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Background: Survival outcomes are poor for patients with metastatic urothelial carcinoma who receive standard, first-line, platinum-based chemotherapy. We assessed the overall survival of patients who received durvalumab (a PD-L1 inhibitor), with or without tremelimumab (a CTLA-4 inhibitor), as a first-line treatment for metastatic urothelial carcinoma. Methods: DANUBE is an open-label, randomised, controlled, phase 3 trial in patients with untreated, unresectable, locally advanced or metastatic urothelial carcinoma, conducted at 224 academic research centres, hospitals, and oncology clinics in 23 countries. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. We randomly assigned patients (1:1:1) to receive durvalumab monotherapy (1500 mg) administered intravenously every 4 weeks; durvalumab (1500 mg) plus tremelimumab (75 mg) administered intravenously every 4 weeks for up to four doses, followed by durvalumab maintenance (1500 mg) every 4 weeks; or standard-of-care chemotherapy (gemcitabine plus cisplatin or gemcitabine plus carboplatin, depending on cisplatin eligibility) administered intravenously for up to six cycles. Randomisation was done through an interactive voice–web response system, with stratification by cisplatin eligibility, PD-L1 status, and presence or absence of liver metastases, lung metastases, or both. The coprimary endpoints were overall survival compared between the durvalumab monotherapy versus chemotherapy groups in the population of patients with high PD-L1 expression (the high PD-L1 population) and between the durvalumab plus tremelimumab versus chemotherapy groups in the intention-to-treat population (all randomly assigned patients). The study has completed enrolment and the final analysis of overall survival is reported. The trial is registered with ClinicalTrials.gov, NCT02516241, and the EU Clinical Trials Register, EudraCT number 2015-001633-24. Findings: Between Nov 24, 2015, and March 21, 2017, we randomly assigned 1032 patients to receive durvalumab (n=346), durvalumab plus tremelimumab (n=342), or chemotherapy (n=344). At data cutoff (Jan 27, 2020), median follow-up for survival was 41·2 months (IQR 37·9–43·2) for all patients. In the high PD-L1 population, median overall survival was 14·4 months (95% CI 10·4–17·3) in the durvalumab monotherapy group (n=209) versus 12·1 months (10·4–15·0) in the chemotherapy group (n=207; hazard ratio 0·89, 95% CI 0·71–1·11; p=0·30). In the intention-to-treat population, median overall survival was 15·1 months (13·1–18·0) in the durvalumab plus tremelimumab group versus 12·1 months (10·9–14·0) in the chemotherapy group (0·85, 95% CI 0·72–1·02; p=0·075). In the safety population, grade 3 or 4 treatment-related adverse events occurred in 47 (14%) of 345 patients in the durvalumab group, 93 (27%) of 340 patients in the durvalumab plus tremelimumab group, and in 188 (60%) of 313 patients in the chemotherapy group. The most common grade 3 or 4 treatment-related adverse event was increased lipase in the durvalumab group (seven [2%] of 345 patients) and in the durvalumab plus tremelimumab group (16 [5%] of 340 patients), and neutropenia in the chemotherapy group (66 [21%] of 313 patients). Serious treatment-related adverse events occurred in 30 (9%) of 345 patients in the durvalumab group, 78 (23%) of 340 patients in the durvalumab plus tremelimumab group, and 50 (16%) of 313 patients in the chemotherapy group. Deaths due to study drug toxicity were reported in two (1%) patients in the durvalumab group (acute hepatic failure and hepatitis), two (1%) patients in the durvalumab plus tremelimumab group (septic shock and pneumonitis), and one (

When price dispersion is prevalent, a relevant question is what happens to the whole distribution of equilibrium prices when the number of firms changes. Using data from the gasoline market in the Netherlands, we find, first, that markets with N competitors have price distributions that first-order stochastically dominate the price distributions in markets with N+1 firms. Second, the effect of competition is stronger for the medium to upper percentiles of the price distribution. Finally, consumer gains from competition are larger for relatively well-informed consumers. To account for these empirical patterns, we extend Varian's [1980] model by allowing for richer heterogeneity in consumer price information.

