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.

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.

Efficacy and Safety of Anti-TNF-α Agents in Inflammatory Bowel Disease After Liver Transplant: A Case Series.

BACKGROUND: Ulcerative colitis (UC) and Crohn disease (CD) can appear de novo or worsen after liver transplant. Our aim was to assess the efficacy and safety of anti-tumor necrosis-alpha (anti-TNF-α) agents after transplantation. METHODS: We reviewed the clinical database of our center searching for all liver transplant patients with inflammatory bowel disease who were treated with anti-TNF-α agents between 1997 and 2017. Clinical response was assessed from clinical activity indices 12 weeks after starting treatment. The median age of the 6 patients (3 women) was 37 years. Four patients were diagnosed before transplantation (2 UC and 2 CD), and in the other 2 the disease appeared de novo (1 UC and 1 CD). The indications for transplant were primary sclerosing cholangitis (n = 3), cryptogenic cirrhosis (n = 2), and hepatitis C virus cirrhosis (n = 1). RESULTS: Clinical response was seen in 3 of the 6 patients and, in the 3 cases for whom endoscopic data were available, no mucous healing was seen. The only adverse effects noted over a mean follow-up of 15 months were 1 cytomegalovirus infection and 1 severe infusion reaction to infliximab. No patients had recurrence of primary sclerosing cholangitis in the graft, and none of the patients died. CONCLUSION: Use of an anti-TNF-α agent in a liver transplant patient with inflammatory bowel disease may be an effective option, with an acceptable risk-benefit ratio. Further studies are required to confirm their use in this context.

Retransplant Due to Fulminant Hepatic Failure From Hepatitis E Virus: A Case Report.

Hepatitis E virus (HEV) usually causes self-limiting acute liver infections from fecal or oral transmission, though other routes of infection exist (vertical transmission, blood transfusion, zoonosis). It may give rise to fulminant hepatic failure in 1% of cases. Cases have recently been reported of chronic infection evolving to cirrhosis in immunosuppressed patients, such as those with a liver or kidney transplant. Nonetheless, development of acute liver failure in these patients is exceptional, with few cases published. We present a case of acute liver failure due to HEV in a liver transplant patient who required a liver retransplant 9 years after receiving the original transplant.

Tropospheric Emissions: Monitoring of Pollution (TEMPO).

TEMPO was selected in 2012 by NASA as the first Earth Venture Instrument, for launch between 2018 and 2021. It will measure atmospheric pollution for greater North America from space using ultraviolet and visible spectroscopy. TEMPO observes from Mexico City, Cuba, and the Bahamas to the Canadian oil sands, and from the Atlantic to the Pacific, hourly and at high spatial resolution (~2.1 km N/S×4.4 km E/W at 36.5°N, 100°W). TEMPO provides a tropospheric measurement suite that includes the key elements of tropospheric air pollution chemistry, as well as contributing to carbon cycle knowledge. Measurements are made hourly from geostationary (GEO) orbit, to capture the high variability present in the diurnal cycle of emissions and chemistry that are unobservable from current low-Earth orbit (LEO) satellites that measure once per day. The small product spatial footprint resolves pollution sources at sub-urban scale. Together, this temporal and spatial resolution improves emission inventories, monitors population exposure, and enables effective emission-control strategies. TEMPO takes advantage of a commercial GEO host spacecraft to provide a modest cost mission that measures the spectra required to retrieve ozone (O3), nitrogen dioxide (NO2), sulfur dioxide (SO2), formaldehyde (H2CO), glyoxal (C2H2O2), bromine monoxide (BrO), IO (iodine monoxide),water vapor, aerosols, cloud parameters, ultraviolet radiation, and foliage properties. TEMPO thus measures the major elements, directly or by proxy, in the tropospheric O3 chemistry cycle. Multi-spectral observations provide sensitivity to O3 in the lowermost troposphere, substantially reducing uncertainty in air quality predictions. TEMPO quantifies and tracks the evolution of aerosol loading. It provides these near-real-time air quality products that will be made publicly available. TEMPO will launch at a prime time to be the North American component of the global geostationary constellation of pollution monitoring together with the European Sentinel-4 (S4) and Korean Geostationary Environment Monitoring Spectrometer (GEMS) instruments.

Contribution of Arctic seabird-colony ammonia to atmospheric particles and cloud-albedo radiative effect.

The Arctic region is vulnerable to climate change and able to affect global climate. The summertime Arctic atmosphere is pristine and strongly influenced by natural regional emissions, which have poorly understood climate impacts related to atmospheric particles and clouds. Here we show that ammonia from seabird-colony guano is a key factor contributing to bursts of newly formed particles, which are observed every summer in the near-surface atmosphere at Alert, Nunavut, Canada. Our chemical-transport model simulations indicate that the pan-Arctic seabird-influenced particles can grow by sulfuric acid and organic vapour condensation to diameters sufficiently large to promote pan-Arctic cloud-droplet formation in the clean Arctic summertime. We calculate that the resultant cooling tendencies could be large (about -0.5 W m-2 pan-Arctic-mean cooling), exceeding -1 W m-2 near the largest seabird colonies due to the effects of seabird-influenced particles on cloud albedo. These coupled ecological-chemical processes may be susceptible to Arctic warming and industrialization.

UK guidelines for the management of Stevens-Johnson syndrome/toxic epidermal necrolysis in adults 2016.

