Efficacy and Safety of a Fixed-Dose Combination of Cinnarizine 20 mg and Dimenhydrinate 40 mg in the Treatment of Patients with Vestibular Vertigo: An Individual Patient Data Meta-Analysis of Randomised, Double-Blind, Controlled Clinical Trials.

BACKGROUND AND OBJECTIVE: The source data of four individual randomised, double-blind, reference- and/or placebo-controlled clinical trials with virtually identical study design were pooled for the present meta-analysis. The main objective was to further evaluate the efficacy and safety of the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg in comparison to various other antivertigo treatments in patients suffering from central and/or peripheral vestibular vertigo. METHODS: Adult male and female outpatients were subjected to a 4-week treatment with the fixed combination of cinnarizine 20 mg and dimenhydrinate 40 mg, cinnarizine (20 mg, 50 mg), dimenhydrinate (40 mg, 100 mg), betahistine dimesylate (12 mg), betahistine dihydrochloride (16 mg) and placebo, respectively. The primary efficacy endpoint was the reduction of a validated mean vertigo score (MVS), a composite score of 12 individual vertigo symptoms, the intensities of which were each evaluated by the patients on a 5-point visual analogue scale. For analysis of primary and further secondary efficacy endpoints, baseline-adjusted analysis of covariance (ANCOVA) was used to calculate adjusted least squares means (LSM) with associated two-sided 95% confidence intervals (CIs) for the difference in MVS reductions between treatment groups. Moreover, various sensitivity analyses, responder and subgroup analyses as well as descriptive analyses with respect to safety/tolerability of the treatments were conducted. RESULTS: Of 795 randomised patients, 779 belonged to the intent-to treat (ITT) and 723 to the per-protocol (PP) population. The main efficacy analysis was based on the ITT population (mean age 52.1 years, 61% female). The mean decrease of the MVS from baseline to Week 4 in the cinnarizine/dimenhydrinate group (-1.10) proved to be significantly larger than in any of the comparator groups. LSM differences for comparators versus the fixed combination ranged between 0.16 (95% confidence interval (CI) 0.03; 0.30, p = 0.017) for cinnarizine 20 mg and 0.60 (95% CI 0.42; 0.78; p < 0.001) for betahistine dimesylate 12 mg in favour of the fixed combination. Furthermore, after 4 weeks of treatment, 74 patients (24.7%) in the cinnarizine/dimenhydrinate group were completely symptom free (MVS = 0), a significantly greater proportion than in any of the comparator groups. Sensitivity analyses showed that baseline characteristics such as age, sex, duration of vertigo and antivertigo pretreatment had only a very minor and clinically non-relevant impact on the efficacy results regarding the primary efficacy outcome. Subgroup analyses with respect to age groups (< 65 years/≥ 65 years) and sex showed no significant differences in efficacy within any of the treatment groups. All treatments were well tolerated. A total of 55 patients (6.9%) reported 75 non-serious adverse events (AEs), and 19 patients (2.4%) discontinued the study prematurely because of AEs. Nearly 95% of the patients (cinnarizine/dimenhydrinate group: 97.9%) rated the tolerability of the study medications as either "good" or "very good". CONCLUSION: The findings of the present meta-analysis indicate that the fixed combination of cinnarizine and dimenhydrinate is a safe and potentially superior treatment option for patients suffering from central and/or peripheral vestibular vertigo, as compared to current standard treatments such as cinnarizine, dimenhydrinate or betahistine given alone in monotherapy.

Impact of meteorological parameters on suicide mortality rates: A case-crossover analysis in Southern Germany (1990-2006).

BACKGROUND: There is evidence for a seasonal pattern of suicides with peaks in spring and early summer; however, only a limited number of studies has investigated whether daily changes in meteorological variables may trigger suicides. METHODS: Daily fatal suicide (N = 10,595) and meteorological data were available for four Bavarian cities and ten counties (Germany) for 1990-2006. City/county-specific immediate, delayed and cumulative effects of air temperature, sunshine duration, and cloud cover on suicides were analyzed using a time-stratified case-crossover approach; city/county-specific effects were then combined using random effects meta-analysis. Potential effect modifiers were specific weather conditions, personal or regional characteristics, and season. RESULTS: A 5 °C increase in air temperature on the day before a suicide compared to the control days was associated with a 5.7% (95% confidence interval (CI): 0.6; 11.0) higher suicide risk. Further, the suicide risk was 6.5% (95% CI: 0.2; 13.3) higher on days with low/medium cloud cover (0-6 oktas) compared to days with high cloud cover (7-8 oktas). While daily changes in temperature were not associated with suicides in spring, we found a higher suicide risk in summer, autumn, and winter in association with temperature increases. The effects of cloud cover were strongest in summer and autumn and on days with temperature above the median (>8.8 °C). Sunshine duration was not associated with suicides. CONCLUSION: We found a higher risk for suicides in association with short-term increases in air temperature on the day before the event compared to the control days and on days with low to medium cloud cover. This may highlight times when people are more likely to commit suicide.

