The socio-economic burden of H1-antihistamine-refractory chronic spontaneous urticaria in Germany.

BACKGROUND AND STUDY AIM: Data from the AWARE study (A Worldwide Antihistamine-Refractory chronic urticaria patient Evaluation) illustrate a substantial disease burden in German patients with H1-antihistamine (-H1-AH)-refractory chronic spontaneous urticaria (CSU). Detrimental effects on patients' quality of life, poor disease control and impairment in the ability to work and perform other daily activities are reported. Based on these findings, this study aims to quantify the epidemiological and socio-economic burden of H1-AH-refractory CSU in Germany. METHODS: To determine the epidemiological burden of H1-AH-refractory CSU, the age- and gender-specific prevalence of CSU and the proportion of H1-AH-refractory patients in Germany anonymized data from the InGef research database have been used. In a second step, the socio-economic burden in terms of lost numbers of hours in paid and unpaid work was calculated by extrapolating the age- and gender-specific work productivity and activity impairment (WPAI) observed in AWARE to the H1-AH-refractory CSU population in Germany. Finally, productivity losses in paid and unpaid work were monetized using the human capital and the friction cost approach respectively. Moreover, socio-economic burden was calculated depending on symptom control of the patients (measured by urticaria control test [UCT]). RESULTS: In Germany, over 203,000 patients (20 years or older) had H1-AH-refractory CSU in 2018. The avoided lost paid and unpaid work hours attributable to H1-AH-refractory CSU summed up to over 100 million. Overall, the socio-economic burden of H1-AH-refractory CSU in monetary terms was evaluated at € 2.2 billion and the majority of this was due to unpaid work loss. Patients with poor disease control, as indicated by UCT score < 12, were more likely to suffer from high impairment than patients with controlled disease, resulting in a higher socio-economic burden. CONCLUSIONS: The results of our analyses picture the substantial socio-economic burden of H1-AH-refractory CSU and therefore the tremendous impact it has on daily lives of individuals and society overall.

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.

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.

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.

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.

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.

Effects of long-term exposure to air pollution on natural-cause mortality: an analysis of 22 European cohorts within the multicentre ESCAPE project.

BACKGROUND: Few studies on long-term exposure to air pollution and mortality have been reported from Europe. Within the multicentre European Study of Cohorts for Air Pollution Effects (ESCAPE), we aimed to investigate the association between natural-cause mortality and long-term exposure to several air pollutants. METHODS: We used data from 22 European cohort studies, which created a total study population of 367,251 participants. All cohorts were general population samples, although some were restricted to one sex only. With a strictly standardised protocol, we assessed residential exposure to air pollutants as annual average concentrations of particulate matter (PM) with diameters of less than 2.5 µm (PM2.5), less than 10 µm (PM10), and between 10 µm and 2.5 µm (PMcoarse), PM2.5 absorbance, and annual average concentrations of nitrogen oxides (NO2 and NOx), with land use regression models. We also investigated two traffic intensity variables-traffic intensity on the nearest road (vehicles per day) and total traffic load on all major roads within a 100 m buffer. We did cohort-specific statistical analyses using confounder models with increasing adjustment for confounder variables, and Cox proportional hazards models with a common protocol. We obtained pooled effect estimates through a random-effects meta-analysis. FINDINGS: The total study population consisted of 367,251 participants who contributed 5,118,039 person-years at risk (average follow-up 13.9 years), of whom 29,076 died from a natural cause during follow-up. A significantly increased hazard ratio (HR) for PM2.5 of 1.07 (95% CI 1.02-1.13) per 5 µg/m(3) was recorded. No heterogeneity was noted between individual cohort effect estimates (I(2) p value=0.95). HRs for PM2.5 remained significantly raised even when we included only participants exposed to pollutant concentrations lower than the European annual mean limit value of 25 µg/m(3) (HR 1.06, 95% CI 1.00-1.12) or below 20 µg/m(3) (1.07, 1.01-1.13). INTERPRETATION: Long-term exposure to fine particulate air pollution was associated with natural-cause mortality, even within concentration ranges well below the present European annual mean limit value. FUNDING: European Community's Seventh Framework Program (FP7/2007-2011).

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.

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.

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.

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 and nonmalignant respiratory mortality in 16 cohorts within the ESCAPE project.

