Mortality-Air Pollution Associations in Low Exposure Environments (MAPLE): Phase 2.

INTRODUCTION: Mortality is associated with long-term exposure to fine particulate matter (particulate matter ≤2.5 µm in aerodynamic diameter; PM2.5), although the magnitude and form of these associations remain poorly understood at lower concentrations. Knowledge gaps include the shape of concentration-response curves and the lowest levels of exposure at which increased risks are evident and the occurrence and extent of associations with specific causes of death. Here, we applied improved estimates of exposure to ambient PM2.5 to national population-based cohorts in Canada, including a stacked cohort of 7.1 million people who responded to census year 1991, 1996, or 2001. The characterization of the shape of the concentration-response relationship for nonaccidental mortality and several specific causes of death at low levels of exposure was the focus of the Mortality-Air Pollution Associations in Low Exposure Environments (MAPLE) Phase 1 report. In the Phase 1 report we reported that associations between outdoor PM2.5 concentrations and nonaccidental mortality were attenuated with the addition of ozone (O3) or a measure of gaseous pollutant oxidant capacity (Ox), which was estimated from O3 and nitrogen dioxide (NO2) concentrations. This was motivated by our interests in understanding both the effects air pollutant mixtures may have on mortality and also the role of O3 as a copollutant that shares common sources and precursor emissions with those of PM2.5. In this Phase 2 report, we further explore the sensitivity of these associations with O3 and Ox, evaluate sensitivity to other factors, such as regional variation, and present ambient PM2.5 concentration-response relationships for specific causes of death. METHODS: PM2.5 concentrations were estimated at 1 km2 spatial resolution across North America using remote sensing of aerosol optical depth (AOD) combined with chemical transport model (GEOS-Chem) simulations of the AOD:surface PM2.5 mass concentration relationship, land use information, and ground monitoring. These estimates were informed and further refined with collocated measurements of PM2.5 and AOD, including targeted measurements in areas of low PM2.5 concentrations collected at five locations across Canada. Ground measurements of PM2.5 and total suspended particulate matter (TSP) mass concentrations from 1981 to 1999 were used to backcast remote-sensing-based estimates over that same time period, resulting in modeled annual surfaces from 1981 to 2016.Annual exposures to PM2.5 were then estimated for subjects in several national population-based Canadian cohorts using residential histories derived from annual postal code entries in income tax files. These cohorts included three census-based cohorts: the 1991 Canadian Census Health and Environment Cohort (CanCHEC; 2.5 million respondents), the 1996 CanCHEC (3 million respondents), the 2001 CanCHEC (3 million respondents), and a Stacked CanCHEC where duplicate records of respondents were excluded (Stacked CanCHEC; 7.1 million respondents). The Canadian Community Health Survey (CCHS) mortality cohort (mCCHS), derived from several pooled cycles of the CCHS (540,900 respondents), included additional individual information about health behaviors. Follow-up periods were completed to the end of 2016 for all cohorts. Cox proportional hazard ratios (HRs) were estimated for nonaccidental and other major causes of death using a 10-year moving average exposure and 1-year lag. All models were stratified by age, sex, immigrant status, and where appropriate, census year or survey cycle. Models were further adjusted for income adequacy quintile, visible minority status, Indigenous identity, educational attainment, labor-force status, marital status, occupation, and ecological covariates of community size, airshed, urban form, and four dimensions of the Canadian Marginalization Index (Can-Marg; instability, deprivation, dependency, and ethnic concentration). The mCCHS analyses were also adjusted for individual-level measures of smoking, alcohol consumption, fruit and vegetable consumption, body mass index (BMI), and exercise behavior.In addition to linear models, the shape of the concentration-response function was investigated using restricted cubic splines (RCS). The number of knots were selected by minimizing the Bayesian Information Criterion (BIC). Two additional models were used to examine the association between nonaccidental mortality and PM2.5. The first is the standard threshold model defined by a transformation of concentration equaling zero if the concentration was less than a specific threshold value and concentration minus the threshold value for concentrations above the threshold. The second additional model was an extension of the Shape Constrained Health Impact Function (SCHIF), the eSCHIF, which converts RCS predictions into functions potentially more suitable for use in health impact assessments. Given the RCS parameter estimates and their covariance matrix, 1,000 realizations of the RCS were simulated at concentrations from the minimum to the maximum concentration, by increments of 0.1 µg/m3. An eSCHIF was then fit to each of these RCS realizations. Thus, 1,000 eSCHIF predictions and uncertainty intervals were determined at each concentration within the total range.Sensitivity analyses were conducted to examine associations between PM2.5 and mortality when in the presence of, or stratified by tertile of, O3 or Ox. Additionally, associations between PM2.5 and mortality were assessed for sensitivity to lower concentration thresholds, where person-years below a threshold value were assigned the mean exposure within that group. We also examined the sensitivity of the shape of the nonaccidental mortality-PM2.5 association to removal of person-years at or above 12 µg/m3 (the current U.S. National Ambient Air Quality Standard) and 10 µg/m3 (the current Canadian and former [2005] World Health Organization [WHO] guideline, and current WHO Interim Target-4). Finally, differences in the shapes of PM2.5-mortality associations were assessed across broad geographic regions (airsheds) within Canada. RESULTS: The refined PM2.5 exposure estimates demonstrated improved performance relative to estimates applied previously and in the MAPLE Phase 1 report, with slightly reduced errors, including at lower ranges of concentrations (e.g., for PM2.5 <10 µg/m3).Positive associations between outdoor PM2.5 concentrations and nonaccidental mortality were consistently observed in all cohorts. In the Stacked CanCHEC analyses (1.3 million deaths), each 10-µg/m3 increase in outdoor PM2.5 concentration corresponded to an HR of 1.084 (95% confidence interval [CI]: 1.073 to 1.096) for nonaccidental mortality. For an interquartile range (IQR) increase in PM2.5 mass concentration of 4.16 µg/m3 and for a mean annual nonaccidental death rate of 92.8 per 10,000 persons (over the 1991-2016 period for cohort participants ages 25-90), this HR corresponds to an additional 31.62 deaths per 100,000 people, which is equivalent to an additional 7,848 deaths per year in Canada, based on the 2016 population. In RCS models, mean HR predictions increased from the minimum concentration of 2.5 µg/m3 to 4.5 µg/m3, flattened from 4.5 µg/m3 to 8.0 µg/m3, then increased for concentrations above 8.0 µg/m3. The threshold model results reflected this pattern with -2 log-likelihood values being equal at 2.5 µg/m3 and 8.0 µg/m3. However, mean threshold model predictions monotonically increased over the concentration range with the lower 95% CI equal to one from 2.5 µg/m3 to 8.0 µg/m3. The RCS model was a superior predictor compared with any of the threshold models, including the linear model.In the mCCHS cohort analyses inclusion of behavioral covariates did not substantially change the results for both linear and nonlinear models. We examined the sensitivity of the shape of the nonaccidental mortality-PM2.5 association to removal of person-years at or above the current U.S. and Canadian standards of 12 µg/m3 and 10 µg/m3, respectively. In the full cohort and in both restricted cohorts, a steep increase was observed from the minimum concentration of 2.5 µg/m3 to 5 µg/m3. For the full cohort and the <12 µg/m3 cohort the relationship flattened over the 5 to 9 µg/m3 range and then increased above 9 µg/m3. A similar increase was observed for the <10 µg/m3 cohort followed by a clear decline in the magnitude of predictions over the 5 to 9 µg/m3 range and an increase above 9 µg/m3. Together these results suggest that a positive association exists for concentrations >9 µg/m3 with indications of adverse effects on mortality at concentrations as low as 2.5 µg/m3.Among the other causes of death examined, PM2.5 exposures were consistently associated with an increased hazard of mortality due to ischemic heart disease, respiratory disease, cardiovascular disease, and diabetes across all cohorts. Associations were observed in the Stacked CanCHEC but not in all other cohorts for cerebrovascular disease, pneumonia, and chronic obstructive pulmonary disease (COPD) mortality. No significant associations were observed between mortality and exposure to PM2.5 for heart failure, lung cancer, and kidney failure.In sensitivity analyses, the addition of O3 and Ox attenuated associations between PM2.5 and mortality. When analyses were stratified by tertiles of copollutants, associations between PM2.5 and mortality were only observed in the highest tertile of O3 or Ox. Across broad regions of Canada, linear HR estimates and the shape of the eSCHIF varied substantially, possibly reflecting underlying differences in air pollutant mixtures not characterized by PM2.5 mass concentrations or the included gaseous pollutants. Sensitivity analyses to assess regional variation in population characteristics and access to healthcare indicated that the observed regional differences inconcentration-mortality relationships, specifically the flattening of the concentration-mortality relationship over the 5 to 9 µg/m3 range, was not likely related to variation in the makeup of the cohort or its access to healthcare, lending support to the potential role of spatially varying air pollutant mixtures not sufficiently characterized by PM2.5 mass concentrations. CONCLUSIONS: In several large, national Canadian cohorts, including a cohort of 7.1 million unique census respondents, associations were observed between exposure to PM2.5 with nonaccidental mortality and several specific causes of death. Associations with nonaccidental mortality were observed using the eSCHIF methodology at concentrations as low as 2.5 µg/m3, and there was no clear evidence in the observed data of a lower threshold, below which PM2.5 was not associated with nonaccidental mortality.