Temporal variations in the triggering of myocardial infarction by air temperature in Augsburg, Germany, 1987-2014.

AIMS: The association between air temperature and mortality has been shown to vary over time, but evidence of temporal changes in the risk of myocardial infarction (MI) is lacking. We aimed to estimate the temporal variations in the association between short-term exposures to air temperature and MI in the area of Augsburg, Germany. METHODS AND RESULTS: Over a 28-years period from 1987 to 2014, a total of 27 310 cases of MI and coronary deaths were recorded. Daily meteorological parameters were measured in the study area. A time-stratified case-crossover analysis with a distributed lag non-linear model was used to estimate the risk of MI associated with air temperature. Subgroup analyses were performed to identify subpopulations with changing susceptibility to air temperature. Results showed a non-significant decline in cold-related MI risks. Heat-related MI relative risk significantly increased from 0.93 [95% confidence interval (CI): 0.78-1.12] in 1987-2000 to 1.14 (95% CI: 1.00-1.29) in 2001-14. The same trend was also observed for recurrent and non-ST-segment elevation MI events. This increasing population susceptibility to heat was more evident in patients with diabetes mellitus and hyperlipidaemia. Future studies using multicentre MI registries at different climatic, demographic, and socioeconomic settings are warranted to confirm our findings. CONCLUSION: We found evidence of rising population susceptibility to heat-related MI risk from 1987 to 2014, suggesting that exposure to heat should be considered as an environmental trigger of MI, especially under a warming climate.

Ambient and controlled exposures to particulate air pollution and acute changes in heart rate variability and repolarization.

Previous studies have reported increased risks of myocardial infarction in association with elevated ambient particulate matter (PM) in the previous hour(s). However, whether PM can trigger mechanisms that act on this time scale is still unclear. We hypothesized that increases in PM are associated with rapid changes in measures of heart rate variability and repolarization. We used data from panel studies in Augsburg, Germany, and Rochester, New York, USA, and two controlled human exposure studies in Rochester. Data included ECG recordings from all four studies, controlled exposures to (concentrated) ultrafine particles (UFP; particles with an aerodynamic diameter <100 nm) and ambient concentrations of UFP and fine PM (PM2.5, aerodynamic diameter <2.5 µm). Factor analysis identified three representative ECG parameters: standard deviation of NN-intervals (SDNN), root mean square of successive differences (RMSSD), and T-wave complexity. Associations between air pollutants and ECG parameters in the concurrent and previous six hours were estimated using additive mixed models adjusting for long- and short-term time trends, meteorology, and study visit number. We found decreases in SDNN in relation to increased exposures to UFP in the previous five hours in both of the panel studies (e.g. Augsburg study, lag 3 hours: -2.26%, 95% confidence interval [CI]: -3.98% to -0.53%; Rochester panel study, lag 1 hour: -2.69%; 95% CI: -5.13% to -0.26%) and one of the two controlled human exposure studies (1-hour lag: -13.22%; 95% CI: -24.11% to -2.33%). Similarly, we observed consistent decreases in SDNN and RMSSD in association with elevated PM2.5 concentrations in the preceding six hours in both panel studies. We did not find consistent associations between particle metrics and T-wave complexity. This study provided consistent evidence that recent exposures to UFP and PM2.5 can induce acute pathophysiological responses.

Two-way effect modifications of air pollution and air temperature on total natural and cardiovascular mortality in eight European urban areas.

BACKGROUND: Although epidemiological studies have reported associations between mortality and both ambient air pollution and air temperature, it remains uncertain whether the mortality effects of air pollution are modified by temperature and vice versa. Moreover, little is known on the interactions between ultrafine particles (diameter ≤ 100 nm, UFP) and temperature. OBJECTIVE: We investigated whether the short-term associations of particle number concentration (PNC in the ultrafine range (≤100 nm) or total PNC ≤ 3000 nm, as a proxy for UFP), particulate matter ≤ 2.5 µm (PM2.5) and ≤ 10 µm (PM10), and ozone with daily total natural and cardiovascular mortality were modified by air temperature and whether air pollution levels affected the temperature-mortality associations in eight European urban areas during 1999-2013. METHODS: We first analyzed air temperature-stratified associations between air pollution and total natural (nonaccidental) and cardiovascular mortality as well as air pollution-stratified temperature-mortality associations using city-specific over-dispersed Poisson additive models with a distributed lag nonlinear temperature term in each city. All models were adjusted for long-term and seasonal trend, day of the week, influenza epidemics, and population dynamics due to summer vacation and holidays. City-specific effect estimates were then pooled using random-effects meta-analysis. RESULTS: Pooled associations between air pollutants and total and cardiovascular mortality were overall positive and generally stronger at high relatively compared to low air temperatures. For example, on days with high air temperatures (>75th percentile), an increase of 10,000 particles/cm3 in PNC corresponded to a 2.51% (95% CI: 0.39%, 4.67%) increase in cardiovascular mortality, which was significantly higher than that on days with low air temperatures (<25th percentile) [-0.18% (95% CI: -0.97%, 0.62%)]. On days with high air pollution (>50th percentile), both heat- and cold-related mortality risks increased. CONCLUSION: Our findings showed that high temperature could modify the effects of air pollution on daily mortality and high air pollution might enhance the air temperature effects.

