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Abstract: The complexity of air quality modeling systems, air quality monitoring data make ad-hoc systems for model evaluation important aids to the modeling community. Among those are the ENSEMBLE system developed by the EC-Joint Research Center, and the AMET software developed by the US-EPA. These independent systems provide two examples of state of the art tools to support model evaluation. The two systems are described here mostly from the point of view of the support to air quality model users or developers rather than the technological point of view. While ENSEMBLE is a web based platform for model evaluation that allows the collection, share and treatment of model results as well as monitoring data, AMET is a standalone tool that works directly on single model data. The complementarity of the two approaches makes the two systems optimal for operational, diagnostic and probabilistic evaluations. ENSEMBLE and AMET have been extended in occasion of the AQMEII two-continent exercise and the new developments are described in this paper, together with those foreseen for the future. [Copyright &y& Elsevier]

We examine the impact of dimethylsulfide (DMS) emissions on sulfate concentrations over the continental U.S. by using the Community Multiscale Air Quality (CMAQ) model version 5.4 and performing annual simulations without and with DMS emissions for 2018. DMS emissions enhance sulfate not only over seawater but also over land, although to a lesser extent. On an annual basis, the inclusion of DMS emissions increase sulfate concentrations by 36% over seawater and 9% over land. The largest impacts over land occur in California, Oregon, Washington, and Florida, where the annual mean sulfate concentrations increase by ~25%. The increase in sulfate causes a decrease in nitrate concentration due to limited ammonia concentration especially over seawater and an increase in ammonium concentration with a net effect of increased inorganic particles. The largest sulfate enhancement occurs near the surface (over seawater) and the enhancement decreases with altitude, diminishing to 10-20% at an altitude of ~5 km. Seasonally, the largest enhancement of sulfate over seawater occurs in summer, and the lowest in winter. In contrast, the largest enhancements over land occur in spring and fall due to higher wind speeds that can transport more sulfate from seawater into land., Competing Interests: Conflicts of Interest: The authors declare no conflict of interest.

Atmospheric nitrogen oxide and nitrogen dioxide (NO + NO 2 , together termed as NO X ) estimates from annual photochemical simulations for years 2002-2016 are compared to surface network measurements of NO X and total gas-phase-oxidized reactive nitrogen (NO Y ) to evaluate the Community Multiscale Air Quality (CMAQ) modeling system performance by U.S. region, season, and time of day. In addition, aircraft measurements from 2011 Deriving Information on Surface Conditions from Column and Vertically Resolved Observations Relevant to Air Quality are used to evaluate how emissions, chemical mechanism, and measurement uncertainty each contribute to the overall model performance. We show distinct seasonal and time-of-day patterns in NO X performance. Summertime NO X is overpredicted with bimodal peaks in bias during early morning and evening hours and persisting overnight. The summertime morning NO X bias dropped from between 28% and 57% for earlier years (2002-2012) to between -2% and 7% for later years (2013-2016). Summer daytime NO X tends to be unbiased or underpredicted. In winter, the evening NO X overpredictions remain, but NO X is unbiased or underpredicted overnight, in the morning, and during the day. NO X overpredictions are most pronounced in the Midwestern and Southern United States with Western regions having more of a tendency toward model underpredictions of NO X . Modeled NO X performance has improved substantially over time, reflecting updates to the emission inputs and the CMAQ air quality model. Model performance improvements are largest for years simulated with CMAQv5.1 or later and for emission inventory years 2014 and later, coinciding with reduced onroad NO X emissions from vehicles with newer emission control technologies and improved treatment of chemistry, deposition, and vertical mixing in CMAQ. Our findings suggest that emissions temporalization of specific mobile source sectors have a small impact on model performance, while chemistry updates improve predictions of NO Y but do not improve summertime NO X bias in the Baltimore/DC area. Sensitivity runs performed for different locations across the country suggest that the improvement in summer NO X performance can be attributed to updates in vertical mixing incorporated in CMAQv5.1., Competing Interests: Competing interests The authors have no competing interests.