RATIONALE: Prospective cohort studies have shown that chronic exposure to particulate matter and traffic-related air pollution is associated with reduced survival. However, the effects on nonmalignant respiratory mortality are less studied, and the data reported are less consistent. OBJECTIVES: We have investigated the relationship of long-term exposure to air pollution and nonmalignant respiratory mortality in 16 cohorts with individual level data within the multicenter European Study of Cohorts for Air Pollution Effects (ESCAPE). METHODS: Data from 16 ongoing cohort studies from Europe were used. The total number of subjects was 307,553. There were 1,559 respiratory deaths during follow-up. MEASUREMENTS AND MAIN RESULTS: Air pollution exposure was estimated by land use regression models at the baseline residential addresses of study participants and traffic-proximity variables were derived from geographical databases following a standardized procedure within the ESCAPE study. Cohort-specific hazard ratios obtained by Cox proportional hazard models from standardized individual cohort analyses were combined using metaanalyses. We found no significant associations between air pollution exposure and nonmalignant respiratory mortality. Most hazard ratios were slightly below unity, with the exception of the traffic-proximity indicators. CONCLUSIONS: In this study of 16 cohorts, there was no association between air pollution exposure and nonmalignant respiratory mortality.

Immediate ozone effects on heart rate and repolarisation parameters in potentially susceptible individuals.

OBJECTIVES: Elevated ozone levels have been associated with cardiovascular morbidity and mortality. We investigated the effects of ozone on heart rate (HR) and repolarisation parameters in potentially susceptible populations. METHODS: Between March 2007 and December 2008, 363 ECG recordings including >2000 1 h intervals were measured in 64 individuals with type 2 diabetes or impaired glucose tolerance and in 46 healthy individuals with a potential genetic predisposition on the detoxification pathways from Augsburg, Germany. Associations between 1 h averages of ozone and HR, Bazett-corrected QT-interval (QTc), T-wave amplitude and T-wave complexity were analysed using additive mixed models. A variable indicating season and participants' location during the 1 h ECG recordings (summer and outdoors vs winter or indoors) was used as a potential ozone effect modifier. RESULTS: We observed concurrent and 1-4 h lagged increases in HR of 0.5-0.7% for each 20 µg/m(3) increase in ozone. These effects were stronger (1.0-1.2%) when participants were outdoors during the summer. We detected in all participants a concurrent (-1.31%; 95% CI -2.19% to -0.42%) and 1 h lagged (-1.32%; -2.19% to -0.45%) T-wave flattening. Elevated ozone levels were associated with 1 h (2.12%; 0.81 to 3.52) and 2 h lagged (1.89%; 0.55% to 3.26%) increases in T-wave complexity. However, no effects were seen for QTc. Ozone effects were generally more pronounced in individuals with metabolic disorders than a potential genetic predisposition. CONCLUSIONS: Changes in repolarisation might contribute to underlying pathophysiological changes associated with the link between elevated ozone levels and reported adverse cardiovascular outcomes.

Short-term effects of air temperature on blood markers of coagulation and inflammation in potentially susceptible individuals.

OBJECTIVES: Changes in air temperature are associated with an increase in cardiovascular events, but the role of procoagulant and proinflammatory blood markers is still poorly understood. The authors investigated the association between air temperature and fibrinogen, plasminogen activator inhibitor type 1, interleukin-6 and high-sensitivity C reactive protein in two potentially susceptible groups. METHODS: This prospective panel study was conducted between March 2007 and December 2008 in Augsburg, Germany. The study population comprised 187 participants with type 2 diabetes mellitus or impaired glucose tolerance and 87 participants with genetic polymorphisms on the detoxification and inflammation pathways. Overall, 1766 repeated blood measurements were collected. Hourly meteorology data were available from a central measurement site. The association between temperature and blood markers was analysed with additive mixed models. RESULTS: For type 2 diabetes mellitus and impaired glucose tolerance participants, the authors observed immediate, lagged and cumulative increases in fibrinogen (range of percentage changes in geometric mean: 0.6%-0.8%) and plasminogen activator inhibitor type 1 (6.0%-10.1%) in association with a 5°C temperature decrement. Participants with a body mass index above 30 kg/m(2) as well as females showed particularly strong fibrinogen effects. In participants with the special genetic background, 5°C decreases in the 5-day average of temperature led to a change of 8.0% (95% CI 0.5% to 16.2%) in interleukin-6 and of -8.4% (95% CI -15.8% to -0.3%) in high-sensitivity C reactive protein, the latter driven by physically active individuals. CONCLUSIONS: The authors observed different temperature effects on blood markers in two potentially susceptible groups probably indicating varying underlying biological mechanisms. This study results might provide a link between temperature and cardiovascular events.