Statistical Approaches to Address Multi-Pollutant Mixtures and Multiple Exposures: the State of the Science.

PURPOSE OF REVIEW: The purpose of this review is to describe the most recent statistical approaches to estimate the effect of multi-pollutant mixtures or multiple correlated exposures on human health. RECENT FINDINGS: The health effects of environmental chemicals or air pollutants have been widely described. Often, there exists a complex mixture of different substances, potentially highly correlated with each other and with other (environmental) stressors. Single-exposure approaches do not allow disentangling effects of individual factors and fail to detect potential interactions between exposures. In the last years, sophisticated methods have been developed to investigate the joint or independent health effects of multi-pollutant mixtures or multiple environmental exposures. A classification of the most recent methods is proposed. A non-technical description of each method is provided, together with epidemiological applications and operational details for implementation with standard software.

Long-term exposure to ambient air pollution and traffic noise and incident hypertension in seven cohorts of the European study of cohorts for air pollution effects (ESCAPE).

Aims: We investigated whether traffic-related air pollution and noise are associated with incident hypertension in European cohorts. Methods and results: We included seven cohorts of the European study of cohorts for air pollution effects (ESCAPE). We modelled concentrations of particulate matter with aerodynamic diameter ≤2.5 µm (PM2.5), ≤10 µm (PM10), >2.5, and ≤10 µm (PMcoarse), soot (PM2.5 absorbance), and nitrogen oxides at the addresses of participants with land use regression. Residential exposure to traffic noise was modelled at the facade according to the EU Directive 2002/49/EC. We assessed hypertension as (i) self-reported and (ii) measured (systolic BP ≥ 140 mmHg or diastolic BP ≥ 90 mmHg or intake of BP lowering medication (BPLM). We used Poisson regression with robust variance estimation to analyse associations of traffic-related exposures with incidence of hypertension, controlling for relevant confounders, and combined the results from individual studies with random-effects meta-analysis. Among 41 072 participants free of self-reported hypertension at baseline, 6207 (15.1%) incident cases occurred within 5-9 years of follow-up. Incidence of self-reported hypertension was positively associated with PM2.5 (relative risk (RR) 1.22 [95%-confidence interval (CI):1.08; 1.37] per 5 µg/m³) and PM2.5 absorbance (RR 1.13 [95% CI:1.02; 1.24] per 10 - 5m - 1). These estimates decreased slightly upon adjustment for road traffic noise. Road traffic noise was weakly positively associated with the incidence of self-reported hypertension. Among 10 896 participants at risk, 3549 new cases of measured hypertension occurred. We found no clear associations with measured hypertension. Conclusion: Long-term residential exposures to air pollution and noise are associated with increased incidence of self-reported hypertension.

Long-term associations of modeled and self-reported measures of exposure to air pollution and noise at residence on prevalent hypertension and blood pressure.

Air pollution, traffic noise and noise annoyance are suggested to be associated with hypertension and blood pressure (BP); however, the evidence remains inconsistent. Our study examined the long-term associations of modeled and self-reported measures of air pollution and traffic noise on prevalent hypertension and BP. We analyzed cross-sectional data from 2552 participants aged 31-72years from the KORA F4 (2006-2008) study conducted in the region of Augsburg, Germany. Land-use regression models were used to estimate residential long-term exposure to particulate matter <2.5µm (PM2.5), soot content of PM2.5 (PM2.5abs) and nitrogen dioxide (NO2). Road traffic noise levels at the facade of the dwellings were estimated for the participants' residences. Participants filled-in a questionnaire on noise annoyance and heavy traffic passing their residence. Linear and logistic regression models adjusting for confounders were used to assess the association between exposure measures and hypertension and BP. An interquartile increase in annual mean PM2.5 (1µg/m3) was significantly associated with 15% higher prevalence of hypertension, without (95% CI: 2.5; 28.0%) and with (95% CI: 0.7; 30.8%) adjustment for traffic noise. Diastolic blood pressure (DBP) was associated with air pollutants and traffic noise with percent increases in mean of 0.7 (95% CI: 0.2; 1.2), 0.6 (95% CI: 0.1; 1.1) and 0.3 (95% CI: 0.0; 0.7) for an interquartile increase in PM2.5 (1µg/m3) and PM2.5abs (0.2∗10-5/m), and 5dB(A) increase in 24-hour road traffic noise, respectively. Associations of PM2.5abs and NO2 with hypertension or DBP were stronger in men and diabetic individuals. No clear associations were seen with systolic BP or noise annoyance. In conclusion, self-reported measures of air pollution or noise did not perform better than the objective measures. Our findings provide further evidence for a link between air pollution, noise and cardiovascular disease and indicate a stronger association for men and diabetic individuals.

