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Nan Shao,1,* Chuanbo Xie,2,* Yawei Shi,1 Runyi Ye,1 Jianting Long,3 Huijuan Shi,4 Zhen Shan,1 Alastair M Thompson,5 Ying Lin1 1Department of Breast Surgery, Breast Disease Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; 2Department of Cancer Prevention Research, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China; 3Department of Medicinal Oncology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; 4Department of Pathology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China; 5Department of Breast Surgery, Division of Surgical Oncology, Dan L Duncan Comprehensive Cancer, Baylor College of Medicine, Houston, TX, USA *These authors contributed equally to this work Background: The 8th edition of the American Joint Committee on Cancer (AJCC) staging system for breast cancer has incorporated tumor grade, estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 status as staging biologic factors reflecting prognosis. The purpose of this study was to compare the 7th and 8th edition of AJCC staging system for prognostic impact. Materials and methods: Primary breast cancer patients diagnosed from 2010 to 2014 were identified using the Surveillance, Epidemiology and End Results 18 registries research database. Breast cancer-specific survival (BCSS) and overall survival (OS) between stages were estimated using the Kaplan–Meier method and compared using the log-rank test. Multivariable analysis was performed using Cox proportional hazards regression analysis to identify factors independently associated with outcome. Akaike’s information criterion (AIC) was calculated to estimate how well the staging system fitted the data and the complexity of the model. Results: A total of 184,221 primary breast cancer patients were identified in the 7th AJCC staging system; 16,145 (8.8%) patients could not be categorized according to 8th AJCC prognostic staging system leaving 168,076 patients included for final analyses. The 8th AJCC performed well with the BCSS and OS concordant with stage. A total of 89,494 (53.2%) of patients were restaged to a different stage group in the 8th AJCC; stage IIIA in the 7th AJCC migrated to stage IB with a worse prognosis than IIA and IIB in the 8th AJCC. Nevertheless, the 8th AJCC had a better AIC than the 7th staging system. Conclusion: The prognostic accuracy of the 8th AJCC staging system was generally superior to the 7th AJCC, although subtle differences between the two systems should be noted in comparative studies. Keywords: breast cancer, prognosis, AJCC

Angela M Thompson, Jennifer M TrujilloDepartment of Clinical Pharmacy, University of Colorado Skaggs School of Pharmacy and Pharmaceutical Sciences, Aurora, CO, USA Abstract: The purpose of this review is to provide a review of current data of the most recently approved glucagon-like peptide (GLP)-1-receptor agonist, dulaglutide, in the treatment of type 2 diabetes. To complete this, a PubMed search was performed to identify manuscripts published from 1947 to July 2015. The search terms “Trulicity”, “dulaglutide”, and “LY2189265” were utilized, and publications were included if they evaluated the pharmacology, pharmacokinetics, efficacy, safety, or patient-reported outcomes of dulaglutide. Dulaglutide is a GLP-1 receptor agonist that mimics endogenous GLP-1, the hormone produced in response to food intake. Modifications have been made to the molecule to delay breakdown and allow for once-weekly dosing. Dulaglutide has been studied as monotherapy and in combination with several agents, including metformin, glimepiride, pioglitazone, and insulin lispro. Dulaglutide has demonstrated superior efficacy compared to placebo, metformin, insulin glargine, sitagliptin, and twice-daily exenatide. It was found to be noninferior to liraglutide. The most common adverse effects in clinical studies were gastrointestinal-related adverse events, and patient satisfaction was high with the use of dulaglutide. Dulaglutide is an appealing option for the treatment of type 2 diabetes, based on its once-weekly dosing, A1c lowering comparable to liraglutide, weight reduction comparable to exenatide, and a similar adverse-effect profile to other GLP-1 receptor agonists. Keywords: dulaglutide, GLP-1 receptor agonist, T2D