Extracellular matrix stiffness negatively affects axon elongation, growth cone area and F-actin levels in a collagen type I 3D culture.

Three dimensional (3D) in vitro neuronal cultures can better reproduce physiologically relevant phenotypes compared to 2D-cultures, because in vivo neurons reside in a 3D microenvironment. Interest in neuronal 3D cultures is emerging, with special attention to the mechanical forces that regulate axon elongation and sprouting in three dimensions. Type I collagen (Col-I) is a native substrate since it is present in the extracellular matrix and hence emulates an in vivo environment to study axon growth. The impact of its mechanical properties needs to be further investigated. Here, we generated Col-I 3D matrices of different mechanical stiffness and evaluated axon growth in three dimensions. Superior cervical ganglion (SCG) explants from neonatal rats were cultured in soft and stiff Col-I 3D matrices and neurite outgrowth was assessed by measuring: maximum neuritic extent; neuritic halo area and fasciculation. Axonal cytoskeletal proteins were examined. Axon elongation in stiff Col-I 3D matrices was reduced (31%) following 24 h in culture compared to soft matrices. In stiff matrices, neurites fasciculated and formed less dense halos. Consistently, almost no F-actin rich growth cones were recognized, and F-actin staining was strongly reduced in the axonal compartment. This study shows that stiffness negatively affects 3D neurite outgrowth and adds insights on the cytoskeletal responses upon mechanic interactions of axons with a 3D environment. Our data will serve to facilitate the development of model systems that are mechanically well-behaved but still mimic key physiologic properties observed in vivo.

Global Burden of Disease from Major Air Pollution Sources (GBD MAPS): A Global Approach.

