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To explore the role of β1 -adrenoceptors (ARs) in the heart rate response to the selective β3 -adrenoceptor agonist mirabegron, 12 young male volunteers received single oral doses of the nonselective β1/2 -AR antagonist propranolol (160 mg), the selective β1 -AR antagonist bisoprolol (10 mg), or placebo on days 1 and 5 of each period in a 3-period crossover study. On day 5, dosing was followed by a supratherapeutic dose of mirabegron (200 mg). Vital signs, impedance cardiography, and plasma renin activity were collected. Mirabegron increased heart rate and systolic blood pressure and reduced stroke volume, whereas cardiac output and diastolic blood pressure were unaffected. Mirabegron-induced changes were attenuated by propranolol and bisoprolol. The data indicate that mirabegron has a positive chronotropic effect at supratherapeutic concentrations, which is at least partly mediated by stimulation of β1 -AR. [ABSTRACT FROM AUTHOR]

Purpose We investigated improvements in overactive bladder and patient reported outcomes in patients with overactive bladder and refractory incontinence treated with mirabegron 50 mg plus solifenacin 5 mg vs solifenacin 5 or 10 mg. Materials and Methods Patients with overactive bladder who were incontinent despite 4 weeks of single-blind daily solifenacin 5 mg were randomized 1:1:1 to a double-blind daily combination of mirabegron 50 mg/solifenacin 5 mg, or solifenacin 5 or 10 mg for 12 weeks. The mirabegron dose was increased from 25 to 50 mg after week 4. Symptom bother, health related quality of life and patient perception of bladder condition were assessed by OAB-q (Overactive Bladder Questionnaire) and the PPBC (Patient Perception of Bladder Condition) questionnaire, respectively. Responder rates were based on a 50% reduction in daily incontinence, zero incontinence episodes and fewer than 8 micturitions per 24 hours with minimal important differences in OAB-q and PPBC. Results Overall 2,174 patients with a median age of 59 years were randomized, including 727 to the combination, 728 to solifenacin 5 mg and 719 to solifenacin 10 mg. Symptom bother, total health related quality of life and its subscales (coping, concern and social), and PPBC were significantly improved with combination vs solifenacin monotherapy (p <0.05). The odds of achieving clinically meaningful improvements in incontinence, micturition frequency, symptom bother, health related quality of life and PPBC were significantly higher for combination than solifenacin monotherapy. The odds of becoming continent was 47% and 28% higher for combination vs solifenacin 5 and 10 mg (OR 1.47, 95% CI 1.17–1.84, p = 0.001 and OR 1.28; 95% CI 1.02–1.61, p = 0.033, respectively). Conclusions Significantly more patients on the combination achieved clinically meaningful improvements in incontinence and micturition frequency. Improvements were accompanied by similar improvements in PPBC, symptom bother and health related quality of life. [ABSTRACT FROM AUTHOR]

As part of an EPA-sponsored workshop to investigate the use of source apportionment in health effects analyses, the associations between the participant's estimated source contributions of PM2.5 for Phoenix, AZ for the period from 1995–1997 and cardiovascular and total nonaccidental mortality were analyzed using Poisson generalized linear models (GLM). The base model controlled for extreme temperatures, relative humidity, day of week, and time trends using natural spline smoothers. The same mortality model was applied to all of the apportionment results to provide a consistent comparison across source components and investigators/methods. Of the apportioned anthropogenic PM2.5 source categories, secondary sulfate, traffic, and copper smelter-derived particles were most consistently associated with cardiovascular mortality. The sources with the largest cardiovascular mortality effect size were secondary sulfate (median estimate=16.0% per 5th-to-95th percentile increment at lag 0 day among eight investigators/methods) and traffic (median estimate=13.2% per 5th-to-95th percentile increment at lag 1 day among nine investigators/methods). For total mortality, the associations were weaker. Sea salt was also found to be associated with both total and cardiovascular mortality, but at 5 days lag. Fine particle soil and biomass burning factors were not associated with increased risks. Variations in the maximum effect lag varied by source category suggesting that past analyses considering only single lags of PM2.5 may have underestimated health impact contributions at different lags. Further research is needed on the possibility that different PM2.5 source components may have different effect lag structure. There was considerable consistency in the health effects results across source apportionments in their effect estimates and their lag structures. Variations in results across investigators/methods were small compared to the variations across source categories. These results indicate reproducibility of source apportionment results across investigative groups and support applicability of these methods to effects studies. However, future research will also need to investigate a number of other important issues including accuracy of results.Journal of Exposure Science and Environmental Epidemiology (2006) 16, 311–320. doi:10.1038/sj.jea.7500465; published online 16 November 2005 [ABSTRACT FROM AUTHOR]