Land use regression modeling of ultrafine particles, ozone, nitrogen oxides and markers of particulate matter pollution in Augsburg, Germany.

Important health relevance has been suggested for ultrafine particles (UFP) and ozone, but studies on long-term effects are scarce, mainly due to the lack of appropriate spatial exposure models. We designed a measurement campaign to develop land use regression (LUR) models to predict the spatial variability focusing on particle number concentration (PNC) as indicator for UFP, ozone and several other air pollutants in the Augsburg region, Southern Germany. Three bi-weekly measurements of PNC, ozone, particulate matter (PM10, PM2.5), soot (PM2.5abs) and nitrogen oxides (NOx, NO2) were performed at 20 sites in 2014/15. Annual average concentration were calculated and temporally adjusted by measurements from a continuous background station. As geographic predictors we offered several traffic and land use variables, altitude, population and building density. Models were validated using leave-one-out cross-validation. Adjusted model explained variance (R2) was high for PNC and ozone (0.89 and 0.88). Cross-validation adjusted R2 was slightly lower (0.82 and 0.81) but still indicated a very good fit. LUR models for other pollutants performed well with adjusted R2 between 0.68 (PMcoarse) and 0.94 (NO2). Contrary to previous studies, ozone showed a moderate correlation with NO2 (Pearson's r=-0.26). PNC was moderately correlated with ozone and PM2.5, but highly correlated with NOx (r=0.91). For PNC and NOx, LUR models comprised similar predictors and future epidemiological analyses evaluating health effects need to consider these similarities.

Association Between Long-term Exposure to Air Pollution and Biomarkers Related to Insulin Resistance, Subclinical Inflammation, and Adipokines.

Insulin resistance (IR) is present long before the onset of type 2 diabetes and results not only from inherited and lifestyle factors but also likely from environmental conditions. We investigated the association between modeled long-term exposure to air pollution at residence and biomarkers related to IR, subclinical inflammation, and adipokines. Data were based on 2,944 participants of the KORA (Cooperative Health Research in the Region Augsburg) F4 study conducted in southern Germany (2006-2008). We analyzed associations between individual air pollution concentration estimated by land use regression and HOMA-IR, glucose, insulin, HbA1c, leptin, and high-sensitivity C-reactive protein levels from fasting samples using multivariable linear regression models. Effect estimates were calculated for the whole study population and subgroups of individuals who did not have diabetes, had prediabetes, or had diabetes. Among all participants, a 7.9 µg/m3 increment in particulate matter of <10 µm was associated with higher HOMA-IR (15.6% [95% CI 4.0; 28.6]) and insulin (14.5% [3.6; 26.5]). Nitrogen dioxide was associated with HOMA-IR, glucose, insulin, and leptin. Effect estimates for individuals with prediabetes were much larger and highly statistically significant, whereas individuals who did not have diabetes or had diabetes showed rather weak associations. No association was seen for HbA1c level. Our results suggested an association between long-term exposure to air pollution and IR in the general population that was attributable mainly to individuals with prediabetes.

Short-term effects of air temperature on plasma metabolite concentrations in patients undergoing cardiac catheterization.

BACKGROUND: Epidemiological studies have shown associations between air temperature and cardiovascular health outcomes. Metabolic dysregulation might also play a role in the development of cardiovascular disease. OBJECTIVES: To investigate short-term temperature effects on metabolites related to cardiovascular disease. METHODS: Concentrations of 45 acylcarnitines, 15 amino acids, ketone bodies and total free fatty acids were available in 2869 participants from the CATHeterization GENetics cohort recruited at the Duke University Cardiac Catheterization Clinic (Durham, NC) between 2001 and 2007. Ten metabolites were selected based on quality criteria and cluster analysis. Daily averages of meteorological variables were obtained from the North American Regional Reanalysis project. Immediate, lagged, and cumulative temperature effects on metabolite concentrations were analyzed using (piecewise) linear regression models. RESULTS: Linear temperature effects were found for glycine, C16-OH:C14:1-DC, and aspartic acid/asparagine. A 5°C increase in temperature was associated with a 1.8% [95%-confidence interval: 0.3%; 3.3%] increase in glycine (5-day average), a 3.2% [0.1%; 6.3%] increase in C16-OH:C14:1-DC (lag of four days), and a -1.4% [-2.4%; -0.3%] decrease in aspartic acid/asparagine (lag of two days). Non-linear temperature effects were observed for alanine and total ketone bodies with breakpoint of 4°C and 20°C, respectively. Both a 5°C decrease in temperature on colder days (<4°C)and a 5°C increase in temperature on warmer days (≥4°C) were associated with a four day delayed increase in alanine by 6.6% [11.7; 1.8%] and 1.9% [0.3%; 3.4%], respectively. For ketone bodies we found immediate (0-day lag) increases of 4.2% [-0.5%; 9.1%] and 12.3% [0.1%; 26.0%] associated with 5°C decreases on colder (<20°C) days and 5°C increases on warmer days (≥20°C), respectively. CONCLUSIONS: We observed multiple effects of air temperature on metabolites several of which are reported to be involved in cardiovascular disease. Our findings might help to understand the link between air temperature and cardiovascular disease.