NASA's Deriving Information on Surface Conditions from Column and Vertically Resolved Observations Relevant to Air Quality (DISCOVER-AQ, conducted in 2011-2014) campaign in the United States and the joint NASA and National Institute of Environmental Research (NIER) Korea-United States Air Quality Study (KORUS-AQ, conducted in 2016) in South Korea were two field study programs that provided comprehensive, integrated datasets of airborne and surface observations of atmospheric constituents, including nitrogen dioxide (NO 2 ), with the goal of improving the interpretation of spaceborne remote sensing data. Various types of NO 2 measurements were made, including in situ concentrations and column amounts of NO 2 using ground- and aircraft-based instruments, while NO 2 column amounts were being derived from the Ozone Monitoring Instrument (OMI) on the Aura satellite. This study takes advantage of these unique datasets by first evaluating in situ data taken from two different instruments on the same aircraft platform, comparing coincidently sampled profile-integrated columns from aircraft spirals with remotely sensed column observations from ground-based Pandora spectrometers, intercomparing column observations from the ground (Pandora), aircraft (in situ vertical spirals), and space (OMI), and evaluating NO 2 simulations from coarse Global Modeling Initiative (GMI) and high-resolution regional models. We then use these data to interpret observed discrepancies due to differences in sampling and deficiencies in the data reduction process. Finally, we assess satellite retrieval sensitivity to observed and modeled a priori NO 2 profiles. Contemporaneous measurements from two aircraft instruments that likely sample similar air masses generally agree very well but are also found to differ in integrated columns by up to 31.9 %. These show even larger differences with Pandora, reaching up to 53.9 %, potentially due to a combination of strong gradients in NO 2 fields that could be missed by aircraft spirals and errors in the Pandora retrievals. OMI NO 2 values are about a factor of 2 lower in these highly polluted environments due in part to inaccurate retrieval assumptions (e.g., a priori profiles) but mostly to OMI's large footprint (> 312 km 2 )., Competing Interests: Competing interests. The authors declare that they have no conflict of interest.

