Roche (France)

Abstract On 2017 August 17, the gravitational-wave event GW170817 was observed by the Advanced LIGO and Virgo detectors, and the gamma-ray burst (GRB) GRB 170817A was observed independently by the Fermi Gamma-ray Burst Monitor, and the Anti-Coincidence Shield for the Spectrometer for the International Gamma-Ray Astrophysics Laboratory . The probability of the near-simultaneous temporal and spatial observation of GRB 170817A and GW170817 occurring by chance is <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mn>5.0</mml:mn> <mml:mo>×</mml:mo> <mml:msup> <mml:mrow> <mml:mn>10</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>8</mml:mn> </mml:mrow> </mml:msup> </mml:math> . We therefore confirm binary neutron star mergers as a progenitor of short GRBs. The association of GW170817 and GRB 170817A provides new insight into fundamental physics and the origin of short GRBs. We use the observed time delay of <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mo stretchy="false">(</mml:mo> <mml:mo>+</mml:mo> <mml:mn>1.74</mml:mn> <mml:mo>±</mml:mo> <mml:mn>0.05</mml:mn> <mml:mo stretchy="false">)</mml:mo> <mml:mspace width="0.25em"/> <mml:mi mathvariant="normal">s</mml:mi> </mml:math> between GRB 170817A and GW170817 to: (i) constrain the difference between the speed of gravity and the speed of light to be between <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mo>−</mml:mo> <mml:mn>3</mml:mn> <mml:mo>×</mml:mo> <mml:msup> <mml:mrow> <mml:mn>10</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>15</mml:mn> </mml:mrow> </mml:msup> </mml:math> and <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" overflow="scroll"> <mml:mo>+</mml:mo> <mml:mn>7</mml:mn> <mml:mo>×</mml:mo> <mml:msup> <mml:mrow> <mml:mn>10</mml:mn> </mml:mrow> <mml:mrow> <mml:mo>−</mml:mo> <mml:mn>16</mml:mn> </mml:mrow> </mml:msup> </mml:math> times the speed of light, (ii) place new bounds on the violation of Lorentz invariance, (iii) present a new test of the equivalence principle by constraining the Shapiro delay between gravitational and electromagnetic radiation. We also use the time delay to constrain the size and bulk Lorentz factor of the region emitting the gamma-rays. GRB 170817A is the closest short GRB with a known distance, but is between 2 and 6 orders of magnitude less energetic than other bursts with measured redshift. A new generation of gamma-ray detectors, and subthreshold searches in existing detectors, will be essential to detect similar short bursts at greater distances. Finally, we predict a joint detection rate for the Fermi Gamma-ray Burst Monitor and the Advanced LIGO and Virgo detectors of 0.1–1.4 per year during the 2018–2019 observing run and 0.3–1.7 per year at design sensitivity.

BACKGROUND: Whether noninvasive ventilation should be administered in patients with acute hypoxemic respiratory failure is debated. Therapy with high-flow oxygen through a nasal cannula may offer an alternative in patients with hypoxemia. METHODS: We performed a multicenter, open-label trial in which we randomly assigned patients without hypercapnia who had acute hypoxemic respiratory failure and a ratio of the partial pressure of arterial oxygen to the fraction of inspired oxygen of 300 mm Hg or less to high-flow oxygen therapy, standard oxygen therapy delivered through a face mask, or noninvasive positive-pressure ventilation. The primary outcome was the proportion of patients intubated at day 28; secondary outcomes included all-cause mortality in the intensive care unit and at 90 days and the number of ventilator-free days at day 28. RESULTS: A total of 310 patients were included in the analyses. The intubation rate (primary outcome) was 38% (40 of 106 patients) in the high-flow-oxygen group, 47% (44 of 94) in the standard group, and 50% (55 of 110) in the noninvasive-ventilation group (P=0.18 for all comparisons). The number of ventilator-free days at day 28 was significantly higher in the high-flow-oxygen group (24±8 days, vs. 22±10 in the standard-oxygen group and 19±12 in the noninvasive-ventilation group; P=0.02 for all comparisons). The hazard ratio for death at 90 days was 2.01 (95% confidence interval [CI], 1.01 to 3.99) with standard oxygen versus high-flow oxygen (P=0.046) and 2.50 (95% CI, 1.31 to 4.78) with noninvasive ventilation versus high-flow oxygen (P=0.006). CONCLUSIONS: In patients with nonhypercapnic acute hypoxemic respiratory failure, treatment with high-flow oxygen, standard oxygen, or noninvasive ventilation did not result in significantly different intubation rates. There was a significant difference in favor of high-flow oxygen in 90-day mortality. (Funded by the Programme Hospitalier de Recherche Clinique Interrégional 2010 of the French Ministry of Health; FLORALI ClinicalTrials.gov number, NCT01320384.).