Ambient fine particulate matter (particles <2.5 µm in aerodynamic diameter [PM2.5]) is the world's leading environmental health risk factor. Reducing the PM2.5 disease burden requires specific strategies that target dominant sources across multiple spatial scales. The Global Burden of Disease from Major Air Pollution Sources (GBD MAPS) project provides a contemporary and comprehensive evaluation of contributions to the ambient PM2.5 disease burden from source sectors and fuels across 21 regions, 204 countries, and 200 subnational areas. We first derived quantitative contributions from 24 emission sensitivity simulations using an updated global atmospheric chemistry-transport model, input with a newly developed detailed anthropogenic emissions dataset that includes emissions specific to source sector and fuels. These simulation results were integrated with newly available high-resolution satellite-derived PM2.5 exposure estimates and disease-specific concentration-response relationships consistent with the GBD project to quantify contributions of specific source sector and fuel to the ambient PM2.5 disease burden across all regions, countries, and subnational areas. To improve the transparency and reproducibility of this and future work, we publicly provided the global atmospheric chemistry-transport model source code, emissions dataset and emissions model source code, analysis scripts, and source sensitivity results, and further described the emissions dataset and source contribution results in two publications.We found that nearly 1.05 million (95% uncertainty interval [UI]: 0.74-1.36 million) deaths worldwide (27.3% of the total mortality attributable to PM2.5) would be avoidable by eliminating fossil fuel combustion, with coal contributing over half of that burden. Residential (19.2%; 736,000 deaths [95% UI: 521,000-955,000]), industrial (11.7%; 448,000 deaths [95% UI: 318,000-582,000]), and energy (10.2%; 391,000 deaths [95% UI: 277,000-507,000]) sector emissions are among the dominant global sources Uncertainty in these estimates reflects those of the input datasets. Regions with the largest anthropogenic contributions generally have the highest numbers of attributable deaths, which clearly demonstrates the importance of reducing these emissions to realize reductions in global air pollution and its disease burden.

A phase 1, single centre, open label, escalating dose study to assess the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) for HPV-associated head and neck cancer (HNC).

BACKGROUND: We conducted a phase 1 dose escalation study (ACTRN12618000140257 registered on 30/01/2018) to evaluate the safety, tolerability and immunogenicity of a therapeutic human papillomavirus (HPV) DNA vaccine (AMV002) in subjects previously treated for HPV-associated oropharyngeal squamous cell carcinoma (OPSCC). METHODS: Eligible subjects had to have no evidence of recurrent and/or metastatic disease at least 12 weeks following the completion of treatment. Three dosing cohorts each consisted of four subjects: group 1: 0.25 mg/dose, group 2: 1 mg/dose, group 3: 4 mg/dose. AMV002 was delivered intradermally on days 0, 28 and 56. Incidence and severity of treatment-emergent adverse events (TEAE) including local reaction at the injection site, and vaccination compliance were recorded. T cell and antibody responses to HPV16 E6 and E7 were measured by interferon gamma (IFN-γ) enzyme-linked immunosorbent spot (ELISpot) assay and enzyme-linked immunosorbent assay (ELISA). RESULTS: All subjects completed the vaccination programme and experienced mild discomfort at the injection site(s). Pre-immunisation, cell-mediated responses to HPV16 E6 and E7 were evident in all subjects, and E7-specific antibodies were detected in 11 (91.7%), reflecting previous exposure to HPV. Post-vaccination, 10 of 12 (83.3%) subjects responded to one or more of the E6 and/or E7 peptide pools, while 2 (16.7%) did not show additional vaccine-induced cell-mediated responses. Vaccination resulted in a ≥ 4-fold increase in anti-HPV16 E7 antibody titre in one subject in group 3. CONCLUSIONS: AMV002 was well tolerated at all dose levels and resulted in enhanced specific immunity to virus-derived tumour-associated antigens in subjects previously treated for HPV-associated OPSCC.

Building the embryo of Developmental Biology in Uruguay.

In Uruguay, a country with a small population, and hence a small scientific community, there were no classical embryologists as such in the past. However, in the decade of the 1950s, a cumulus of favorable conditions gave rise to highly active and modern research groups in the fields of cytology and physiology, which eventually contributed to developmental biology. The advent of a long dictatorship between the 1970's and 1980's caused two things: a strong lag in local research and the migration of young investigators who learned abroad new disciplines and technologies. The coming back to democracy allowed for the return of some, now as solid researchers, and together with those who stayed, built a previously inexistent postgraduate training program and a globally-integrated academy that fostered diversity of research disciplines, including developmental biology. In this paper, we highlight the key contributions of pioneer researchers and the significant role played by academic and funding national institutions in the growth and consolidation of developmental biology in our country.

Mortality-Air Pollution Associations in Low-Exposure Environments (MAPLE): Phase 1.