Background: CheckMate 171 (NCT02409368) is an open-label, multicentre, phase 2 trial of nivolumab in previously treated advanced squamous non-small cell lung cancer (NSCLC), conducted as part of a post-approval commitment to the European Medicines Agency (EMA). We report outcomes from this trial., Methods: Patients with Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2 and disease progression during/after ≥1 systemic treatment (≥1 being platinum-based chemotherapy) for advanced or metastatic disease were treated with nivolumab 3 mg/kg every 2 weeks until progression or unacceptable toxicity. The primary end-point was incidence of grade 3-4 treatment-related select adverse events (AEs). Other end-points included overall survival (OS) and safety., Results: Of 811 patients treated, 103 had ECOG PS 2; 278 were aged ≥70 years and 125 were ≥75 years of age. Minimum follow-up was ~18 months. Safety was similar across populations; the most frequent grade 3-4 treatment-related select AEs in all treated patients were diarrhoea (1%), increased alanine aminotransferase (ALT, 1%), pneumonitis (0.7%), colitis (0.6%) and increased aspartate aminotransferase (AST, 0.5%). Median OS was similar in all treated patients and those aged ≥70 and ≥75: 10.0 months, 10.0 months and 11.2 months, respectively. Median OS was 5.2 months in patients with ECOG PS 2., Conclusion: These results suggest that nivolumab is well tolerated and active in patients with advanced, relapsed squamous NSCLC, including the elderly, with OS outcomes consistent with phase 3 data. In patients with ECOG PS 2, nivolumab had similar tolerability, but outcomes were worse, as expected in this difficult-to-treat, poor prognosis population., Clinical Trial Registration: NCT02409368., Competing Interests: Conflict of interest statement E.F. reports receiving personal fees from AbbVie, AstraZeneca, Blueprint medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Eli Lilly, Guardant Health, Janssen, Medscape, Merck KGaA, Merck Sharp & Dohme, Novartis, Pfizer, priME Oncology, Roche, Samsung, Springer, Takeda, and Touchtime, outside the submitted work. A.A. reports receiving personal fees from Boehringer Ingelheim, Eli Lilly, MSD, and Pfizer, grants from Celgene, and grants and personal fees from Bristol-Myers Squibb and Roche, outside the submitted work. T.C. reports receiving personal fees from Amgen, Astellas, AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Janssen, MSD, Novartis/GSK, Pfizer, Roche, Sanofi, and Servier, outside the submitted work. M.C., K.L., M.S., E.C., M.A.G., D.I., and J.M. have nothing to disclose. R.C. reports receiving grants from Bristol-Myers Squibb during the conduct of the study, and personal fees from AstraZeneca, Boehringer Ingelheim, Bristol-Myers Squibb, Lilly Oncology, MSD, Novartis, Pfizer, Roche, and Takeda, outside the submitted work. R.G. reports receiving personal fees from Bristol-Myers Squibb, outside the submitted work. L. P-A. reports receiving personal fees from Amgen, Bayer, Blueprint, Eli Lilly, Incyte, Merck, MSD, Novartis, Roche, and Takeda, and grants and personal fees from AstraZeneca and Bristol-Myers Squibb, outside the submitted work. R.D. reports receiving travel grants from Amgen and Roche, receiving travel grants and holding advisory position for Pfizer, and acting in an advisory role for Ely Lilly and Novartis, outside the submitted work. J.J. reports receiving personal fees from AstraZeneca, Bristol-Myers Squibb, MSD, Pfizer, Roche, and Takeda, and receiving travel support from Roche, outside the submitted work. W.A. reports receiving non-financial support from Boehringer Ingelheim and Bristol-Myers Squibb, personal fees from AstraZeneca and Pfizer, personal fees and non-financial support from Amgen and Roche, outside the submitted work. J.P.V.M. reports receiving travel support from Bristol-Myers Squibb and institutional grants from Pfizer, outside the submitted work. J.W. reports receiving personal fees from AbbVie, AstraZeneca, Blueprint, Boehringer Ingelheim, Chugai, Eli Lilly, Ignyta, Loxo, Roche, and Takeda, and grants and personal fees from Bristol-Myers Squibb, Janssen, MSD, Novartis, and Pfizer, outside the submitted work. A.L. and A.A. were employees of Bristol-Myers Squibb during the conduct of the study and A.A. has received company stock from Bristol-Myers Squibb. S.P. reports receiving personal fees from Bristol-Myers Squibb during the conduct of the study; personal fees from AbbVie, AstraZeneca, Boehringer Ingelheim, Elsevier, EMD Serono, Guardant Health, Medscape, MSD, Novartis, OncLive, Pfizer, Roche, Takeda, and Tesaro, outside the submitted work., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Ammonia surface flux is bidirectional; that is, net flux can be either upward or downward. In fertilized agricultural croplands and grasslands there is usually more emission than deposition especially in midday during warmer seasons. In North America, most of the ammonia emissions are from agriculture with a significant fraction of that coming from fertilizer. A new bidirectional ammonia flux modeling system has been developed in the Community Multiscale Air Quality (CMAQ) model, which has close linkages with the Environmental Policy Integrated Climate (EPIC) agricultural ecosystem model. Daily inputs from EPIC are used to calculate soil ammonia concentrations that are combined with air concentrations in CMAQ to calculate bidirectional surface flux. The model is evaluated against surface measurements of NH 3 concentrations, NH 4 + and SO 4 2- aerosol concentrations, NH 4 + wet deposition measurements, and satellite retrievals of NH 3 concentrations. The evaluation shows significant improvement over the base model without bidirectional ammonia flux. Comparisons to monthly average satellite retrievals show similar spatial distribution with the highest ammonia concentrations in the Central Valley of California (CA), the Snake River valley in Idaho, and the western High Plains. In most areas the model underestimates, but in the Central Valley of CA, it generally overestimates ammonia concentration. Case study analyses indicate that modeled high fluxes of ammonia in CA are often caused by anomalous high soil ammonia loading from EPIC for particular crop types. While further improvements to parameterizations in EPIC and CMAQ are recommended, this system is a significant advance over previous ammonia bidirectional surface flux models.