Around the world, daily variations in ambient air pollution have been consistently associated with variations in daily mortality. The aim of the study presented here was to assess the effects of ambient air pollution on daily mortality during a period of tremendous changes in air quality in the city of Erfurt, in eastern Germany, from October 1991 to March 2002. Data on particle size distributions were obtained from September 1995 to March 2002 at a research monitoring station. For particles from 0.01 microm to 2.5 microm in diameter, number concentrations (NCs)* and mass concentrations (MCs) were calculated. Particles with diameters less than or equal to 0.10 microm are defined as ultrafine particles (UFP). Data on the gaseous pollutants NO2, CO, SO2, and O3 and on PM10 (particulate matter [PM] with aerodynamic diameter less than or equal to 10 microm) were obtained from a government air-monitoring station. Data on changes in energy consumption, car fleet composition, and population were collected from local authorities. Death certificates of persons living in and dying in Erfurt were abstracted, and daily mortality counts were calculated. Poisson regression models were used to analyze the data, applying penalized splines (also known as P-splines) to model nonlinear relationships in the confounders. Model selection was done without air pollutants in the models, based on a combination of goodness-of-fit criteria and avoidance of autocorrelation in error terms. Final models included P-splines of time trend, meteorologic data, and influenza epidemics as well as day of the week with an indicator variable. Results are presented as change per interquartile range (IQR), i.e., change in the relative risk of mortality associated with a change in the concentration from the 25th to the 75th percentile of a given pollutant. Air pollutants were considered both as linear terms and as P-splines to assess the exposure-response functions. Changes in effect estimates over time were calculated using fully Bayesian time-varying coefficient models. This method was selected over four other approaches tested in simulation studies. Air-pollution concentrations decreased substantially in Erfurt during the decade under observation. The strongest changes were observed for SO2, for which annual concentrations decreased from 64 microg/m3 in 1992 to 4 microg/m3 in 2001. Concentrations of PM10, PM2.5 (particulate matter with aerodynamic diameter less than or equal to 2.5 microm), and CO decreased by more than 50%. NO2, O3, and ultrafine particles also decreased, though to a lesser extent. Based on visual inspection of the data on the changes in ambient air-pollution concentrations during the study period, we defined three study subperiods: A first subperiod from 1991 to 1995; a second, transitional subperiod from 1995 to 1998; and a third subperiod from 1998 to 2002. Generally, air-pollution concentrations decreased substantially from the first subperiod to the second, and some additional decreases occurred from the second subperiod to the third. During the second, transitional subperiod, natural gas replaced coal as the main energy source in Erfurt. In addition, the number of cars with catalytic converters increased over time, as did the number of cars in general. To facilitate the interpretation of the results, we organized the air pollutants into four groups: (1) NO2, CO, and ultrafine particles, (2) PM10 and PM2.5, (3) SO2, and (4) O3. We observed a 1.6% increased risk for daily mortality (CI, -0.4% to 3.5%) for an increase of 19.7 microg/m3 in NO2 (lag day 3), a 1.9% increased risk (CI, 0.2%-3.6%) for an increase of 0.48 mg/m3 in CO (lag day 4), and a 2.9% increased risk (CI, 0.3%-5.5%) for an increase of 9743/cm3 in ultrafine particles (lag day 4). No consistent associations were observed for PM10, PM2.5, or SO2. For O3, a 4.6% increased risk for daily mortality (CI, 1.1%-8.3%) was associated with a 43.8 microg/m3 maximum 8-hr concentration of O3 per day (lag day 2). For all four pollutants, exposure-response functions suggested no deviation from linearity. However, in time-varying models the strongest associations were observed for NO2, CO, and ultrafine particles during the transition subperiod, from 1995 to 1998, when O3 concentrations were lowest. Changes in source characteristics or ambient air-pollution concentrations were not able to explain these observations in a straightforward manner. However, the observations suggested that changes such as the introduction of three-way catalytic converters in cars and the substitution natural gas for coal might have been beneficial. Overall we concluded that: 1. Economic and political changes and the adoption of new technologies in eastern Germany resulted in distinct improvements in ambient air quality; 2. Urban air pollution in Erfurt changed within one decade from the eastern mixture toward that of western Europe ("western mixture"), which is dominated by concentrations of NOx, O3, fine particles, and ultrafine particles with low concentrations of SO2; 3. There was an association between daily mortality and ultrafine particles and combustion-related gases (lag days 3 or 4); 4. Ultrafine particles seemed to be the best pollution indicator and to point to the role of local combustion in the pollution mixture; 5. Regression coefficients showed variation over time for NO2, CO, ultrafine particles, and O3 that could not be explained by nonlinearity in the exposure-response functions; 6. Mortality associated with pollution was lower at the end of the 1990s than during the 1990s, except for mortality associated with O3; and 7. Mortality associated with pollution was strongest in the second, transitional subperiod, from 1995 to 1998, when changes in source characteristics had taken place but the benefits of improved ambient air quality had not yet been completely achieved.