INTRODUCTION: Fine particulate matter (particulate matter ≤2.5 µm in aerodynamic diameter, or PM2.5) is associated with mortality, but the lower range of relevant concentrations is unknown. Novel satellite-derived estimates of outdoor PM2.5 concentrations were applied to several large population-based cohorts, and the shape of the relationship with nonaccidental mortality was characterized, with emphasis on the low concentrations (<12 µg/m3) observed throughout Canada. METHODS: Annual satellite-derived estimates of outdoor PM2.5 concentrations were developed at 1-km2 spatial resolution across Canada for 2000-2016 and backcasted to 1981 using remote sensing, chemical transport models, and ground monitoring data. Targeted ground-based measurements were conducted to measure the relationship between columnar aerosol optical depth (AOD) and ground-level PM2.5. Both existing and targeted ground-based measurements were analyzed to develop improved exposure data sets for subsequent epidemiological analyses.Residential histories derived from annual tax records were used to estimate PM2.5 exposures for subjects whose ages ranged from 25 to 90 years. About 8.5 million were from three Canadian Census Health and Environment Cohort (CanCHEC) analytic files and another 540,900 were Canadian Community Health Survey (CCHS) participants. Mortality was linked through the year 2016. Hazard ratios (HR) were estimated with Cox Proportional Hazard models using a 3-year moving average exposure with a 1-year lag, with the year of follow-up as the time axis. All models were stratified by 5-year age groups, sex, and immigrant status. Covariates were based on directed acyclical graphs (DAG), and included contextual variables (airshed, community size, neighborhood dependence, neighborhood deprivation, ethnic concentration, neighborhood instability, and urban form). A second model was examined including the DAG-based covariates as well as all subject-level risk factors (income, education, marital status, indigenous identity, employment status, occupational class, and visible minority status) available in each cohort. Additional subject-level behavioral covariates (fruit and vegetable consumption, leisure exercise frequency, alcohol consumption, smoking, and body mass index [BMI]) were included in the CCHS analysis.Sensitivity analyses evaluated adjustment for covariates and gaseous copollutants (nitrogen dioxide [NO2] and ozone [O3]), as well as exposure time windows and spatial scales. Estimates were evaluated across strata of age, sex, and immigrant status. The shape of the PM2.5-mortality association was examined by first fitting restricted cubic splines (RCS) with a large number of knots and then fitting the shape-constrained health impact function (SCHIF) to the RCS predictions and their standard errors (SE). This method provides graphical results indicating the RCS predictions, as a nonparametric means of characterizing the concentration-response relationship in detail and the resulting mean SCHIF and accompanying uncertainty as a parametric summary.Sensitivity analyses were conducted in the CCHS cohort to evaluate the potential influence of unmeasured covariates on air pollution risk estimates. Specifically, survival models with all available risk factors were fit and compared with models that omitted covariates not available in the CanCHEC cohorts. In addition, the PM2.5 risk estimate in the CanCHEC cohort was indirectly adjusted for multiple individual-level risk factors by estimating the association between PM2.5 and these covariates within the CCHS. RESULTS: Satellite-derived PM2.5 estimates were low and highly correlated with ground monitors. HR estimates (per 10-µg/m3 increase in PM2.5) were similar for the 1991 (1.041, 95% confidence interval [CI]: 1.016-1.066) and 1996 (1.041, 1.024-1.059) CanCHEC cohorts with a larger estimate observed for the 2001 cohort (1.084, 1.060-1.108). The pooled cohort HR estimate was 1.053 (1.041-1.065). In the CCHS an analogous model indicated a HR of 1.13 (95% CI: 1.06-1.21), which was reduced slightly with the addition of behavioral covariates (1.11, 1.04-1.18). In each of the CanCHEC cohorts, the RCS increased rapidly over lower concentrations, slightly declining between the 25th and 75th percentiles and then increasing beyond the 75th percentile. The steepness of the increase in the RCS over lower concentrations diminished as the cohort start date increased. The SCHIFs displayed a supralinear association in each of the three CanCHEC cohorts and in the CCHS cohort.In sensitivity analyses conducted with the 2001 CanCHEC, longer moving averages (1, 3, and 8 years) and smaller spatial scales (1 km2 vs. 10 km2) of exposure assignment resulted in larger associations between PM2.5 and mortality. In both the CCHS and CanCHEC analyses, the relationship between nonaccidental mortality and PM2.5 was attenuated when O3 or a weighted measure of oxidant gases was included in models. In the CCHS analysis, but not in CanCHEC, PM2.5 HRs were also attenuated by the inclusion of NO2. Application of the indirect adjustment and comparisons within the CCHS analysis suggests that missing data on behavioral risk factors for mortality had little impact on the magnitude of PM2.5-mortality associations. While immigrants displayed improved overall survival compared with those born in Canada, their sensitivity to PM2.5 was similar to or larger than that for nonimmigrants, with differences between immigrants and nonimmigrants decreasing in the more recent cohorts. CONCLUSIONS: In several large population-based cohorts exposed to low levels of air pollution, consistent associations were observed between PM2.5 and nonaccidental mortality for concentrations as low as 5 µg/m3. This relationship was supralinear with no apparent threshold or sublinear association.

[How many potential organ donors are there really? : Retrospective analysis of why determination of irreversible loss of brain function was not performed in deceased patients with relevant brain damage]. / Wie viele potenzielle Organspender gibt es wirklich? : Retrospektive Analyse zu nichterfolgter Diagnostik des irreversiblen Hirnfunktionsausfalls bei verstorbenen Patienten mit relevanter Hirnschädigung.

BACKGROUND: No systematic study has previously been undertaken in Germany to ascertain why irreversible brain death determination (BDD) has not been carried out. OBJECTIVE: A comprehensive analysis of reasons for unperformed BDD in deceased patients with acute, severe brain damage could improve the identification of potential organ donors. METHOD: Using the Transplantcheck program of the German Organ Transplantation Foundation (DSO) an analysis of the data from 2016 was undertaken in participating hospitals in Saxony, Saxony-Anhalt and Thuringia (Region East of the DSO), regarding why a BDD was not initiated in deceased patients with primary or secondary brain damage. RESULTS: In 128 of the 144 Region East hospitals, 7889 deceased patients with primary or secondary brain damage were detected. In 7389 patients a BDD was out of the question for a variety of reasons. In 232 patients organ donation was not considered due to an advance directive. In 195 cases treatment was limited based on the patient's infaust neurological prognosis without the possibility of organ donation being discussed with relatives. In 73 cases initiation of BDD was indicated but not performed. CONCLUSION: The number of potential organ donors in Region East of the DSO could be significantly increased by identifying patients where BDD is indicated. By consistent evaluation of patients' wills in terms of organ donation before treatment is withdrawn in patients with poor neurological prognosis, additional potential organ donors could be identified. Furthermore, involving neurointensive care physicians in the care of all patients with brain damage could improve the prognostic assessment.