Association of novel metrics of particulate matter with vascular markers of inflammation and coagulation in susceptible populations -results from a panel study.

BACKGROUND AND AIMS: Epidemiological studies have shown adverse effects of ambient air pollutants on health with inflammation and oxidative stress playing an important role. We examine the association between blood biomarkers of inflammation and coagulation and physical attributes of particulate matter which are not routinely measured such as particle length or surface area concentration and apparent density of PM. METHODS: Between 3/2007 and 12/2008 187 non-smoking individuals with type 2 diabetes mellitus (T2D) or impaired glucose tolerance (IGT) were examined within the framework of the KORA Study in Augsburg, Germany. In addition, we selected 87 participants with a potential genetic predisposition on detoxifying and inflammatory pathways. This was defined by the null polymorphism for glutathione S-transferase M1 in combination with a certain single nucleotide polymorphism on the C-reactive protein (CRP) gene (rs1205) or the fibrinogen gene (rs1800790). Participants had blood drawn up to seven different times, resulting in 1765 blood samples. Air pollutants were collected at a central measurement station and individual 24-h averages calculated. Associations between air pollutants and high sensitivity CRP, myeloperoxidase (MPO), interleukin (IL)-6 and fibrinogen were analysed using additive mixed models. RESULTS: For the panel with genetic susceptibility, increases were seen for CRP and MPO with most attributes, specifically particle length and active surface concentration. The %change of geometric mean and 95% confidence intervals for the 5-day average exposure for CRP and MPO were 34.6% [21.8;48.8] and 8.3% [3.2;13.6] per interquartile range increase of particle length concentration and 29.8% [15.9;45.3] and 10.4 [4.4;16.7] for active surface area. Results for the panel of T2D and IGT and the other blood biomarkers were less conclusive. CONCLUSIONS: Particle length concentration and active surface concentration showed strong positive associations with blood biomarkers reflecting inflammation. These air pollution metrics might reflect harmful aerosol properties better than particulate mass or number concentration. They might therefore be important for epidemiological studies.

Ambient and Controlled Particle Exposures as Triggers for Acute ECG Changes.