Until recently, Prothrombin Time/International Normalized Ratio (PT/INR) measurements have typically been used to monitor patients on warfarin through institutional laboratories via venous puncture. The Point-of-Care Testing (POCT) device has revolutionized the patient care process by allowing for laboratory testing outside of the central laboratory. Objective: To analyze humanistic and clinical outcomes in patients currently treated with warfarin and monitored through a pharmacist-managed anticoagulation clinic using point-of-care testing (POCT) device versus venipuncture within ambulatory care clinics at our institution. Methods: All patients currently treated with warfarin therapy who were managed by clinical pharmacists for anticoagulation monitoring at the Medical University of South Carolina (MUSC) Family Medicine Center and University Diagnostic Center, were enrolled. Patients were asked to complete a satisfaction survey regarding their anticoagulation monitoring. In addition, data related to emergency department (ED) visits, hospitalizations and percent of time in the INR therapeutic range for 6 months pre- and post-implementation of POCT device was collected. This information was obtained through an electronic patient information database, Oacis. Results: A total of 145 patients were included in the data collection from the two clinics. The majority (41%) of these patients were taking warfarin for atrial fibrillation. Satisfaction surveys were completed by 86 (59 %) of patients. The surveys revealed that POCT device was preferred over venipuncture in 95% of patients. Reasons for the preference included more face-to-face interaction, less wait time, less pain, less blood needed, and quicker results. Of the 145 patients who were included in the objective data analysis, no significant differences were found in the number of hospitalizations, ED visits, or percent of time in the INR therapeutic range pre- and post- implementation of POCT device.Conclusion: The results of this study demonstrate improvement in patient satisfaction with POCT compared to venipuncture, with limited value in clinical outcomes.

© Author(s) 2018. Accurate and consistent monitoring of anthropogenic combustion is imperative because of its significant health and environmental impacts, especially at city-to-regional scale. Here, we assess the performance of the Copernicus Atmosphere Monitoring Service (CAMS) global prediction system using measurements from aircraft, ground sites, and ships during the Korea-United States Air Quality (KORUS-AQ) field study in May to June 2016. Our evaluation focuses on CAMS CO and CO2 analyses as well as two higher-resolution forecasts (16 and 9km horizontal resolution) to assess their capability in predicting combustion signatures over east Asia. Our results show a slight overestimation of CAMS CO2 with a mean bias against airborne CO2 measurements of 2.2, 0.7, and 0.3ppmv for 16 and 9km CO2 forecasts, and analyses, respectively. The positive CO2 mean bias in the 16km forecast appears to be consistent across the vertical profile of the measurements. In contrast, we find a moderate underestimation of CAMS CO with an overall bias against airborne CO measurements of -19.2 (16km), -16.7 (9km), and -20.7ppbv (analysis). This negative CO mean bias is mostly seen below 750hPa for all three forecast/analysis configurations. Despite these biases, CAMS shows a remarkable agreement with observed enhancement ratios of CO with CO2 over the Seoul metropolitan area and over the West (Yellow) Sea, where east Asian outflows were sampled during the study period. More efficient combustion is observed over Seoul (dCO dCO2 Combining double low line 9ppbvppmv-1) compared to the West Sea (dCO dCO2 Combining double low line 28ppbvppmv-1). This "combustion signature contrast" is consistent with previous studies in these two regions. CAMS captured this difference in enhancement ratios (Seoul: 8-12ppbvppmv-1, the West Sea: ∼ 30ppbvppmv-1) regardless of forecast/analysis configurations. The correlation of CAMS CO bias with CO2 bias is relatively high over these two regions (Seoul: 0.64-0.90, the West Sea: ∼ 0.80) suggesting that the contrast captured by CAMS may be dominated by anthropogenic emission ratios used in CAMS. However, CAMS shows poorer performance in terms of capturing local-to-urban CO and CO2 variability. Along with measurements at ground sites over the Korean Peninsula, CAMS produces too high CO and CO2 concentrations at the surface with steeper vertical gradients (∼ 0.4ppmvhPa-1 for CO2 and 3.5ppbvhPa-1 for CO) in the morning samples than observed (∼ 0.25ppmvhPa-1 for CO2 and 1.7ppbvhPa-1 for CO), suggesting weaker boundary layer mixing in the model. Lastly, we find that the combination of CO analyses (i.e., improved initial condition) and use of finer resolution (9km vs. 16km) generally produces better forecasts.