Purpose: Prophylactic irradiation to the chest wall after diagnostic or therapeutic procedures in patients with malignant pleural mesothelioma (MPM) has been a widespread practice across Europe, although the efficacy of this treatment is uncertain. In this study, we aimed to determine the efficacy of prophylactic radiotherapy in reducing the incidence of chest wall metastases (CWM) after a procedure in MPM., Methods: After undergoing a chest wall procedure, patients with MPM were randomly assigned to receive prophylactic radiotherapy (within 42 days of the procedure) or no radiotherapy. Open thoracotomies, needle biopsies, and indwelling pleural catheters were excluded. Prophylactic radiotherapy was delivered at a dose of 21 Gy in three fractions over three consecutive working days, using a single electron field adapted to maximize coverage of the tract from skin surface to pleura. The primary outcome was the incidence of CWM within 6 months from random assignment, assessed in the intention-to-treat population. Stratification factors included epithelioid histology and intention to give chemotherapy., Results: Between July 30, 2012, and December 12, 2015, 375 patients were recruited from 54 centers and randomly assigned to receive prophylactic radiotherapy (n = 186) or no prophylactic radiotherapy (n = 189). Participants were well matched at baseline. No significant difference was seen in the incidence of CWM at 6 months between the prophylactic radiotherapy and no radiotherapy groups (no. [%]: 6 [3.2] v 10 [5.3], respectively; odds ratio, 0.60; 95% CI, 0.17 to 1.86; P = .44). Skin toxicity was the most common radiotherapy-related adverse event in the prophylactic radiotherapy group, with 96 patients (51.6%) receiving grade 1; 19 (10.2%), grade 2; and 1 (0.5%) grade 3 radiation dermatitis (Common Terminology Criteria for Adverse Events, version 4.0)., Conclusion: There is no role for the routine use of prophylactic irradiation to chest wall procedure sites in patients with MPM.

Wildland fire emissions are routinely estimated in the US Environmental Protection Agency's National Emissions Inventory, specifically for fine particulate matter (PM 2.5 ) and precursors to ozone (O 3 ); however, there is a large amount of uncertainty in this sector. We employ a brute-force zero-out sensitivity method to estimate the impact of wildland fire emissions on air quality across the contiguous US using the Community Multiscale Air Quality (CMAQ) modelling system. These simulations are designed to assess the importance of wildland fire emissions on CMAQ model performance and are not intended for regulatory assessments. CMAQ ver. 5.0.1 estimated that fires contributed 11% to the mean PM 2.5 and less than 1% to the mean O 3 concentrations during 2008-2012. Adding fires to CMAQ increases the number of 'grid-cell days' with PM 2.5 above 35 μg m -3 by a factor of 4 and the number of grid-cell days with maximum daily 8-h average O 3 above 70 ppb by 14%. Although CMAQ simulations of specific fires have improved with the latest model version (e.g. for the 2008 California wildfire episode, the correlation r = 0.82 with CMAQ ver. 5.0.1 v. r = 0.68 for CMAQ ver. 4.7.1), the model still exhibits a low bias at higher observed concentrations and a high bias at lower observed concentrations. Given the large impact of wildland fire emissions on simulated concentrations of elevated PM 2.5 and O 3 , improvements are recommended on how these emissions are characterised and distributed vertically in the model., Competing Interests: Conflicts of interest The authors declare that they have no conflicts of interest.