INTRODUCTION: Previous studies have examined changes in heart rate variability (HRV*) and repolarization associated with increased particulate matter (PM) concentrations on the same and previous few days. However, few studies have examined whether these health responses to PM occur within a few hours or even less. Moreover, it is not clear whether exposure of subjects to ambient or-controlled PM concentrations both lead to similar health effects or whether any of the subjects' individual characteristics modify any of their responses to PM. The aims of the cur- rent study were to investigate whether exposure to PM was associated with rapid changes (< 60 minutes or con- current hour up to a delay of 6 hours) in markers of car- diac rhythni or changes in total antioxidant capacity (a marker of protection against oxidative stress) and whether any PM effects on cardiac rhythm markers were modified by total antioxidant capacity, age, obesity, smoking, hypertension, exertion, prior myocardial infarction (MI), or medication. METHODS: We obtained data from a completed study in Augsburg, Germany (a panel study in N= 109 subjects, including a group with type 2 diabetes or impaired glucose tolerance [IGT; also known as prediabetes]) and a group of other- wise healthy subjects with a potential genetic susceptibil- ity to detoxifying and inflammatory pathways (Hampel et al. 2012b), as well as three completed studies in Rochester, New York (the REHAB panel study of N= 76 postinfarction patients in a cardiac rehabilitation pro- gram [Rich et al. 2012b]; the UPDIABETES study of con- trolled exposure to ultrafine particles [UFPs, particles with an aerodynamic diameter < 100 nm] of N = 19 patients with type 2 diabetes [Stewart et al. 2010; Vora et al. 2014j; and the UPCON controlled-exposure study of concentrated UFP exposure in N = 20 young, healthy, life- time nonsmokers). Data included 5-minute and 1-hour values for HRV and repolarization parameters from elec- trocardiogram (ECG) recordings and total antioxidant capacity measured in stored blood samples. Ambient con- centrations of UFPs, accumulation-mode particles (AMP, particles with an aerodynamic diameter of 100-500 nm), fine PM (PM2.5, particles with an aerodynamic diameter 2.5 pm), and black carbon (BC) were also available. We first conducted factor analyses in each study to find subgroups of correlated ECG outcomes and to reduce the number of outcomes examined in our statistical models. We then restricted the statistical analyses to the factors and representative.outcomes that were common to all four studies, including total HRV (measured as the standard deviation of normal-to-normal [NN] beat intervals [SDNNj), parasympathetic modulation (measured as the root mean square of the successive differences [RMSSD between adjacent NN beat intervals), and T-wave morphol- ogy (measured as T-wave complexity). Next, we used addi- tive mixed models to estimate the change in each outcome associated with increased pollutant concentrations in the . concurrent and previous 6 hours and with 5-minute inter- vals up to the previous 60 minutes, accounting for the correlation of repeated outcome measures for each subject and adjusting for time trend, hour of the day, temperature, relative humidity, day of the week, month, and visit number. Because multiple comparisons were an issue in our. analyses, we used a discovery-and-replication approach to draw conclusions across studies for each research question. RESULTS: In the Augsburg study, interquartile range (IQR) increases in UFP concentrations lagged 2 to 5 hours were associated with 1%-3% decreases in SDNN (e.g., lagged 3 hours in the group with a genetic susceptibility: -2.26%; 95% confidence interval [CI], -3.98% to -0.53%). In the REHAB study, similarly, IQR increases in UFP concentra- tions in the previous 5 hours were associated with < 3% decreases in SDNN (e.g., lagged 1 hour: -2.69%; 95% CI, -5.13% to -0.26%). We also found decreases in SDNN associated with IQR increases in total particle count-(a surrogate for UFP) in the UPDIABETES study (lagged 1 hour: -13.22%; 95% CI, -24.11% to -2.33%) but not in the UPCON study. In the Augsburg study, IQR increases in PM2.5 concen- trations in the concurrent hour and lagged 1-5 hours, AMP concentrations lagged 1 and 3 hours, and BC con- centrations lagged 1-5 hours were associated with -1%-5% decreases in SDNN (e.g., PM2.5 lagged 2 hours in the group with diabetes or IGT: -4.59%; 95% CI, -7.44% to -1.75%). In the REHAB study, IQR increases in PM2.5 concentrations lagged 5 and 6 hours and AMP concentra- tions in the concurrent hour and lagged up to 5 hours were associated with 1%-2% decreases in SDNN (e.g., PM2.5 lagged 4 hours: -2.13%; 95% CI, -3.91% to -0.35%). In the Augsburg study, IQR increases in PM2.5 concen- trations in the concurrent hour and BC lagged 1 and 6 hours were associated with 3%-7% decreases in RMSSD (e.g., PM2.5 concurrent hour in the group with diabetes or IGT: -7.20%; 95% CI, -12.11% to -2.02%). In the REHAB study, similarly, increases in PM2.5 concen- trations lagged 4 to 6 hours-though not AMP or BC con- centrations at any lag hour-were associated with -2.5%-3.5% decreases in RMSSD (e.g., PM2.5 lagged 5 hours: -3.49%; 95% CI, -6.13% to -0.84%). We did not find consistent evidence of any pollutant effects on T-wave complexity in 1-hour recordings. For 5-minute record- ings, there was no consistent evidence of UFP effects on SDNN, RMSSD, or T-wave complexity at any 5-minute interval within 60 minutes. We further concluded that these replicated hourly effects of UFP and PM2.5 on short-term measures of SDNN and RMSSD generally did not differ between the groups in the studies (i.e., type 2 diabetes, pre-diabetes/IGT, post- infarction, and healthy subjects). Last, we found no con- sistent evidence of effects of any pollutant on total anti- oxidant capacity and no consistent evidence of modification of our PM2.5-outcome associations by any of the potential effect modifiers. ONCLUSIONS: Increased UFP concentrations were associated with decreased SDNN in both of the panel studies and one of the two controlled-exposure studies. We also found that decreased SDNN was associated with both increased PM2.5 and AMP concentrations in the previous 6 hours in the panel studies and that decreased RMSSD was associ- ated with increased PM2.5 concentrations in the previous 6 hours in the panel studies. We therefore concluded that the research questions were replicated. Our findings suggest that both UFPs and PM2.5 are associated with autonomic dysfunction within hours of exposure, which may in part. explain the previously reported risk of acute cardiovascular events associated with increased PM in the previous few hours. Despite the heterogeneity of the study populations,and protocols, our findings provided consistent evidence for the induction of rapid pathophysiological responses by UFPs and PM2.5- The absence of consistent associations between UFPs, PM2.5, and these outcomes when examining shorter time intervals indicates that the 5- to 60-minute responses may be less pronounced than the responses occurring within hours. However, the findings from the 5-minute intervals may have been affected by the variety of proto- cols and conditions from study to study as well as by the potential effects of underlying diseases (e.g., healthy indi- viduals versus individuals with diabetes or a recent cor- onary artery. event), physical activity, circadian rhythms, stress, and/or medications.

Assessing responses of cardiovascular mortality to particulate matter air pollution for pre-, during- and post-2008 Olympics periods.