High mixing ratios of ozone (O3) in the northern Front Range (NFR) of Colorado are not limited to the urban Denver area but were also observed in rural areas where oil and gas activity is the primary source of O3 precursors. On individual days, oil and gas O3 precursors can contribute in excess of 30 ppb to O3 growth and can lead to exceedances of the EPA O3 National Ambient Air Quality Standard. Data used in this study were gathered from continuous surface O3 monitors for June–August 2013–2015 as well as additional flask measurements and mobile laboratories that were part of the FRAPPE/DISCOVER-AQ field campaign of July–August 2014. Overall observed O3 levels during the summer of 2014 were lower than in 2013, likely due to cooler and damper weather than an average summer. This study determined the median hourly surface O3 mixing ratio in the NFR on summer days with limited photochemical production to be approximately 45–55 ppb. Mobile laboratory and flask data collected on three days provide representative case studies of different O3 formation environments in and around Greeley, Colorado. Observations of several gases (including methane, ethane, CO, nitrous oxide) along with O3 are used to identify sources of O3 precursor emissions. A July 23 survey demonstrated low O3 (45–60 ppb) while August 3 and August 13 surveys recorded O3 levels of 75–80 ppb or more. August 3 exemplifies influence of moderate urban and high oil and gas O3 precursor emissions. August 13 demonstrates high oil and gas emissions, low agricultural emissions, and CO measurements that were well correlated with ethane from oil and gas, suggesting an oil and gas related activity as a NOx and O3 precursor source. Low isoprene levels indicated that they were not a significant contributor to O3 precursors measured during the case studies.

High time resolution measurements of volatile organic compounds (VOCs) were collected using a proton-transfer-reaction quadrupole mass spectrometry (PTR-QMS) instrument at the Platteville Atmospheric Observatory (PAO) in Colorado to investigate how oil and natural gas (O&NG) development impacts air quality within the Wattenburg Gas Field (WGF) in the Denver-Julesburg Basin. The measurements were carried out in July and August 2014 as part of NASA’s “Deriving Information on Surface Conditions from Column and Vertically Resolved Observations Relevant to Air Quality” (DISCOVER-AQ) field campaign. The PTR-QMS data were supported by pressurized whole air canister samples and airborne vertical and horizontal surveys of VOCs. Unexpectedly high benzene mixing ratios were observed at PAO at ground level (mean benzene = 0.53 ppbv, maximum benzene = 29.3 ppbv), primarily at night (mean nighttime benzene = 0.73 ppbv). These high benzene levels were associated with southwesterly winds. The airborne measurements indicate that benzene originated from within the WGF, and typical source signatures detected in the canister samples implicate emissions from O&NG activities rather than urban vehicular emissions as primary benzene source. This conclusion is backed by a regional toluene-to-benzene ratio analysis which associated southerly flow with vehicular emissions from the Denver area. Weak benzene-to-CO correlations confirmed that traffic emissions were not responsible for the observed high benzene levels. Previous measurements at the Boulder Atmospheric Observatory (BAO) and our data obtained at PAO allow us to locate the source of benzene enhancements between the two atmospheric observatories. Fugitive emissions of benzene from O&NG operations in the Platteville area are discussed as the most likely causes of enhanced benzene levels at PAO.