A Dynamic Three-Dimensional Air Pollution Exposure Model for Hong Kong.

INTRODUCTION: High-density high-rise cities have become a more prominent feature globally. Air quality is a significant public health risk in many of these cities. There is a need to better understand the extent to which vertical variation in air pollution and population mobility in such cities affect exposure and exposure-response relationships in epidemiological studies. METHODS: We used a novel strategy to execute a staged model development that incorporated horizontal and vertical pollutant dispersion, building infiltration, and population mobility patterns in estimating traffic-related air pollution (TRAP) exposures in the Hong Kong Special Administrative Region (HK SAR).Two street-level spatial monitoring campaigns were undertaken to facilitate the creation of a two-dimensional land-use regression (LUR) model. A network of approximately 100 passive nitric oxide-nitrogen dioxide (NO-NO2) monitors was deployed for two-week periods during the cool and warm seasons. Sampling locations were selected based on population and road network density with a range of physical and geographical characteristics represented. Eight sets of portable monitors for black carbon (BC) and particulate matter ≤2.5 µm in aerodynamic diameter (PM2.5) were rotated so as to be deployed at 80 locations for a 24-hour period. Land-use, geographical, and emissions layers were combined with the spatial monitoring campaign results to create spatiotemporal exposure models.Vertical air pollution monitoring was carried out at six strategic locations for two weeks in the warm season and two weeks in the cool season. Continuous measurements were carried out at four different heights of a residential building and on both sides of a street canyon. The heights ranged from as close to street level as practically possible up to a maximum of 50 meters (i.e., below the 20th floor). Paired indoor monitoring was included to allow the calculation of infiltration coefficients to feed into the dynamic component of the exposure model.The final phase of model development addressed population mobility. A population-representative travel behavior survey (n = 89,358) was used to produce the dynamic component of the model, with time-weighted exposure estimates split between home and work or school. Transport microenvironment exposures were taken from published literature. Time-activity exposure estimates were split by age, sex, and employment status.Development of the exposure model in distinct packages allowed the application of a staged approach to an existing cohort data set. Mortality risk estimates for an elderly cohort of 66,000 Hong Kong residents were calculated using increasing exposure model complexity. RESULTS: The street-level (2-dimensional [2D]) LUR modeling captured important spatial parameters and represented spatial patterns of air quality in Hong Kong that were consistent with the literature. Higher concentrations of gaseous pollutants were centered in Kowloon and the northern region of Hong Kong Island. PM2.5 and BC predictions exhibited a north-south/west-east gradient, with higher concentrations in the northwest due to regional transport of particulate pollutants from Mainland China. While the degree of explained variance of the models was in line with other LUR modeling efforts in Asia, R2 values ranged from 0.46 (NO2) to 0.59 (PM2.5).Exponential decay rates (k) were calculated at each monitoring location. While it was clear that k values were higher during the warm season than the cool season, no robust patterns were identified relating to the canyon physical parameters. Therefore, a single decay rate was used for each pollutant across the whole region for derivation of the 3-dimensional (3D) exposure layer (k = 0.004 and 0.012 for PM2.5 and BC, respectively). An alternative decay profile that capped decay at 20 meters above street level was proposed and evaluated. The electrochemical sensors deployed during the canyon campaigns did not exhibit the degree of interunit precision necessary to detect vertical variations in gaseous pollutants, and these results were excluded from the study.We found that values of the median infiltration efficiencies (Finf) for both BC and PM2.5 were especially high during the cool season (91%). Finf values were somewhat lower during the warm season (81% and 88% for PM2.5 and BC, respectively), and we found a significant negative correlation between air conditioning use and Finf. The Finf for a mechanically ventilated office building was 45% and 40% during the cool and warm seasons, respectively.Dynamic exposure estimates were compared against home outdoor estimates. As expected, the addition of an indoor component decreased time-weighted exposure estimates, which were balanced out to some extent by the inclusion of transport microenvironments. Overall, mean time-weighted exposures for the full dynamic model were around 20% lower than home outdoor estimates.Higher levels of exposures were found with working adults and students than for those neither in work nor study. This was due to the increased mobility of people going to work or school. The exposures to PM2.5, BC, and NO2 were, respectively, 13%, 39%, and 14% higher for people who were under age 18, compared with people who were 65 or older. Exposure estimates for the female population were approximately 4% lower.The availability of an existing cohort data set of elderly Hong Kong residents (n = 66,820) facilitated the calculation and comparison of mortality risk estimates for the different exposure models.Overall, results indicated that the application of exposure estimates that incorporated infiltration, vertical, and to a lesser extent, dynamic components resulted in higher hazard ratios (HRs) than the standard street-level model and increased the number of significant associations with all-natural-cause, cardiovascular, and respiratory mortality outcomes. CONCLUSIONS: The results from the study provided the first evidence that considering air pollution exposure in a dynamic 3D landscape would benefit epidemiological studies. Higher HRs and a greater number of significant associations were found between mortality and pollutant exposures that would not have been found had standard 2D exposure models been used. Dynamic models can also identify differential exposures between population subtypes (e.g., students and working adults; those neither in work nor study).Improved urban building design appears to be stimulating the dispersion of local TRAP in street canyons. Conversely, Finf values found in naturally ventilated buildings were high, and residences provided little protection from ambient air pollution.We have demonstrated that the creation of effective advanced exposure models is possible in Asian cities without an undue burden on resources. We recommend that vertical exposure patterns be incorporated in future epidemiological studies in high-rise cities where the floor of residence is recorded in health record data.