BACKGROUND: The link between particulate air pollution and cardiovascular (CVD) mortality has been investigated. However, there is little direct evidence that reduction measures which decrease particulate air pollution would lead to a reduction in CVD mortality. OBJECTIVES: In Beijing, China, air quality improvement strategies were developed and actions were taken before and during the 2008 Olympic and Paralympic Games. Taking advantage of this opportunity, the aim of the study was to assess the effects of changes in particulate air pollution before (May 20-July 20, 2008), during (August 1-September 20, 2008) and after (October 1-December 1, 2008) the Olympics period. METHODS: Concentrations of air pollution, meteorology and CVD death counts were obtained from official networks and monitoring sites located on the Peking University campus. Air pollution effects with lags of 0-4 days as well as of the 5-day average on cause-specific CVD mortality were investigated for the complete study period (May 20-December 1, 2008) using Quasi-Poisson regression models. Different gender and age subgroups were taken into account. Additionally, effect modification by air mass origin was investigated. In a second step, air pollution effects were estimated for the three specific periods by including an interaction term in the models. RESULTS: We observed large concentration decreases in all measured air pollutants during the unique pollution intervention for the Beijing 2008 Olympics. For the whole period, adverse effects of particulate air pollution were observed on CVD mortality with a 1-day delay as well as for the 5-day average exposure, e.g. an 8.8% (95%CI: 2.7-15.2%) increase in CVD mortality with an interquartile range increase in ultrafine particles. The effects were more pronounced in females, the elderly and for cerebrovascular deaths, but not modified by air mass origin. The specific sub-period analysis results suggested that the risks of CVD mortality were lowest during the Olympic Games where strongest reduction measures have been applied. CONCLUSIONS: The results indicated that the reduction of air pollution due to air quality control measures led to a decreased risk of CVD mortality in Beijing. Our findings provide new insight into efforts to reduce ambient air pollution.

Long-term effects of elemental composition of particulate matter on inflammatory blood markers in European cohorts.

BACKGROUND: Epidemiological studies have associated long-term exposure to ambient particulate matter with increased mortality from cardiovascular and respiratory disorders. Systemic inflammation is a plausible biological mechanism behind this association. However, it is unclear how the chemical composition of PM affects inflammatory responses. OBJECTIVES: To investigate the association between long-term exposure to elemental components of PM and the inflammatory blood markers high-sensitivity C-reactive protein (hsCRP) and fibrinogen as part of the European ESCAPE and TRANSPHORM multi-center projects. METHODS: In total, 21,558 hsCRP measurements and 17,428 fibrinogen measurements from cross-sections of five and four cohort studies were available, respectively. Residential long-term concentrations of particulate matter <10µm (PM10) and <2.5µm (PM2.5) in diameter and selected elemental components (copper, iron, potassium, nickel, sulfur, silicon, vanadium, zinc) were estimated based on land-use regression models. Associations between components and inflammatory markers were estimated using linear regression models for each cohort separately. Cohort-specific results were combined using random effects meta-analysis. As a sensitivity analysis the models were additionally adjusted for PM mass. RESULTS: A 5ng/m(3) increase in PM2.5 copper and a 500ng/m(3) increase in PM10 iron were associated with a 6.3% [0.7; 12.3%] and 3.6% [0.3; 7.1%] increase in hsCRP, respectively. These associations between components and fibrinogen were slightly weaker. A 10ng/m(3) increase in PM2.5 zinc was associated with a 1.2% [0.1; 2.4%] increase in fibrinogen; confidence intervals widened when additionally adjusting for PM2.5. CONCLUSIONS: Long-term exposure to transition metals within ambient particulate matter, originating from traffic and industry, may be related to chronic systemic inflammation providing a link to long-term health effects of particulate matter.

Individual daytime noise exposure in different microenvironments.

BACKGROUND: Numerous studies showed that chronic noise exposure modeled through noise mapping is associated with adverse health effects. However, knowledge about real individual noise exposure, emitted by several sources, is limited. OBJECTIVES: To explain the variation in individual daytime noise exposure regarding different microenvironments, activities and individual characteristics. MATERIALS AND METHODS: In a repeated measures study in Augsburg, Germany (March 2007-December 2008), 109 individuals participated in 305 individual noise measurements with a mean duration of 5.5h. Whereabouts and activities were recorded in a diary. One-minute averages of A-weighted equivalent continuous sound pressure levels (Leq) were determined. We used mixed additive models to elucidate the variation of Leq by diary-based information, baseline characteristics and time-invariant variables like long-term noise exposure. RESULTS: Overall noise levels were highly variable (median: 64 dB(A); range: 37-105 dB(A)). Highest noise levels were measured in traffic during bicycling (69 dB(A); 49-97 dB(A)) and lowest while resting at home (54 dB(A); 37-94 dB(A)). Nearly all diary-based information as well as physical activity, sex and age-group had significant influences on individual noise. In an additional analysis restricted to times spent at the residences, long-term noise exposure did not improve the model fit. CONCLUSIONS: Individual exposures to day-time noise were moderate to high and showed high variations in different microenvironments except when being in traffic. Individual noise levels were greatly determined by personal activities but also seemed to depend on environmental noise levels.