A model intercomparison activity was inspired by the large suite of observations of atmospheric composition made during the International Polar Year (2008) in the Arctic. Nine global and two regional chemical transport models participated in this intercomparison and performed simulations for 2008 using a common emissions inventory to assess the differences in model chemistry and transport schemes. This paper summarizes the models and compares their simulations of ozone and its precursors and presents an evaluation of the simulations using a variety of surface, balloon, aircraft and satellite observations. Each type of measurement has some limitations in spatial or temporal coverage or in composition, but together they assist in quantifying the limitations of the models in the Arctic and surrounding regions. Despite using the same emissions, large differences are seen among the models. The cloud fields and photolysis rates are shown to vary greatly among the models, indicating one source of the differences in the simulated chemical species. The largest differences among models, and between models and observations, are in NOy partitioning (PAN vs. HNO3) and in oxygenated volatile organic compounds (VOCs) such as acetaldehyde and acetone. Comparisons to surface site measurements of ethane and propane indicate that the emissions of these species are significantly underestimated. Satellite observations of NO2 from the OMI (Ozone Monitoring Instrument) have been used to evaluate the models over source regions, indicating anthropogenic emissions are underestimated in East Asia, but fire emissions are generally overestimated. The emission factors for wildfires in Canada are evaluated using the correlations of VOCs to CO in the model output in comparison to enhancement factors derived from aircraft observations, showing reasonable agreement for methanol and acetaldehyde but underestimate ethanol, propane and acetone, while overestimating ethane emission factors.

The International Tamoxifen Pharmacogenomics Consortium was established to address the controversy regarding cytochrome P450 2D6 (CYP2D6) status and clinical outcomes in tamoxifen therapy. We performed a meta-analysis on data from 4,973 tamoxifen-treated patients (12 globally distributed sites). Using strict eligibility requirements (postmenopausal women with estrogen receptor-positive breast cancer, receiving 20 mg/day tamoxifen for 5 years, criterion 1); CYP2D6 poor metabolizer status was associated with poorer invasive disease-free survival (IDFS: hazard ratio = 1.25; 95% confidence interval = 1.06, 1.47; P = 0.009). However, CYP2D6 status was not statistically significant when tamoxifen duration, menopausal status, and annual follow-up were not specified (criterion 2, n = 2,443; P = 0.25) or when no exclusions were applied (criterion 3, n = 4,935; P = 0.38). Although CYP2D6 is a strong predictor of IDFS using strict inclusion criteria, because the results are not robust to inclusion criteria (these were not defined a priori), prospective studies are necessary to fully establish the value of CYP2D6 genotyping in tamoxifen therapy.

Analysis of chemical transport on Flight 10 of the 1999 Pacific Exploratory Mission (PEM) Tropics B mission clarifies the role of the South Pacific Convergence Zone (SPCZ) in establishing ozone and other trace gas distributions in the southwestern tropical Pacific. The SPCZ is found to be a barrier to mixing in the lower troposphere but a mechanism for convective mixing of tropical boundary layer air from northeast of the SPCZ with upper tropospheric air arriving from the west. A two-dimensional cloud-resolving model is used to quantify three critical processes in global and regional transport: convective mixing, lightning NOx production, and wet scavenging of soluble species. Very low NO and O3 tropical boundary layer air from the northeastern side of the SPCZ entered the convective updrafts and was transported to the upper troposphere where it mixed with subtropical upper tropospheric air containing much larger NO and O3 mixing ratios that had arrived from Australia. Aircraft observations show that very little NO appears to have been produced by electrical discharges within the SPCZ convection. We estimate that at least 90% of the HNO3 and H2O2 that would have been in upper tropospheric cloud outflow had been removed during transport through the cloud. Lesser percentages are estimated for less soluble species (e.g.,

Mixing ratios of nonmethane hydrocarbons (NMHCs) were not enhanced in whole air samples collected within the North Atlantic Flight Corridor (NAFC) during the fall of 1997. The investigation was conducted aboard NASA's DC-8 research aircraft, as part of the Subsonic Assessment (SASS) Ozone and Nitrogen Oxide Experiment (SONEX). NMHC enhancements were not detected within the general organized tracking system of the NAFC, nor during two tail chases of the DC-8's own exhaust. Because positive evidence of aircraft emissions was demonstrated by enhancements in both nitrogen oxides and condensation nuclei during SONEX, the NMHC results suggest that the commercial air traffic fleet operating in the North Atlantic region does not contribute at all or contributes negligibly to NMHCs in the NAFC. Copyright 2000 by the American Geophysical Union.