Quantifying the Contribution to Uncertainty in Mortality Attributed to Household, Ambient, and Joint Exposure to PM2.5 From Residential Solid Fuel Use.

While there have been substantial efforts to quantify the health burden of exposure to PM2.5 from solid fuel use (SFU), the sensitivity of mortality estimates to uncertainties in input parameters has not been quantified. Moreover, previous studies separate mortality from household and ambient air pollution. In this study, we develop a new estimate of mortality attributable to SFU due to the joint exposure from household and ambient PM2.5 pollution and perform a variance-based sensitivity analysis on mortality attributable to SFU. In the joint exposure calculation, we estimate 2.81 (95% confidence interval: 2.48-3.28) million premature deaths in 2015 attributed to PM2.5 from SFU, which is 580,000 (18%) fewer deaths than would be calculated by summing separate household and ambient mortality calculations. Regarding the sources of uncertainties in these estimates, in China, India, and Latin America, we find that 53-56% of the uncertainty in mortality attributable to SFU is due to uncertainty in the percent of the population using solid fuels and 42-50% from the concentration-response function. In sub-Saharan Africa, baseline mortality rate (72%) and the concentration-response function (33%) dominate the uncertainty space. Conversely, the sum of the variance contributed by ambient and household PM2.5 exposure ranges between 15 and 38% across all regions (the percentages do not sum to 100% as some uncertainty is shared between parameters). Our findings suggest that future studies should focus on more precise quantification of solid fuel use and the concentration-response relationship to PM2.5, as well as mortality rates in Africa.

Reinnervation of rat endometrium in the anterior eye chamber model of experimental endometriosis: Old methods for new questions.

Endometriosis is a benign estrogen-dependent chronic gynecological disease characterized by the presence of endometrial-like tissue outside the uterine cavity. In both women and experimental endometriotic rats, endometriosis lesions endow autonomic and sensory nerves, which are thought to contribute to the disease-associated pain. Some evidence indicates that the reinnervation of lesions is regulated by factors produced by the endometrial tissue as well as by environmental factors from the peritoneum. In this study, we examined the reinnervation of the rat endometrial tissue in an ectopic environment different from the peritoneum employing the anterior eye chamber model of experimental endometriosis. At 3 and 6weeks following transplantation, endometrial grafts retained many histological features of the eutopic tissue. Both sympathetic and sensory nerves reinnervated endometrial grafts and distributed in the stroma-like tissue, around blood vessels and in close proximity to the glands and lining epithelium. Sympathetic innervation was more robust than sensory innervation. No significant topographical relationship between sympathetic nerves and macrophages was observed. These results suggest that the rat endometrium possesses intrinsic neuritogenic capacities and can be reinnervated by sympathetic and sensory nerves in ectopic sites different from the peritoneum.

Estrogen-induced collagen reorientation correlates with sympathetic denervation of the rat myometrium.

Estrogen inhibits the growth and causes the degeneration (pruning) of sympathetic nerves supplying the rat myometrium. Previous cryoculture studies evidenced that substrate-bound signals contribute to diminish the ability of the estrogenized myometrium to support sympathetic nerve growth. Using electron microscopy, here we examined neurite-substrate interactions in myometrial cryocultures, observing that neurites grew associated to collagen fibrils present in the surface of the underlying cryosection. In addition, we assessed quantitatively the effects of estrogen on myometrial collagen organization in situ, using ovariectomized rats treated with estrogen and immature females undergoing puberty. Under low estrogen levels, most collagen fibrils were oriented in parallel to the muscle long axis (83% and 85%, respectively). Following estrogen treatment, 89% of fibrils was oriented perpendicularly to the muscle main axis; while after puberty, 57% of fibrils acquired this orientation. Immunohistochemistry combined with histology revealed that the vast majority of fine sympathetic nerve fibers supplying the myometrium courses within the areas where collagen realignment was observed. Finally, to assess whether depending on their orientation collagen fibrils can promote or inhibit neurite outgrowth, we employed cryocultures, now using as substrate tissue sections of rat-tail tendon. We observed that neurites grew extensively in the direction of the parallel-aligned collagen fibrils in the tendon main axis but were inhibited to grow perpendicularly to this axis. Collectively, these findings support the hypothesis that collagen reorientation may be one of the factors contributing to diminish the neuritogenic capacity of the estrogen-primed myometrial substrate.

Residential greenness is differentially associated with childhood allergic rhinitis and aeroallergen sensitization in seven birth cohorts.