Background: Suffocation due to foreign bodies (FB) is a leading cause of death in children aged 0-3. No data from the former U.S.S.R. are available in the international scientific literature. Methods: Consecutive patients admitted at the Iashvili Central Children Hospital in Tbilisi, Georgia from 1989 to 2011 were analyzed. Injuries in the upper airways due to foreign bodies' inhalation were collected and compared with the Susy Safe Registry and the pooled estimates of the meta-analysis. Results: 2896 cases were collected. Distribution of injuries in children younger than 3 years was significantly higher than in the Susy Safe Registry and in the "High-Income" countries in the meta-analysis. Percentage of injuries due to organic objects (86%) was significantly higher than in published data. Conclusions: Since Georgia is not showing any substantial difference, both in epidemiology and treatment of foreign bodies injuries, as compared to the other case series, translation of public health initiatives from other most advanced prevention experiences is possible and it is likely to be effective. Level of evidence: Level V, Epidemiological case series. © 2015 Elsevier Ireland Ltd.

The AQUAREF group of experts has been asked to take position on the use of passive integrative samplers (PIS) in a Water Framework Directive (WFD) context. The main objective of this 2015 present note is to complete (as much as possible) the 2014 report concerning the possibility of using PIS in comparison with current regulatory surveillance, for the WFD reporting in coastal and continental waters. The SBSE extraction technique was also taken into account for hydrophobic organic substances, as this technique limits the drawbacks of water samples transport (substance degradation in water samples, extra-cost induced by sample volume and weight) for remote sites like French overseas territories. The AQUAREF group took in consideration: on the one hand the priority substances from the EQS directive (2013/39/CE directive) for which an EQS (environmental quality standard) defined as an annual average concentration is mentioned for water samples; on the other hand the specific pollutants for the determination of ecological state (25/01/2010 and 07/08/2015 French decrees) and the substances of the Marine Strategy Framework Directive (2008/56/EC directive). The methodology consists in checking, for each substances, if the sampling and analysis techniques, both conventional (used in laboratories which fulfill official criteria for water samples) and possible (for laboratories with SBSE and PIS expertise) can meet with the regulatory WFD requirements (Limit of Quantification ≤ EQS/3). This report summarizes the available knowledge regarding this question. As a conclusion, regarding the relevant substances for the determination of the ecological state, this knowledge is still very fragmentary, limiting the relevance of a comparison between PIS and classical sampling performances. The project of an in situ demonstration exercise concerning EIP relevance for water monitoring (2016-2019) shall aim at gathering useful information to progress on this question.; Le groupe d’experts AQUAREF a été mobilisé pour statuer sur l’usage des échantillonneurs intégratifs passifs (EIP) dans le cadre de l’application de la Directive cadre sur l’eau (DCE). L’objectif de cette note 2015 est de compléter le rapport 2014 sur la possibilité du recours aux EIP par rapport à la surveillance réglementaire actuelle, pour ce qui concerne l’enjeu du rapportage DCE dans les Eaux littorales et continentales. Nous avons aussi considéré l’extraction des substances organiques hydrophobes par SBSE dans les échantillons ponctuels d’eau, qui permet de limiter les inconvénients du transport d’échantillons d’eau (dégradation des substances dans les échantillons d’eau, volume et poids des échantillons d’eau induisant un surcoût) pour les sites éloignés comme les Départements d’Outre-Mer. Dans ce travail, ont été prises en compte d’une part les substances prioritaires de la Directive fille NQE (directive 2013/39/CE) pour lesquelles une NQE MA (norme de qualité environnementale en moyenne annuelle) existe; d’autre part les polluants spécifiques de l’Etat Ecologique (arrêtés français du 25/01/2010 et du 07/08/2015) et celles de la Directive Cadre Stratégie pour le Milieu Marin (directive DCSMM 2008/56/CE). La méthode de travail consiste à vérifier, pour chaque substance, si les méthodes conventionnelles d’échantillonnage et d’analyse (pratiquées au sein des laboratoires agréés pour la matrice eau) et les méthodes nouvelles (pratiquées par des laboratoires experts pour les technique SBSE et les EIP) permettent de répondre aux exigences réglementaires DCE (Limite de Quantification ≤ NQE/3). Le présent rapport fait la synthèse des connaissances actuelles sur le sujet. Au final, pour ce qui concerne les substances pertinentes de l’Etat Ecologique ces connaissances sont aujourd’hui encore très parcellaires pour comparer les performances in-situ des EIP avec la surveillance classique par prélèvements ponctuels. Le projet d’un exercice in situ de démonstration de la pertinence des EIP pour la surveillance (2016-2019) se fixera notamment pour objectif de combler ce manque de connaissance.