Background: Concurrent chemoradiotherapy is the standard of care in limited-stage small-cell lung cancer, but the optimal radiotherapy schedule and dose remains controversial. The aim of this study was to establish a standard chemoradiotherapy treatment regimen in limited-stage small-cell lung cancer., Methods: The CONVERT trial was an open-label, phase 3, randomised superiority trial. We enrolled adult patients (aged ≥18 years) who had cytologically or histologically confirmed limited-stage small-cell lung cancer, Eastern Cooperative Oncology Group performance status of 0-2, and adequate pulmonary function. Patients were recruited from 73 centres in eight countries. Patients were randomly assigned to receive either 45 Gy radiotherapy in 30 twice-daily fractions of 1·5 Gy over 19 days, or 66 Gy in 33 once-daily fractions of 2 Gy over 45 days, starting on day 22 after commencing cisplatin-etoposide chemotherapy (given as four to six cycles every 3 weeks in both groups). The allocation method used was minimisation with a random element, stratified by institution, planned number of chemotherapy cycles, and performance status. Treatment group assignments were not masked. The primary endpoint was overall survival, defined as time from randomisation until death from any cause, analysed by modified intention-to-treat. A 12% higher overall survival at 2 years in the once-daily group versus the twice-daily group was considered to be clinically significant to show superiority of the once-daily regimen. The study is registered with ClinicalTrials.gov (NCT00433563) and is currently in follow-up., Findings: Between April 7, 2008, and Nov 29, 2013, 547 patients were enrolled and randomly assigned to receive twice-daily concurrent chemoradiotherapy (274 patients) or once-daily concurrent chemoradiotherapy (273 patients). Four patients (one in the twice-daily group and three in the once-daily group) did not return their case report forms and were lost to follow-up; these patients were not included in our analyses. At a median follow-up of 45 months (IQR 35-58), median overall survival was 30 months (95% CI 24-34) in the twice-daily group versus 25 months (21-31) in the once-daily group (hazard ratio for death in the once daily group 1·18 [95% CI 0·95-1·45]; p=0·14). 2-year overall survival was 56% (95% CI 50-62) in the twice-daily group and 51% (45-57) in the once-daily group (absolute difference between the treatment groups 5·3% [95% CI -3·2% to 13·7%]). The most common grade 3-4 adverse event in patients evaluated for chemotherapy toxicity was neutropenia (197 [74%] of 266 patients in the twice-daily group vs 170 [65%] of 263 in the once-daily group). Most toxicities were similar between the groups, except there was significantly more grade 4 neutropenia with twice-daily radiotherapy (129 [49%] vs 101 [38%]; p=0·05). In patients assessed for radiotherapy toxicity, was no difference in grade 3-4 oesophagitis between the groups (47 [19%] of 254 patients in the twice-daily group vs 47 [19%] of 246 in the once-daily group; p=0·85) and grade 3-4 radiation pneumonitis (4 [3%] of 254 vs 4 [2%] of 246; p=0·70). 11 patients died from treatment-related causes (three in the twice-daily group and eight in the once-daily group)., Interpretation: Survival outcomes did not differ between twice-daily and once-daily concurrent chemoradiotherapy in patients with limited-stage small-cell lung cancer, and toxicity was similar and lower than expected with both regimens. Since the trial was designed to show superiority of once-daily radiotherapy and was not powered to show equivalence, the implication is that twice-daily radiotherapy should continue to be considered the standard of care in this setting., Funding: Cancer Research UK (Clinical Trials Awards and Advisory Committee), French Ministry of Health, Canadian Cancer Society Research Institute, European Organisation for Research and Treatment of Cancer (Cancer Research Fund, Lung Cancer, and Radiation Oncology Groups)., (Copyright © 2017 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC-BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Purpose: Venous thromboembolism (VTE) is common in cancer patients. Evidence has suggested that low molecular weight heparin (LMWH) might improve survival in patients with cancer by preventing both VTE and the progression of metastases. No trial in a single cancer type has been powered to demonstrate a clinically significant survival difference. The aim of this trial was to investigate this question in patients with lung cancer., Patients and Methods: We conducted a multicenter, open-label, randomized trial to evaluate the addition of a primary prophylactic dose of LMWH for 24 weeks to standard treatment in patients with newly diagnosed lung cancer of any stage and histology. The primary outcome was 1-year survival. Secondary outcomes included metastasis-free survival, VTE-free survival, toxicity, and quality of life., Results: For this trial, 2,202 patients were randomly assigned to the two treatment arms over 4 years. The trial did not reach its intended number of events for the primary analysis (2,047 deaths), and data were analyzed after 2,013 deaths after discussion with the independent data monitoring committee. There was no evidence of a difference in overall or metastasis-free survival between the two arms (hazard ratio [HR], 1.01; 95% CI, 0.93 to 1.10; P = .814; and HR, 0.99; 95% CI, 0.91 to 1.08; P = .864, respectively). There was a reduction in the risk of VTE from 9.7% to 5.5% (HR, 0.57; 95% CI, 0.42 to 0.79; P = .001) in the LMWH arm and no difference in major bleeding events but evidence of an increase in the composite of major and clinically relevant nonmajor bleeding in the LMWH arm., Conclusion: LMWH did not improve overall survival in the patients with lung cancer in this trial. A significant reduction in VTE is associated with an increase in clinically relevant nonmajor bleeding. Strategies to target those at greatest risk of VTE are warranted., (© 2015 by American Society of Clinical Oncology.)