BACKGROUND: The prevalence of allergic rhinitis is high, but the role of environmental factors remains unclear. We examined cohort-specific and combined associations of residential greenness with allergic rhinitis and aeroallergen sensitization based on individual data from Swedish (BAMSE), Australian (MACS), Dutch (PIAMA), Canadian (CAPPS and SAGE), and German (GINIplus and LISAplus) birth cohorts (n = 13 016). METHODS: Allergic rhinitis (doctor diagnosis/symptoms) and aeroallergen sensitization were assessed in children aged 6-8 years in six cohorts and 10-12 years in five cohorts. Residential greenness was defined as the mean Normalized Difference Vegetation Index (NDVI) in a 500-m buffer around the home address at the time of health assessment. Cohort-specific associations per 0.2 unit increase in NDVI were assessed using logistic regression models and combined in a random-effects meta-analysis. RESULTS: Greenness in a 500-m buffer was positively associated with allergic rhinitis at 6-8 years in BAMSE (odds ratio = 1.42, 95% confidence interval [1.13, 1.79]) and GINI/LISA South (1.69 [1.19, 2.41]) but inversely associated in GINI/LISA North (0.61 [0.36, 1.01]) and PIAMA (0.67 [0.47, 0.95]). Effect estimates in CAPPS and SAGE were also conflicting but not significant (0.63 [0.32, 1.24] and 1.31 [0.81, 2.12], respectively). All meta-analyses were nonsignificant. Results were similar for aeroallergen sensitization at 6-8 years and both outcomes at 10-12 years. Stratification by NO2 concentrations, population density, an urban vs rural marker, and moving did not reveal consistent trends within subgroups. CONCLUSION: Although residential greenness appears to be associated with childhood allergic rhinitis and aeroallergen sensitization, the effect direction varies by location.

Estrogen and female reproductive tract innervation: cellular and molecular mechanisms of autonomic neuroplasticity.

The female reproductive tract undergoes remarkable functional and structural changes associated with cycling, conception and pregnancy, and it is likely advantageous to both individual and species to alter relationships between reproductive tissues and innervation. For several decades, it has been appreciated that the mammalian uterus undergoes massive sympathetic axon depletion in late pregnancy, possibly representing an adaptation to promote smooth muscle quiescence and sustained blood flow. Innervation to other structures such as cervix and vagina also undergo pregnancy-related changes in innervation that may facilitate parturition. These tissues provide highly tractable models for examining cellular and molecular mechanisms underlying peripheral nervous system plasticity. Studies show that estrogen elicits rapid degeneration of sympathetic terminal axons in myometrium, which regenerate under low-estrogen conditions. Degeneration is mediated by the target tissue: under estrogen's influence, the myometrium produces proteins repulsive to sympathetic axons including BDNF, neurotrimin, semaphorins, and pro-NGF, and extracellular matrix components are remodeled. Interestingly, nerve depletion does not involve diminished levels of classical sympathetic neurotrophins that promote axon growth. Estrogen also affects sympathetic neuron neurotrophin receptor expression in ways that appear to favor pro-degenerative effects of the target tissue. In contrast to the uterus, estrogen depletes vaginal autonomic and nociceptive axons, with the latter driven in part by estrogen-induced suppression of BMP4 synthesis. These findings illustrate that hormonally mediated physiological plasticity is a highly complex phenomenon involving multiple, predominantly repulsive target-derived factors acting in concert to achieve rapid and selective reductions in innervation.

Highlights in basic autonomic neuroscience: Semaphorins in the remodeling of autonomic innervation.

Chemorepellent signals of the semaphorin family are known to play a crucial role in the development of the nervous system. Some semaphorins continue being expressed in the adult life when they regulate plasticity and regeneration. Increasing evidence indicates that semaphorins are implicated in the development of the autonomic nervous system as well as in the regulation of different forms of plasticity observed in the adulthood. Here we present selected examples illustrating the involvement of semaphorins in the regulation of autonomic plasticity in physiological and pathological conditions.

Glutathione-S-transferase P1, early exposure to mould in relation to respiratory and allergic health outcomes in children from six birth cohorts. A meta-analysis.

BACKGROUND: There are conflicting study results regarding the association of exposure to visible mould and fungal components in house dust with respiratory and allergic diseases in children. It has been suggested that functional polymorphisms of the GSTP1 gene may influence the risk for allergic disorders through an impaired defence against oxidant injury. METHODS: We examined in six birth cohorts of over 14 000 children whether the association between early exposure to reported mould at home in relation to respiratory and allergic diseases is modified by a single nucleotide polymorphism of the GSTP1 gene. RESULTS: We observed a positive association of mould exposure with nasal symptoms (2-10 year) aOR: 1.19 (1.02-11.38). Further, there was a borderline significant increased risk of rhinoconjunctivitis (6-8 year) in children homozygous for the minor allele Val/Val, aOR: 1.25 (0.98-1.60). In stratified analyses, subjects homozygous for the minor allele and exposed to mould at home were at increased risk for early wheezing aOR: 1.34 (1.03-1.75), whereas the major allele may confer susceptibility for later nasal outcomes, (6-8 year) aOR: 1.20 (1.00-1.45) and (2-10 year) aOR: 1.30 (1.04-1.61), respectively. For none of the health outcomes studied, we found gene by environment interactions. CONCLUSION: A genetic influence of the GSTP1 gene cannot be ruled out, but the magnitude of the effect is a matter of further research. In conclusion, the interplay between gene and environments is complex and remains subject of further study.

Vasa praevia: risk-adapted modification of the conventional management--a retrospective study.