International audience; This paper, based on the outcome of discussions at a NORMAN Network-supported workshop in Lyon (France) in November 2014 aims to provide a common position of passive sampling community experts regarding concrete actions required to foster the use of passive sampling techniques in support of contaminant risk assessment and management and for routine monitoring of contaminants in aquatic systems. The brief roadmap presented here focusses on the identification of robust passive sampling methodology, technology that requires further development or that has yet to be developed, our current knowledge of the evaluation of uncertainties when calculating a freely dissolved concentration, the relationship between data from PS and that obtained through biomonitoring. A tiered approach to identifying areas of potential environmental quality standard (EQS) exceedances is also shown. Finally, we propose a list of recommended actions to improve the acceptance of passive sampling by policy-makers. These include the drafting of guidelines, quality assurance and control procedures, developing demonstration projects where biomonitoring and passive sampling are undertaken alongside, organising proficiency testing schemes and interlaboratory comparison and, finally, establishing passive sampler-based assessment criteria in relation to existing EQS.

We examine an export game where two (home and foreign) firms produce vertically differentiated products. The foreign firm is more R&D efficient and is based in a larger and richer market. The unique (risk-dominant) Nash equilibrium exhibits intra-industry trade, and the foreign producer manufactures a higher-quality product. When transport costs are low, unilateral dumping by the foreign firm arises; otherwise, reciprocal dumping occurs. For some parameters, a domestic antidumping policy leads to a quality reversal in the international market whereby the home firm becomes the quality leader. This policy is desirable for the implementing country, though world welfare decreases.

Objectives: To provide an epidemiological framework of symptoms related to Foreign Body (FB) injuries due to Button Battery (BB). Methods: Data on BB ingestion/inhalation have been obtained from the ButtonBatteryDB. The ButtonBatteryDB is a database collecting information on BB injuries in children (0-18 years of age). Data on 348 BB injures have been derived from the Registry of Foreign Body Injuries "Susy Safe" (269 cases) and from published scientific literature reporting case reports of FB injuries (79 cases). Results: Most of injured children were male and BBs were found more often in the mouth/esophagus/stomach (ICD935) and in the nose (ICD932). Analyzing symptoms related to BB located in the esophagus/mouth/stomach, we found that children had higher probability of experiencing dysphagia (30.19%, 95% C.I. 17.83-42.55), fever and cough (26.42%, 95% C.I. 14.55-38.28), compared to the other symptoms. Referring to the probability that symptoms occurred simultaneously, fever and cough are more likely (3.72%, 95% C.I. 1.0-6-43) to jointly showing up in children with BB in mouth/esophagus/stomach (ICD935), followed by fever and dysphagia (2.66%, 95% C.I. 0.36-4.96) and by fever and irritability/crying, fever and drooling, dysphagia and irritability/crying (2.13% C.I. 0.00-4.19, 95% C.I.). Conclusions: These findings provide new insight in clinical presentation of BB injuries: the identification of unique patterns of symptoms related to BB injuries is useful to perform an early diagnosis (and to guarantee a prompt medical reaction), also when the injury is un-witnessed. © 2015 Elsevier Ireland Ltd.