Acute air pollution effects on heart rate variability are modified by SNPs involved in cardiac rhythm in individuals with diabetes or impaired glucose tolerance.

BACKGROUND: Epidemiological studies have shown associations between particulate matter (PM) and heart rate variability (HRV). OBJECTIVES: We investigated the effects of air pollution on the root mean square of successive differences (RMSSD) and the standard deviation of normal-to-normal intervals (SDNN) and effect modifications by single nucleotide polymorphisms (SNP). METHODS: Between March 2007 and December 2008 207 ECG recordings comprising 1153 1 h-intervals were measured in 61 individuals with type 2 diabetes or impaired glucose tolerance (IGT) from Augsburg, Germany. Associations between 1 h-averages of air pollutants (PM, sulphate, black carbon, and ultrafine particles) and ECG parameters were analyzed using additive mixed models. Genotypes of 139 SNPs supposed to be involved in cardiac rhythm were identified in the literature. Using regression trees for longitudinal data, SNPs associated with ECG parameters were determined and included as potential air pollution effect modifiers. RESULTS: We observed concurrent and lagged decreases in SDNN by about 2-5% in association with all air pollutants, especially in participants with at least one minor allele of rs332229. Increases in PM<2.5 µm (PM(2.5)) were associated with 4 h-lagged decreases of -6.6% [95%-confidence interval:-10.6;-2.6%] and -13.0% [-20.7;-5.1%] in SDNN in individuals with one or two minor alleles. We observed a -7.2% [-12.2;-1.8%] reduction in RMSSD associated with concurrent increases in PM(2.5.) Individuals with at least one minor allele of rs2096767 or at most one minor allele of rs2745967 exhibited stronger PM(2.5) effects. CONCLUSIONS: We identified a genetic predisposition in persons with diabetes or IGT making them potentially more susceptible to air pollutants with regard to changes in HRV.

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.

Short-term impact of ambient air pollution and air temperature on blood pressure among pregnant women.

BACKGROUND: Epidemiologic studies have reported inconsistent findings for the association between air pollution levels and blood pressure (BP), which has been studied mainly in elderly subjects. Short-term air pollution effects on BP have not been investigated in pregnant women, who may constitute a vulnerable population. METHODS: Between 2002 and 2006, 1500 pregnant women from a mother-child cohort study conducted in Nancy and Poitiers, France, underwent 11,220 repeated BP measurements (average, 7.5 measurements/woman). Nitrogen dioxide (NO2), particulate matter with an aerodynamic diameter below 10 µm (PM10), and meteorologic variables were measured on an hourly basis at permanent monitoring sites. We studied changes of BP in relation to short-term variations of air pollution and temperature with mixed models adjusted for meteorologic and personal characteristics. RESULTS: A 10°C decrease in temperature led to an increase in systolic BP of 0.5% (95% confidence interval = 0.1% to 1.0%). Elevated NO2-levels 1 day, 5 days and averaged over 7 days before the BP measurement were associated with reduced systolic BP. The strongest decrease was observed for the 7-day NO2 average (-0.4% [-0.7% to -0.2%] change for an 11 µg/m³ increase in NO2). PM10 effects on systolic BP differed according to pregnancy trimester: PM10 concentration was associated with systolic BP increases during the first trimester and systolic BP decreases later in pregnancy. CONCLUSIONS: We observed short-term associations of air pollution and of temperature with BP in pregnant women. Whether such changes in BP have clinical implications remains to be investigated.

Air temperature and inflammatory and coagulation responses in men with coronary or pulmonary disease during the winter season.