PURPOSE: Undiagnosed vasa praevia carries an imminent risk of fetal death and increases with IVF. When diagnosed, the question arises as to whether the conventional prenatal management of routine steroid administration for fetal lung maturation and elective caesarean section in week 35 is generally justified in face of the risks involved. We present a retrospective study of a risk-adapted modification of the conventional management of vasa praevia. MATERIAL AND METHODS: We analysed 11 years of records involving 18 cases of antenatally diagnosed vasa praevia at our perinatal centre. Each case was managed by a risk-adapted modification of the conventional treatment where both, the steroid administration and the timing of delivery, were dependent on the patient history and clinical signs for preterm birth. RESULTS: There were no lethal fetal, neonatal, or maternal complications. The earliest caesarean section took place at 34 weeks 1 day, the latest at 37 weeks 1 day, and in more than half of the cases at ≥ 36 weeks. CONCLUSION: Steroid application is generally recommended for pregnancies before 34 weeks carrying a risk for preterm birth. Thus, retrospectively, none of our cases required steroid administration. This supports our protocol of not obligatorily administering steroids. Delaying the caesarean section up to two weeks beyond the conventionally recommended date of 35 weeks in 78% of our cases resulted in no complications. This justifies the suitability of determining the timing of delivery based on our individual patient assessment. In conclusion, the following recommendations for a risk-adapted management of vasa praevia can be made: 1. weekly evaluation of risk factors for preterm delivery; 2. steroid administration only at risk for preterm birth; 3. admission to hospital with full obstetric and neonatal care facilities between 32 and 34 weeks; 4. elective caesarean section between 35 and 37 weeks, risk-adapted.

Estrogen up-regulation of semaphorin 3F correlates with sympathetic denervation of the rat uterus.

Current evidence indicates that rises in systemic levels of estrogen create in the uterus an inhibitory environment for sympathetic nerves. However, molecular insights of these changes are far from complete. We evaluated if semaphorin 3F mRNA, a sympathetic nerve repellent, was produced by the rat uterus and if its expression was modulated by estrogen. We also analyzed whether uterine nerves express the semaphorin 3F binding receptor, neuropilin-2. Uterine levels of semaphorin 3F mRNA were measured using real time reverse transcriptase-polymerase chain reaction in prepubertal rat controls and following chronic estrogen treatment. Localization of semaphorin 3F transcripts was determined by in situ hybridization and the expression of neuropilin-2 was assessed by immunohistochemistry. These studies showed that: (1) chronic estrogen treatment led to a 5-fold induction of semaphorin 3F mRNA in the immature uterus; (2) estrogen provoked a tissue-specific induction of semaphorin 3F which was particularly localized in the connective tissue that borders muscle bundles and surrounds intrauterine blood vessels; (3) two major cell-types were recognized in the areas where transcripts were concentrated, fibroblast-like cells and infiltrating eosinophil leukocytes; and (4) some delicate nerve terminal profiles present in the estrogenized uterus were immunoreactive for neuropilin-2. Temporal and spatial expression patterns of semaphorin 3F/neuropilin-2 are consistent with a possible role of this guidance cue in the remodeling of uterine sympathetic innervation by estrogen. Though correlative in its nature, these data support a model whereby semaphorin 3F, in combination with other inhibitory molecules, converts the estrogenized myometrium to an inhospitable environment for sympathetic nerves.

Combined exposure to dog and indoor pollution: incident asthma in a high-risk birth cohort.

The impact of single exposures on asthma development is better understood than the effect of multiple exposures. The objective of the present study was to evaluate the effect of combined early exposure to dog allergen (Can-f1) plus indoor nitrogen dioxide (NO2) or environmental tobacco smoke (ETS) on asthma and bronchial hyperreactivity (BHR) in a high-risk birth cohort. We also aimed to assess atopy's impact on the effects of these exposures. Peri-birth ETS exposure was measured using cord blood cotinine (CCot). During year 1, atopy, NO2, Can-f1, and urinary cotinine (UCot) were measured. At 7 yrs of age, 380 children were assessed for asthma and BHR. Exposure effects were determined using stepwise multiple linear regression. Co-exposure to elevated Can-f1 and NO2, or Can-f1 and ETS (CCot), increased risk for asthma, relative to having neither such exposure (OR 4.8 (95% CI 1.1-21.5) and 2.7 (1.1-7.1), respectively); similar risks resulted when substituting dog ownership for allergen. Atopy increased asthma and BHR risk associated with several exposures; notably, atopy with elevated UCot, relative to atopy without such exposure, increased risk of BHR (OR 3.1 (95% CI 1.1-8.6)). In a high-risk birth cohort, early co-exposure to Can-f1 and NO2 or ETS increased the risk of incident asthma. Atopy increased the risk of asthma and BHR associated with ETS.

[Management of dichorionic twin delivery at term with cephalic-presenting first twin - a monocentric retrospective cohort study]. / Geburtsleitung bei dichorialen Zwillingen am Termin bei vorangehendem Zwilling in Schädellage - eine monozentrische retrospektive Kohortenstudie.

OBJECTIVE: To assess neonatal outcome and delivery mode in dichorionic twin delivery at term with a cephalic-presenting first twin. METHODS: A retrospective cohort study of 308 twin deliveries after 37 completed weeks of gestation with a cephalic-presenting first twin undertaken in one perinatal center with active management of second twin delivery. The neonatal outcome was measured by the Apgar score, the umbilical artery pH and the transfer into the neonatal unit. RESULTS: In the whole group, 57% were vaginally delivered and 43% needed a Cesarean delivery. The planned vaginal delivery group contained 71% while the planned elective Cesarean delivery group contained 29%. In the planned vaginal delivery group 80% were delivered vaginally, in 15% an emergency Cesarean was necessary, 5% had a vaginal delivery of the first twin followed by Cesarean delivery of the second twin. The neonatal outcome of the second twin shows a higher risk. There are significant differences in the rates of the second twin having lower rates of the umbilical artery pH >7.20 in the group of planned vaginal delivery. The higher risks are compensated in the group of planned elective Cesarean delivery. CONCLUSIONS: Planned vaginal delivery of dichorionic twins at term and active second-stage management is associated with lower rate of normal neonatal outcome. These risks should be considered in prenatal informed consent discussions with the pregnant woman.