetic risk can serve as a biomarker for strokes caused by AF.

Introduction. Efficacy and safety of daratumumab monotherapy (DARA mono) in relapsed/refractory multiple myeloma (rrMM) has been shown in the single-arm phase I/II trial GEN501 and the single-arm phase II trial SIRIUS (1, 2). Since then, several indirect treatment comparisons of DARA mono versus comparator therapies have been published showing consistent results with an overall survival benefit for DARA mono (3, 4, 5, 6). This analysis compares efficacy and for the first time also safety of DARA mono data versus an international historic control group, adjusting for differences in patient populations based on individual patient level data (IPD).

We determined the 10-year progression rate of light chain monoclonal gammopathy of undetermined significance (LCMGUS) and investigated potential associations with cancer utilizing the German population-based Heinz Nixdorf Recall Study. The Heinz Nixdorf Recall Study comprises 4814 men and women aged 45–75 years. Serum samples from baseline (2000–2003) and five-year (2006–2008) and 10-year (2011–2015) follow-up examinations were screened for monoclonal free light chains (FLC). LCMGUS was defined as abnormal FLC ratio, increase of involved FLC with complete loss of immunoglobulin heavy chain, and absence of a history of lymphoproliferative disease (LPD). Seventy-five individuals with LCMGUS were identified across all three evaluation time points (median age 64 years; 43 (57%) male; FLCR > 1.65 65 (87%); FLCR ≤ 0.65 10 (13%)). After a median observation time of 11.5 years, none of the LCMGUS cases had progressed to overt LPD; in particular, we did not observe incident light chain multiple myeloma. On serial analysis 17/31 (55%), LCMGUS could not be confirmed and disappearance of the monoclonal protein was associated with low concentrations of the involved FLC. Individuals with LCMGUS had a 1.5-fold increased risk of cancer but did not show differences in overall survival or renal function as compared to individuals with normal FLC. In conclusion, LCMGUS represents a relatively benign condition with a high disappearance rate of the monoclonal protein on longitudinal analysis and normal overall survival at least in the population-based setting.

Hypoxia-inducible-factor-2α (HIF-2α) and HIF-2 degrading prolyl-hydroxylases (PHD) are key regulators of adaptive hypoxic responses i.e., in acute respiratory distress syndrome (ARDS). Specifically, functionally active genetic variants of HIF-2α (single nucleotide polymorphism (SNP) [ch2:46441523(hg18)]) and PHD2 (C/T; SNP rs516651 and T/C; SNP rs480902) are associated with improved adaptation to hypoxia i.e., in high-altitude residents. However, little is known about these SNPs’ prevalence in Caucasians and impact on ARDS-outcome. Thus, we tested the hypotheses that in Caucasian ARDS patients SNPs in HIF-2α or PHD2 genes are (1) common, and (2) independent risk factors for 30-day mortality. After ethics-committee approval, 272 ARDS patients were prospectively included, genotyped for PHD2 (Taqman SNP Genotyping Assay) and HIF-2α-polymorphism (restriction digest + agarose-gel visualization), and genotype dependent 30-day mortality was analyzed using Kaplan-Meier-plots and multivariate Cox-regression analyses. Frequencies were 99.62% for homozygous HIF-2α CC-carriers (CG: 0.38%; GG: 0%), 2.3% for homozygous PHD2 SNP rs516651 TT-carriers (CT: 18.9%; CC: 78.8%), and 3.7% for homozygous PHD2 SNP rs480902 TT-carriers (CT: 43.9%; CC: 52.4%). PHD2 rs516651 TT-genotype in ARDS was independently associated with a 3.34 times greater mortality risk (OR 3.34, CI 1.09–10.22; p = 0.034) within 30-days, whereas the other SNPs had no significant impact (p = ns). The homozygous HIF-2α GG-genotype was not present in our Caucasian ARDS cohort; however PHD2 SNPs exist in Caucasians, and PHD2 rs516651 TT-genotype was associated with an increased 30-day mortality suggesting a relevance for adaptive responses in ARDS.