The impact of aircraft emissions on reactive nitrogen in the upper troposphere (UT) and lowermost stratosphere (LS) was estimated using the NOy-O3 correlation obtained during the Subsonic Assessment (SASS) Ozone and Nitrogen Oxide Experiment (SONEX) carried out over the U.S. continent and North Atlantic Flight Corridor (NAFC) region in October and November 1997. To evaluate the large-scale impact, we made a reference NOy-O3 relationship in air masses, upon which aircraft emissions were considered to have little impact. For this purpose, the integrated input of NOx from aircraft into an air mass along a 10-day back trajectory (ΔNOy) was calculated based on the Abatement of Nuisance Caused by Air Traffic/European Commission (ANCAT/EC2) emission inventory. The excess NOy (dNOy) was calculated from the observed NOy and the reference NOy-O3 relationship. As a result, a weak positive correlation was found between the dNOy and ΔNOy, and dNOy and NOx/NOy values, while no positive correlation between the dNOy and CO values was found, suggesting that dNOy values can be used as a measure of the NOx input from aircraft emissions. The excess NOy values calculated from another NOy-O3 reference relationship made using in situ condensation nuclei data also agreed with these dNOy values, within the uncertainties. At the NAFC region (45° N-60° N) the median value of dNOy in the troposphere increased with altitude above 9 km and reached 70 parts per trillion by volume (pptv) (20% of NOy) at 11 km. The excess NOx was estimated to be about half of the dNOy values, corresponding to 30% of the observed NOx level. Higher dNOy values were generally found in air masses where O3 = 75-125 ppbv, suggesting a more pronounced effect around the tropopause. The median value of dNOy in the stratosphere at the NAFC region at 8.5-11.5 km was about 120 pptv. The higher dNOy values in the LS were probably due to the accumulated effect of aircraft emissions, given the long residence time of affected air in the LS. Similar dNOy values were also obtained in air masses sampled over the U.S. continent. Copyright 2000 by the American Geophysical Union.

We examine concurrent measurements of CN (size > 8 nm), NO, and NO(y) in the upper troposphere over the North Atlantic during the SONEX Experiment (Oct.-Nov., 1997). High CN and NO(y) observations are attributed largely to the enhancement in convective outflow. Using the ratio of NO/NO(y) as a chemical clock, we estimate that dilution of convective high-CN plumes is rapid (on a time scale of 10000 cm−3) plumes may be attributed to aircraft emissions. The contribution by aircraft emissions to upper tropospheric CN concentrations is estimated to be significantly higher than 7% because aircraft plumes dilute much faster than convective plumes and hence are sampled less frequently.