Long-term Exposure to Particulate Matter Constituents and the Incidence of Coronary Events in 11 European Cohorts.

BACKGROUND: Long-term exposure to particulate matter (PM) has been associated with increased cardiovascular morbidity and mortality but little is known about the role of the chemical composition of PM. This study examined the association of residential long-term exposure to PM components with incident coronary events. METHODS: Eleven cohorts from Finland, Sweden, Denmark, Germany, and Italy participated in this analysis. 5,157 incident coronary events were identified within 100,166 persons followed on average for 11.5 years. Long-term residential concentrations of PM < 10 µm (PM10), PM < 2.5 µm (PM2.5), and a priori selected constituents (copper, iron, nickel, potassium, silicon, sulfur, vanadium, and zinc) were estimated with land-use regression models. We used Cox proportional hazard models adjusted for a common set of confounders to estimate cohort-specific component effects with and without including PM mass, and random effects meta-analyses to pool cohort-specific results. RESULTS: A 100 ng/m³ increase in PM10 K and a 50 ng/m³ increase in PM2.5 K were associated with a 6% (hazard ratio and 95% confidence interval: 1.06 [1.01, 1.12]) and 18% (1.18 [1.06, 1.32]) increase in coronary events. Estimates for PM10 Si and PM2.5 Fe were also elevated. All other PM constituents indicated a positive association with coronary events. When additionally adjusting for PM mass, the estimates decreased except for K. CONCLUSIONS: This multicenter study of 11 European cohorts pointed to an association between long-term exposure to PM constituents and coronary events, especially for indicators of road dust.

Elevated particle number concentrations induce immediate changes in heart rate variability: a panel study in individuals with impaired glucose metabolism or diabetes.

BACKGROUND: The health effects of short-term exposure to ambient ultrafine particles in micro-environments are still under investigation. METHODS: Sixty-four individuals with type 2 diabetes and impaired glucose tolerance recorded ambulatory electrocardiograms over five to six hours on 191 occasions in a panel study in Augsburg, Germany. Personal exposure to particle number concentrations (PNC) was monitored for each individual on 5-minute basis concurrently and particulate matter with an aerodynamic diameter<2.5 µm (PM2.5) was acquired from a central monitoring site on an hourly basis. RESULTS: More than 11,000 5-minute intervals were available for heart rate and measures of heart rate variability including SDNN (standard deviation of NN intervals). A concurrent decrease in 5-minute SDNN of -0.56% (95% confidence limits (CI): -1.02%; -0.09%) and a 5-minute delayed increase in heart rate of 0.23 % (95% CI: 0.11%; 0.36%) was observed with an increase in personal PNC of 16,000 per cm3 in additive mixed models. Models evaluating the association of concurrent 5-minute personal PNC and of 1-hour PM2.5 showed independent effects on SDNN. CONCLUSION: The data suggest that freshly emitted ultrafine particles and aged fine particulate matter are both associated with changes in cardiac function in individuals with type 2 diabetes and impaired glucose tolerance in urban areas.

Air Pollution from Road Traffic and Systemic Inflammation in Adults: A Cross-Sectional Analysis in the European ESCAPE Project.

BACKGROUND: Exposure to particulate matter air pollution (PM) has been associated with cardiovascular diseases. OBJECTIVES: In this study we evaluated whether annual exposure to ambient air pollution is associated with systemic inflammation, which is hypothesized to be an intermediate step to cardiovascular disease. METHODS: Six cohorts of adults from Central and Northern Europe were used in this cross-sectional study as part of the larger ESCAPE project (European Study of Cohorts for Air Pollution Effects). Data on levels of blood markers for systemic inflammation-high-sensitivity C-reactive protein (CRP) and fibrinogen-were available for 22,561 and 17,428 persons, respectively. Land use regression models were used to estimate cohort participants' long-term exposure to various size fractions of PM, soot, and nitrogen oxides (NOx). In addition, traffic intensity on the closest street and traffic load within 100 m from home were used as indicators of traffic air pollution exposure. RESULTS: Particulate air pollution was not associated with systemic inflammation. However, cohort participants living on a busy (> 10,000 vehicles/day) road had elevated CRP values (10.2%; 95% CI: 2.4, 18.8%, compared with persons living on a quiet residential street with < 1,000 vehicles/day). Annual NOx concentration was also positively associated with levels of CRP (3.2%; 95% CI: 0.3, 6.1 per 20 µg/m3), but the effect estimate was more sensitive to model adjustments. For fibrinogen, no consistent associations were observed. CONCLUSIONS: Living close to busy traffic was associated with increased CRP concentrations, a known risk factor for cardiovascular diseases. However, it remains unclear which specific air pollutants are responsible for the association.