Background: Obstructive sleep apnea (OSA) is characterized by intermittent hypoxia (IH). In animal models, IH has been shown to protect the myocardium during periods of ischemia by reducing infarct size. However, this phenomenon of "ischemic preconditioning" has not been investigated among OSA patients with acute myocardial infarction (MI). This study investigates the role of OSA on MI severity as measured by cardiac enzymes, specifically troponin-T, among patients with an acute MI., Methods: This is an observational cohort study of patients ≥18 years of age who were hospitalized with an acute MI. Each participant underwent portable sleep monitoring (Apnea Link Plus); OSA was defined as an apnea-hypopnea index ≥5/h. Multivariable regression analysis was conducted to assess the relationship between OSA and highly sensitive troponin-T levels., Results: In our entire cohort of acute MI patients (n = 136), 77 % of the sample had evidence of sleep disordered breathing, with 35 % of the sample having OSA (i.e., an AHI >5). Higher AHI was associated with lower peak troponin-T levels in partially adjusted models (β = -0.0320, p = 0.0074, adjusted for age, gender, and race) and fully adjusted models (β = -0.0322, p = 0.0085) (additionally adjusted for smoking, hypertension, hyperlipidemia, body mass index, history of prior cardiovascular or cerebrovascular disease, diabetes and baseline admission creatinine levels). The mean value of the log-transformed peak troponin-T variable was used to dichotomize the outcome variable. In both partially (OR 0.949, CI 0.905-0.995, p = 0.03) and fully adjusted (OR 0.918, CI 0.856-0.984, p = 0.0151) logistic regression models, the OR for AHI suggests a protective effect on high troponin-T level., Conclusions: Our study demonstrates that patients with OSA have less severe cardiac injury during an acute non-fatal MI when compared to patients without OSA. This may suggest a cardioprotective role of sleep apnea during acute MI via ischemic preconditioning.

The Grand Round was held at the Christie Hospital on the 26 November 2001. It followed a talk by Professor Kate Vallis of the Princess Margaret Hospital in Toronto on, "A functional genomics approach to understanding normal issue response and ionizing radiation".

Conditional release is the approval of a new drug onto the market, subject to specific conditions relating to effectiveness and safety that, if achieved, will lead to full approval. Conditional approval of a new drug, during which time it is used in normal clinical practice, should allow the collection of data on effectiveness and safety to provide a genuine cost effectiveness evaluation. Proposals put forward in 1977 in the United Kingdom for approving a drug on a conditional basis while monitoring for adverse drug reactions are examined, and issues that would affect a present day conditional release scheme are identified. These issues are: who would do the evaluation and who would pay for it; how would patients be identified and registered; would all new drugs be monitored and for how long; what data would be reported and evaluated; and who would do the reporting? How a conditional release scheme would work in Canada in light of these questions is considered and a method based on pharmacists registering patients and on physicians and/or patients reporting data to an independent organization funded by governments and the pharmaceutical industry is outlined. Under certain conditions, conditional release would provide the information to allow true cost effectiveness and safety assessments instead of the current inadequate predictions based on efficacy and safety data from clinical trials. It is important that academics and drug approval and monitoring agencies work together to develop active systems to improve the postapproval evaluation of effectiveness, safety and cost effectiveness of new drugs in Canada.

Purpose: NSAID use has long been established as a risk factor for severe gastrointestinal (GI) events. It is also known that age and gender affect the risk of such events independently of nonsteroidal antiinflammatory drug (NSAID) use. The objective of the present study is to distinguish between gender as an independent risk factor for severe GI events, and the differences between males and females in risk of NSAID-related severe GI events., Methods: The study design was a nested case-control study. During the study period, 1029 cases were hospitalized with GI bleeds and/or perforations and 14 481 controls without such GI events were selected. Exposure consisted of the number of NSAID prescriptions dispensed by a pharmacy, prior to the data of hospitalization for cases and a corresponding date for controls., Results: Males have a risk of serious GI events 1.4 times greater than females, independent of NSAID use. However, females have the greater increase in risk of NSAID-related GI events, e.g. at four prescriptions women have an odds ratio (OR) of 7.4 (p<0.05), while men have a corresponding OR of 3.2 (p<0.05). The increasing risk of severe GI events with number of NSAID prescriptions was considerably greater for females than for males, indicating effect-modification. In a stratified analysis by age and gender, it was clear that gender was the greater influence. Various metabolic and epidemiological potential explanations are discussed., Conclusions: Age and gender are separate risk factors for GI complications as related to NSAID use. Although implied in other studies, the effect of gender on the risk of NSAID-related GI events is clearly stated in this study., (Copyright 1999 John Wiley & Sons, Ltd.)