The overall objective of the guideline is to provide up-to-date, evidence-based recommendations for the diagnosis and management of the full spectrum of Stevens-Johnson syndrome (SJS), toxic epidermal necrolysis (TEN) and SJS-TEN overlap in adults during the acute phase of the disease. The document aims to.

Fifteen-year global time series of satellite-derived fine particulate matter.

Ambient fine particulate matter (PM2.5) is a leading environmental risk factor for premature mortality. We use aerosol optical depth (AOD) retrieved from two satellite instruments, MISR and SeaWiFS, to produce a unified 15-year global time series (1998-2012) of ground-level PM2.5 concentration at a resolution of 1° x 1°. The GEOS-Chem chemical transport model (CTM) is used to relate each individual AOD retrieval to ground-level PM2.5. Four broad areas showing significant, spatially coherent, annual trends are examined in detail: the Eastern U.S. (-0.39 ± 0.10 µg m(-3) yr(-1)), the Arabian Peninsula (0.81 ± 0.21 µg m(-3) yr(-1)), South Asia (0.93 ± 0.22 µg m(-3) yr(-1)) and East Asia (0.79 ± 0.27 µg m(-3) yr(-1)). Over the period of dense in situ observation (1999-2012), the linear tendency for the Eastern U.S. (-0.37 ± 0.13 µg m(-3) yr(-1)) agrees well with that from in situ measurements (-0.38 ± 0.06 µg m(-3) yr(-1)). A GEOS-Chem simulation reveals that secondary inorganic aerosols largely explain the observed PM2.5 trend over the Eastern U.S., South Asia, and East Asia, while mineral dust largely explains the observed trend over the Arabian Peninsula.

Percutaneous dilational and surgical tracheostomy in burn patients: incidence of complications and dysphagia.

The aim of this study is to evaluate the incidence of complications and dysphagia in relation to the timing of tracheostomy and tracheostomy technique in 49 consecutive adult burn patients. We analysed prospectively collected data. Bronchoscopy was used to diagnose tracheal stenosis and a modified Evans blue dye test was used to diagnose dysphagia. Eighteen patients received a percutaneous dilatational tracheostomy (PDT) and thirty-one patients received an open surgical tracheostomy (OST). Eight patients developed significant complications (16%) following tracheostomy, there is no difference in the incidence of complications; post op infection, stoma infection or tracheal stenosis between PDT and OST groups. Patients with full thickness neck burn who developed complications had a tracheostomy significantly earlier following autografting (p=0.05). Failed extubation is associated with dysphagia (p=0.02) whereas prolonged intubation and ventilation prior to tracheostomy independently predicts dysphagia (p=0.03). We conclude that there is no difference in the complication rates for PDT and OST in our burn patients. We recommend early closure of neck burns and tracheostomy through fully adherent autograft or at least 10 days after grafting to reduce stomal infections. For patients with no neck burn, we support early tracheostomy to reduce the likelihood of dysphagia.

Scaling relationship for NO2 pollution and urban population size: a satellite perspective.

Concern is growing about the effects of urbanization on air pollution and health. Nitrogen dioxide (NO2) released primarily from combustion processes, such as traffic, is a short-lived atmospheric pollutant that serves as an air-quality indicator and is itself a health concern. We derive a global distribution of ground-level NO2 concentrations from tropospheric NO2 columns retrieved from the Ozone Monitoring Instrument (OMI). Local scaling factors from a three-dimensional chemistry-transport model (GEOS-Chem) are used to relate the OMI NO2 columns to ground-level concentrations. The OMI-derived surface NO2 data are significantly correlated (r = 0.69) with in situ surface measurements. We examine how the OMI-derived ground-level NO2 concentrations, OMI NO2 columns, and bottom-up NOx emission inventories relate to urban population. Emission hot spots, such as power plants, are excluded to focus on urban relationships. The correlation of surface NO2 with population is significant for the three countries and one continent examined here: United States (r = 0.71), Europe (r = 0.67), China (r = 0.69), and India (r = 0.59). Urban NO2 pollution, like other urban properties, is a power law scaling function of the population size: NO2 concentration increases proportional to population raised to an exponent. The value of the exponent varies by region from 0.36 for India to 0.66 for China, reflecting regional differences in industrial development and per capita emissions. It has been generally established that energy efficiency increases and, therefore, per capita NOx emissions decrease with urban population; here, we show how outdoor ambient NO2 concentrations depend upon urban population in different global regions.

Síndrome de Klippel-Trénaunay: a propósito de un caso / Klippel-Trénaunay syndrome: based on one case

El síndrome de Klippel-Trénaunay se caracteriza por una tríada de manifestaciones clínicas: angiomatosis cutánea, hipertrofia y venas varicosas, que afectan, por lo general, a una extremidad. Presentamos el caso de una niña de 13 años de edad con un angioma plano unilateral desde el pie derecho hasta la región mamilar derecha, varicosidades e hipotrofia del miembro inferior derecho, que ha precisado tratamiento de rehabilitación por linfedema y después de una intervención ortopédica para el alargamiento de dicho miembro. Con ello queremos recordar la existencia de este síndrome, que hoy por hoy tiene una etiopatogenia no aclarada, y conocer sus principales manifestaciones clínicas, que nos proporcionan el diagnóstico, y su tratamiento, sintomático, donde la rehabilitación desempeña un papel primordial dentro del abordaje multidisciplinar (AU)