BACKGROUND AND OBJECTIVE: Air temperature changes are associated with increased cardiovascular and respiratory risk, but the roles of inflammatory and coagulation markers are not well understood. We investigated the associations between temperature and several blood markers in patients with coronary heart disease (CHD) and pulmonary disease (PD). METHODS: Two studies were conducted in Erfurt, Germany, over two successive winters. 578 and 381 repeated blood measurements were collected from 57 CHD and 38 PD patients, respectively. Data on patient characteristics and disease history were gathered at baseline. Meteorological data were collected from existing networks. Associations were analysed using additive mixed models with random patient effects. Effect modification by diabetes status was investigated only in CHD patients, as only two PD patients had diabetes. RESULTS: Mean daily air temperature varied between -13 degrees C and 16 degrees C in both study periods. A 10 degrees C decrease in the 5-day temperature average before blood withdrawal led to an increase in platelet counts (% change from the mean: 3.0%, 95% CI 0.6% to 5.5%) and fibrinogen (5.5%, 1.3% to 9.7%), no change in C-reactive protein in PD patients, and a decrease in C-reactive protein in CHD patients. A 2-day delayed increase in factor VII associated with temperature decrease was seen in CHD patients (4.9%; 0.7% to 9.2%), while PD patients showed no effect. 'Effects in CHD patients without diabetes' into 'Effects on factor VII in CHD patients without diabetes'. CONCLUSIONS: This study suggests that temperature decrease is associated with change in several blood parameters. The complex interplay of blood markers at low temperature may contribute to the observed association between cold and cardiovascular mortality and morbidity.

Changes in deceleration capacity of heart rate and heart rate variability induced by ambient air pollution in individuals with coronary artery disease.

BACKGROUND AND OBJECTIVE: Exposure to ambient particles has been shown to be responsible for cardiovascular effects, especially in elderly with cardiovascular disease. The study assessed the association between deceleration capacity (DC) as well as heart rate variability (HRV) and ambient particulate matter (PM) in patients with coronary artery disease (CAD). METHODS: A prospective study with up to 12 repeated measurements was conducted in Erfurt, Germany, between October 2000 and April 2001 in 56 patients with physician-diagnosed ischemic heart disease, stable angina pectoris or prior myocardial infarction at an age of at least 50 years. Twenty-minute ECG recordings were obtained every two weeks and 24-hour ECG recordings every four weeks. Exposure to PM (size range from 10 nm to 2.5 µm), and elemental (EC) and organic (OC) carbon was measured. Additive mixed models were used to analyze the association between PM and ECG recordings. RESULTS: The short-term recordings showed decrements in the high-frequency component of HRV as well as in RMSSD (root-mean-square of successive differences of NN intervals) in association with increments in EC and OC 0-23 hours prior to the recordings. The long-term recordings revealed decreased RMSSD and pNN50 (% of adjacent NN intervals that differed more than 50 ms) in association with EC and OC 24-47 hours prior to the recordings. In addition, highly significant effects were found for DC which decreased in association with PM2.5, EC and OC concurrent with the ECG recordings as well as with a lag of up to 47 hours. CONCLUSIONS: The analysis showed significant effects of ambient particulate air pollution on DC and HRV parameters reflecting parasympathetic modulation of the heart in patients with CAD. An air pollution-related decrease in parasympathetic tone as well as impaired heart rate deceleration capacity may contribute to an increased risk for cardiac morbidity and sudden cardiac death in vulnerable populations.

Impact of ambient air pollution on the differential white blood cell count in patients with chronic pulmonary disease.

Epidemiologic studies report associations between particulate air pollution and increased mortality from pulmonary diseases. This study was performed to examine whether the exposure to ambient gaseous and particulate air pollution leads to an alteration of the differential white blood cell count in patients with chronic pulmonary diseases like chronic bronchitis, chronic obstructive pulmonary disease, and asthma. A prospective panel study was conducted in Erfurt, Eastern Germany, with 12 repeated differential white blood cell counts in 38 males with chronic pulmonary diseases. Hourly particulate and gaseous air pollutants and meteorological data were acquired. Mixed models with a random intercept adjusting for trend, meteorology, weekday, and other risk variables were used. In this explorative analysis, we found an immediate decrease of polymorphonuclear leukocytes in response to an increase of most gaseous and particulate pollutants. Lymphocytes increased within 24 h in association with all gaseous pollutants but showed only minor effects in regard to particulate air pollution. Monocytes showed an increase associated with ultrafine particles, and nitrogen monoxide. The effect had two peaks in time, one 0-23 h before blood withdrawal and a second one with a time lag of 48-71 h. The increase of particulate and gaseous air pollution was associated with multiple changes in the differential white blood cell count in patients with chronic pulmonary diseases.