A large neoplasm that replaced 1 testis of a Long Evans Rat was noted at the final necropsy of a dietary 2-yr study. By light microscopy, the morphological features were consistent with a poorly differentiated seminoma. Ultrastructurally, the cells were polygonal, had a round nucleus, had straight cellular boundaries, and bore no resemblance to Sertoli cells. Although there was little evidence of spermatocytic differentiation, the presence of proacrosomal granules and vesicles, prominent Golgi apparatus, tight intercellular junctions, and a few centriolar pairs without axoneme development, in conjunction with the absence of lipid droplets or abundant smooth endoplasmic reticulum, supported the diagnosis of seminoma rather than Leydig cell tumor. The cells were S-100- and vimentin-positive, although cytokeratin- and alpha-fetoprotein-negative. Seminomas are extremely rare neoplasms in rats; this is the first report in this strain and the first extensive analysis of a rat seminoma without spermatocytic differentiation.

Recent reports have suggested that production of superoxide or other reactive oxygen species by activated osteoclasts may play a role in the complex process of bone resorption; however, the enzyme responsible for production of superoxide by osteoclasts has not been characterized. To determine if osteoclasts express NADPH-oxidase, a superoxide-generating enzyme found in phagocytic leukocytes, immunohistochemical studies were performed on tibia from 1-5-d-old rats using mAbs 449 and 48 and an antiserum specific for p47-phox. These antibodies recognize epitopes on the alpha and beta subunits of cytochrome b558, respectively, and the p47 cytosolic component of NADPH-oxidase. We found that osteoclasts attached to bone surfaces in tibia expressed all three components, as did mature polymorphonuclear and some mononuclear leukocytes in the bone marrow. In many adherent osteoclasts, the cytochrome b558 subunits were localized to the ruffled-border and bone interfaces. Studies were also performed on mature rat tibia that had undergone controlled fracture. By two weeks the healing fractures develop a callus rich in actively resorbing osteoclasts. Osteoclasts within the calluses, and attached to bone surface, also expressed the cytochrome b558 proteins. In addition to demonstrating the expression of NADPH-oxidase, the active production of superoxide by osteoclasts was also demonstrated in situ in freshly isolated tibia using 3,3'-diaminobenzidine (DAB)-Mn2+, a histochemical method specific for superoxide localization. Osteoclasts attached to bone surfaces contained deposits of oxidized DAB which were observed by light microscopy. Nonstimulated polymorphonuclear and mononuclear leukocytes in the bone marrow did not contain DAB deposits unless stimulated with phorbol myristate acetate, a known activator of NADPH-oxidase. These findings indicate that osteoclasts contain NADPH-oxidase, and during the process of resorbing bone, are actively producing superoxide.

We wished to assess whether the previously developed 3,3'-diaminobenzidine (DAB)-Mn++ cytochemical method, purportedly specific for superoxide localization, is detecting superoxide O2.- and/or the superoxide product, O2(1 delta g). We show here that polymorphonuclear leukocytes (PMNs) produce O2(1 delta g) extracellularly in response to non-phagocytic stimuli and that this production is inhibited by addition of superoxide dismutase, an enzyme typically used to demonstrate that a reaction is mediated by O2.-. Because O2(1 delta g) is highly reactive and can be generated from O2.-, the reactivity of a pure chemical source of O2(1 delta g) with the cytochemical probe DAB was examined in the presence and absence of Mn++. Reactions between DAB and O2(1 delta g), thermally released from 1,4-dimethyl-napthalene-1,4-endoperoxide (DNE), indicated that O2(1 delta g) directly reacted with DAB, forming an insoluble DAB polymer, and that this reaction was increased by the presence of Mn++. The direct reaction of O2(1 delta g) with DAB was confirmed using near-IR emission spectroscopy. The near-IR emission spectrum of DNE as it was warmed showed the characteristic energy emission peak of O2(1 delta g) and the intensity of this peak was reduced by the addition of DAB; kq = 1.7 x 10(8) M-1 sec-1. The requirement of Mn++ for oxidation of DAB by O2.- was reconfirmed using potassium superoxide as a pure chemical source of O2.-. In cell studies, however, DAB deposits were not observed in PMNs stimulated under conditions that lead to O2(1 delta g) production [e.g., 0.040 or 0.162 microM 4B-phorbol-12-myristate-13-acetate (PMA)], regardless of whether Mn++ was present in the cytochemical medium. Nor were DAB deposits found in cells stimulated with PMA in the absence of Mn++ or in unstimulated PMNs. Only cells incubated in cytochemical medium containing Mn++ and stimulated to produce large amounts of O2.- (e.g., 3.24 microM PMA) contained DAB deposits. In summary, the DAB-Mn++ cytochemical method remains an excellent method for localizing the production sites of O2.-, since the concentration of O2(1 delta g) within vesicles of stimulated cells is too low to directly oxidize DAB to an electron-dense deposit.