The AQUAREF group of experts has been asked to take position on the use of passive integrative samplers (PIS) in a Water Framework Directive (WFD) context. The main objective of this 2015 present note is to complete (as much as possible) the 2014 report concerning the possibility of using PIS in comparison with current regulatory surveillance, for the WFD reporting in coastal and continental waters. The SBSE extraction technique was also taken into account for hydrophobic organic substances, as this technique limits the drawbacks of water samples transport (substance degradation in water samples, extra-cost induced by sample volume and weight) for remote sites like French overseas territories. The AQUAREF group took in consideration: on the one hand the priority substances from the EQS directive (2013/39/CE directive) for which an EQS (environmental quality standard) defined as an annual average concentration is mentioned for water samples; on the other hand the specific pollutants for the determination of ecological state (25/01/2010 and 07/08/2015 French decrees) and the substances of the Marine Strategy Framework Directive (2008/56/EC directive). The methodology consists in checking, for each substances, if the sampling and analysis techniques, both conventional (used in laboratories which fulfill official criteria for water samples) and possible (for laboratories with SBSE and PIS expertise) can meet with the regulatory WFD requirements (Limit of Quantification ≤ EQS/3). This report summarizes the available knowledge regarding this question. As a conclusion, regarding the relevant substances for the determination of the ecological state, this knowledge is still very fragmentary, limiting the relevance of a comparison between PIS and classical sampling performances. The project of an in situ demonstration exercise concerning EIP relevance for water monitoring (2016-2019) shall aim at gathering useful information to progress on this question.; Le groupe d’experts AQUAREF a été mobilisé pour statuer sur l’usage des échantillonneurs intégratifs passifs (EIP) dans le cadre de l’application de la Directive cadre sur l’eau (DCE). L’objectif de cette note 2015 est de compléter le rapport 2014 sur la possibilité du recours aux EIP par rapport à la surveillance réglementaire actuelle, pour ce qui concerne l’enjeu du rapportage DCE dans les Eaux littorales et continentales. Nous avons aussi considéré l’extraction des substances organiques hydrophobes par SBSE dans les échantillons ponctuels d’eau, qui permet de limiter les inconvénients du transport d’échantillons d’eau (dégradation des substances dans les échantillons d’eau, volume et poids des échantillons d’eau induisant un surcoût) pour les sites éloignés comme les Départements d’Outre-Mer. Dans ce travail, ont été prises en compte d’une part les substances prioritaires de la Directive fille NQE (directive 2013/39/CE) pour lesquelles une NQE MA (norme de qualité environnementale en moyenne annuelle) existe; d’autre part les polluants spécifiques de l’Etat Ecologique (arrêtés français du 25/01/2010 et du 07/08/2015) et celles de la Directive Cadre Stratégie pour le Milieu Marin (directive DCSMM 2008/56/CE). La méthode de travail consiste à vérifier, pour chaque substance, si les méthodes conventionnelles d’échantillonnage et d’analyse (pratiquées au sein des laboratoires agréés pour la matrice eau) et les méthodes nouvelles (pratiquées par des laboratoires experts pour les technique SBSE et les EIP) permettent de répondre aux exigences réglementaires DCE (Limite de Quantification ≤ NQE/3). Le présent rapport fait la synthèse des connaissances actuelles sur le sujet. Au final, pour ce qui concerne les substances pertinentes de l’Etat Ecologique ces connaissances sont aujourd’hui encore très parcellaires pour comparer les performances in-situ des EIP avec la surveillance classique par prélèvements ponctuels. Le projet d’un exercice in situ de démonstration de la pertinence des EIP pour la surveillance (2016-2019) se fixera notamment pour objectif de combler ce manque de connaissance.