The NASA GTE TRACE A mission sampled air over the South Atlantic and western Indian Oceans. Thirteen flight legs were flown within the marine boundary layer (MBL). The MBL was typically the cleanest air sampled (e.g., CH4 < 1680 ppb, CO < 70 ppb, C2H6 < 400 ppt, C3H8 < 40 ppt, NOx < 15 ppt, and midday NO < 5 ppt) but was overlain by polluted air. The photochemistry of the MBL was influenced by oceanic emissions, surface deposition, and entrainment of pollutants from aloft. Chemical budgets were constructed for several species in the MBL in order to investigate these effects and are presented for ethane, ethylene, propane, propylene, n-butane, formic acid (HFo), methylhydroperoxide (CH3OOH), oxides of nitrogen (i.e., NO, NO2, PAN, HNO3), hydrogen peroxide (H2O2), and ozone (O3). A photochemical point model was used to evaluate local chemical production and loss. An entrainment model was used to assess material exchange between the lower free troposphere (FT) and the MBL and a resistance deposition model was used to evaluate material exchange across the air-sea interface. The results suggested the ocean to be the source of measured alkenes in the MBL and to be the most likely source of the shorter-lived alkanes: propane and n-butane. Ethane was the only hydrocarbon for which input from aloft may have exceeded its photochemical destruction. The estimated hydrocarbon sources from the ocean were in agreement with prior analyses. Transport from the lower FT together with surface loss could not account for measured concentrations of CH2O, HFo, and HNO3. The transport of peroxyacetylnitrate (PAN) from the FT to the MBL exceeded the rate of HNO3 production and was more than sufficient to maintain observed NOx levels without having to invoke an oceanic source for NO. The flux of NOx, PAN, and HNO3 was in balance with the surface deposition flux of HNO3. However, the predicted rates of HNO3 formation from the oxidation of NO2 and HNO3 entrainment from aloft were inadequate to maintain observed levels of HNO3 unless HNO3 was partitioned between the gas phase and a more slowly depositing aerosol phase. The estimated dry deposition flux of HNO3 to the South Atlantic during TRACE A, 2-4 × 109 molecules cm-2 s-1, was about 10 times the annual average estimate for this region. The destruction of O3 within the MBL was found to be exceeded by transport into the MBL from aloft, 6 ±2 × 1010 compared to 11 ± 10 × 1010 molecules cm-2 s-1. The principal O3 destruction process was mediated by the formation and surface deposition of H2O2 and CH3OOH, 4 ± 4 × 1010 and 1.1 ± 0.5 × 1010 molecules cm-2 s-1. The direct loss of O3 to the sea surface was estimated to be 1.7 ± 0.2 × 1010 molecules cm-2 s-1. CH3OOH was lost to the sea and transported into the FT from the MBL. Its first-order loss rate was estimated to be 7 × 10-6 s-1 for a mean MBL height of 700 m. H2O2 and CH2O losses from the MBL were estimated at rates of 1.3 × 10-5 s-1 for both species. The inclusion of surface deposition improved the agreement between predicted and measured concentrations of HNO3, CH3OOH, H2O2, and CH2O. However, model CH2O remained significantly greater than that measured in the MBL.

Atmospheric methane, CO and the gaseous OH radical are interdependent: If CH4, CO or OH is perturbed, background concentrations of the other two constituents are affected. Perturbations to OH alter photo-oxidation rates of numerous natural and anthropogenic trace gases and affect lifetimes of those species that pass from the Earth's surface to the free troposphere and stratosphere. It is now known that global atmospheric methane concentrations are increasing1-6; less definite data suggest that carbon monoxide is also increasing1,7-9. Even before the measurements of refs 1-9 were made, modelling studies of CH4-CO-OH coupling had led to predictions10-12 of future temporal increases of CH4 and CO. Here we look backwards in time, using a photochemical model to simulate the trace-gas composition of the unpolluted troposphere at the start of the industrial era (taken as 1860), and at intervals up to 1985. We find that the OH concentration in the background troposphere has decreased significantly and O3 has increased due to increases of CH4 and CO; calculated changes depend on temporal trends of NOx (NOx = NO + NO2), for which no historical data are available. The calculations allow recent trace-gas trends affecting background chemistry and climate to be viewed in a longer-term context. © 1986 Nature Publishing Group.

We describe a modeling study of the effects of clouds and wet removal on the chemistry of the remote marine troposphere. Using a time-dependent model with parameterized vertical transport to calculate trace-gas concentrations, we find that large variations in key species result from simulations of sporadic rainfall, changes in cloud cover, and external inputs such as surface NO sources. -from Authors