The analytical performance of the three analytical systems Reflotron, Ektachem DT60 and Seralyzer III was studied according to ECCLS guidelines (1) and partly according to a protocol of the Société Francaise de Biologie Clinique (SFBC) (2) in a multicentre evaluation involving four laboratories. The determination of 11 analytes led to more than 180,000 data. With the Ektachem DT60, imprecision was acceptable for all analytes except for sodium. With the Reflotron, imprecision for glucose and creatinine was wider than the acceptable limits. With the Seralyzer III, imprecision for glucose, uric acid, cholesterol, creatinine and potassium was not within acceptance limits. The recovery of system assigned control sera values was acceptable for all analytes, except for glucose, creatinine and sodium with the Ektachem DT60 system, and for all but glucose and cholesterol with the Reflotron. On the Seralyzer III, the limits of acceptance were exceeded only with the creatinine assay. The recovery of the reference method values with Kontrollogen L caused problems with all three systems and for all analytes. Only 30% of the mean values of Kontrollogen L measured with the Ektachem and with the Seralyzer III were within the limits of acceptance. 40% of the mean values determined with the Reflotron were inside these limits. The upper limits of linearity as claimed by the manufacturers were obtained with all analytes and systems with the exception of cholesterol on all systems and the creatinine assay on the Seralyzer III. The systems under test and several different comparison methods showed good agreement for the analysis of patient samples, except in one laboratory for the analysis of sodium and aspartate aminotransferase with the Ektachem system and potassium with the Seralyzer III. Turbidity showed no significant influence on the measurements of all analytes and all systems. Haemolysis, hyperproteinaemia, and bilirubinaemia affected several methods on all three systems. A start time delay of up to 60 s did not affect the results of the Reflotron, except in the case of the triacylglycerol assay, which was affected by start time delays greater than 45 s. The results of 4 assays on the Seralyzer III were decreased considerably by a delayed start time (triacylglycerols and creatinine above 5 s, aspartate aminotransferase above 35 s and creatine kinase above 15 s). For reliable results from all the assays in each of the three analytical systems, it was necessary to use the prescribed sample volume within certain limits. The practicability of all analytical systems tested was found to be very good. A field study was conducted with the Reflotron system. The analyte concentration was determined in venous blood from various patients. In 25 out of 30 experiments, the results of the "field" laboratories showed a greater spread about the fitting line than those obtained in the "expert" laboratories.

Thirty patients are described on whom computed tomography was carried out because of endocrine ophthalmopathies. Fifteen patients had had the disease for more than two years, in the others it was acute. Determinations of muscle thickness and Hertel values show that there is no thickening of the extraocular muscles in patients with longstanding disease, but a significant increase in the Hertel values. Patients with recent disease show a definite increase in muscle thickness and corresponding protrusion of the globe, which can be explained by the changes in the muscles. The computer tomographic appearances of the striated ocular muscles in long-standing disease can be explained by fibrosis. These characteristics are of significance when considering the indications for radiation therapy.

The conception of Warren's Shunt--selective decompression of esophageal varices while maintaining prograde portal flow--was controlled by pre- and postoperative angiographic examinations on 12 patients: No change in portal perfusion was established angiographically in ten of the patients. Two patients developed aneurysmatic, arterio-portal fistulae as a result of postoperative portal decompression. In one of these cases, a thrombosis of the portal vein with hepatofugal perfusion of the left gastric vein was detected. The postoperative examinations indicated functioning shunts in 9 out of 12 patients. These results formed the basis for the discussion regarding the value of visceral angiography in the selection of the surgical technique and regarding its value in control of therapy. Surgical questions concerning the visceral vascular anatomy can be answered sufficiently. Furthermore, celiac and mesenteric angiography yield information on portal hemodynamics. Nevertheless, the additional application of invasive scintigraphy seems to be necessary for establishing quantitative radiological parameters of prognostic relevance.