Objectives We investigated the association of shift and night work with the incidence of prostate cancer using data of the population-based prospective Heinz Nixdorf Recall Study from the highly industrialized Ruhr area in Germany. Methods Participants of the baseline survey were recruited between 2000-2003. A follow-up survey including, a detailed interview on shift and night work, was conducted from 2011-2014. We included 1757 men who did not report a history of prostate cancer at baseline. We assessed shift- and night-work exposure up to time of the baseline interview. Incident prostate cancers were recorded from baseline through September 2014. We calculated hazard ratios (HR) of shift- and night-work exposure using Cox proportional hazards regression with age at event as timescale, adjusting for smoking status, family history of prostate cancer, education (≤13, 14-17, ≥18 years), and equivalent income (low, medium, high). Results We observed a twofold increased HR for prostate cancer among shift and night workers. Ever employment in shift work was associated with HR 2.29, 95% confidence interval (CI) 1.43-3.67 and night work with HR 2.27, 95% CI 1.42-3.64. HR increased steadily with duration of employment in shift or night work. Stratifying analyses by preferred midpoint of sleep, yielded strongly elevated HR among subjects with early sleep preference, although these analyses were limited by small number of cases. Conclusions We identified increased risks for prostate cancer among men with employment in shift or night work. HR were strongly elevated among long-term employed shift workers and men with early preferred midpoint of sleep.

Occupational exposure to manganese (Mn) has been associated with impairments in olfaction and motor functions, but it has yet to be determined if such effects persist upon cessation of exposure. The objective of this study was to evaluate the influence of former occupational Mn exposure on olfaction within the framework of a prospective cohort study among an elderly German population. Information on job tasks with recognized Mn exposure and data on odor identification assessed with Sniffin' sticks was collected during the second follow-up of the Heinz Nixdorf Recall Study. The study population consisted of 1385 men aged 55-86 years, 354 of whom ever worked in jobs with potential Mn exposure (median 58.3 mu g/m(3) years, interquartile range 19.0-185 mu g/m(3) years). Multiple exposure measures, including job tasks, cumulative Mn exposure, and Mn determined in blood samples (MnB) archived at baseline, were used to estimate effects of Mn on olfaction. Having ever worked as welder was associated with better olfaction compared to other blue-collar workers without Mn exposure. Blue-collar workers identified less odors in comparison to white-collar workers. Concentrations of previous Mn exposure >185 mu g/m(3) years or MnB >= 15 mu g/L were not associated with impaired olfaction. In addition to a strong age effect, participants with lower occupational qualification identified less odors. We found no relevant association of former Mn exposure at relatively low levels with impaired olfaction. Possible neurotoxic Mn effects may not be persistent after cessation. (C) 2016 Elsevier B.V. All rights reserved.

Background: Exposure to air pollution activates the innate immune system and influences the adaptive immune system in experimental settings. We investigated the association of residential long-term exposure to particulate matter (PM) and NO2 air pollution with monoclonal gammopathy of undetermined significance (MGUS) as a marker of adaptive immune system activation. Methods: We used data from the baseline (2000-2003), 5-year (2006-2008) and 10-year (2011-2015) followup examinations of the German Heinz Nixdorf Recall cohort study of 4814 participants (45-75 years). Residential exposure to PM size fractions and NO2 was estimated by land-use regression (ESCAPE-LUR, annual mean 2008/2009) and dispersion chemistry transport models (EURAD-CTM, 3-year mean at baseline). We used logistic regression to estimate the effects of air pollutants on incident MGUS, adjusting for age, sex, education, smoking status, physical activity, and BMI. As a non-linear approach, we looked at quartiles (2-4) of the air pollutants in comparison to quartile 1. Results: Of the 3949 participants with complete data, 100 developed MGUS during the 10-year follow-up. In the main model, only PMcoarse was associated with incident MGUS (OR per IQR (1.9 mu g/m(3)): 1.32, 95% CI 1.04-1.67). We further found positive associations between PM size fractions estimated by ESCAPE-LUR and incident MGUS by quartiles of exposure (OR Q4 vs Q1: PM2.5 2.03 (1.08-3.80); PM10 1.97 (1.05-3.67); PMcoarse 1.98 (1.09-3.60)). Conclusions: Our results indicate that an association between long-term exposure to PM and MGUS may exist. Further epidemiologic studies are needed to corroborate this possible link.