The Yen–Mullins model, also known as the modified Yen model, specifies the predominant molecular and colloidal structure of asphaltenes in crude oils and laboratory solvents and consists of the following: The most probable asphaltene molecular weight is ∼750 g/mol, with the island molecular architecture dominant. At sufficient concentration, asphaltene molecules form nanoaggregates with an aggregation number less than 10. At higher concentrations, nanoaggregates form clusters again with small aggregation numbers. The Yen–Mullins model is consistent with numerous molecular and colloidal studies employing a broad array of methodologies. Moreover, the Yen–Mullins model provides a foundation for the development of the first asphaltene equation of state for predicting asphaltene gradients in oil reservoirs, the Flory–Huggins–Zuo equation of state (FHZ EoS). In turn, the FHZ EoS has proven applicability in oil reservoirs containing condensates, black oils, and heavy oils. While the development of the Yen–Mullins model was founded on a very large number of studies, it nevertheless remains essential to validate consistency of this model with important new data streams in asphaltene science. In this paper, we review recent advances in asphaltene science that address all critical aspects of the Yen–Mullins model, especially molecular architecture and characteristics of asphaltene nanoaggregates and clusters. Important new studies are shown to be consistent with the Yen–Mullins model. Wide ranging studies with direct interrogation of the Yen–Mullins model include detailed molecular decomposition analyses, optical measurements coupled with molecular orbital calculations, nuclear magnetic resonance (NMR) spectroscopy, centrifugation, direct-current (DC) conductivity, interfacial studies, small-angle neutron scattering (SANS), and small-angle X-ray scattering (SAXS), as well as oilfield studies. In all cases, the Yen–Mullins model is proven to be at least consistent if not valid. In addition, several studies previously viewed as potentially inconsistent with the Yen–Mullins model are now largely resolved. Moreover, oilfield studies using the Yen–Mullins model in the FHZ EoS are greatly improving the understanding of many reservoir concerns, such as reservoir connectivity, heavy oil gradients, tar mat formation, and disequilibrium. The simple yet powerful advances codified in the Yen–Mullins model especially with the FHZ EoS provide a framework for future studies in asphaltene science, petroleum science, and reservoir studies.

Abstract The fourth generation of the Sloan Digital Sky Survey (SDSS-IV) has been in operation since 2014 July. This paper describes the second data release from this phase, and the 14th from SDSS overall (making this Data Release Fourteen or DR14). This release makes the data taken by SDSS-IV in its first two years of operation (2014–2016 July) public. Like all previous SDSS releases, DR14 is cumulative, including the most recent reductions and calibrations of all data taken by SDSS since the first phase began operations in 2000. New in DR14 is the first public release of data from the extended Baryon Oscillation Spectroscopic Survey; the first data from the second phase of the Apache Point Observatory (APO) Galactic Evolution Experiment (APOGEE-2), including stellar parameter estimates from an innovative data-driven machine-learning algorithm known as “The Cannon”; and almost twice as many data cubes from the Mapping Nearby Galaxies at APO (MaNGA) survey as were in the previous release ( N = 2812 in total). This paper describes the location and format of the publicly available data from the SDSS-IV surveys. We provide references to the important technical papers describing how these data have been taken (both targeting and observation details) and processed for scientific use. The SDSS web site ( www.sdss.org ) has been updated for this release and provides links to data downloads, as well as tutorials and examples of data use. SDSS-IV is planning to continue to collect astronomical data until 2020 and will be followed by SDSS-V.

We present here a new solution for the astronomical computation of the orbital motion of the Earth spanning from 0 to −250 Myr. The main improvement with respect to our previous numerical solution La2004 is an improved adjustment of the parameters and initial conditions through a fit over 1 Myr to a special version of the highly accurate numerical ephemeris INPOP08 (Intégration Numérique Planétaire de l’Observatoire de Paris). The precession equations have also been entirely revised and are no longer averaged over the orbital motion of the Earth and Moon. This new orbital solution is now valid over more than 50 Myr in the past or into the future with proper phases of the eccentricity variations. Owing to the chaotic behavior, the precision of the solution decreases rapidly beyond this time span, and we discuss the behavior of various solutions beyond 50 Myr. For paleoclimate calibrations, we provide several different solutions that are all compatible with the most precise planetary ephemeris. We have thus reached the time where geological data are now required to discriminate between planetary orbital solutions beyond 50 Myr.

Background: Geriatric Assessment is an appropriate method for identifying older cancer patients at risk of life-threatening events during therapy. Yet, it is underused in practice, mainly because it is time-and resource-consuming. This study aims to identify the best screening tool to identify older cancer patients requiring geriatric assessment by comparing the performance of two short assessment tools the G8 and the Vulnerable Elders Survey (VES-13).

Purpose The purpose of this paper is to investigate the relationship between corporate debt-like compensation and the value of excess cash holdings. Design/methodology/approach The environmental, social and governance (ESG) disclosure score provided by Bloomberg is used as a proxy for the extent of corporate social responsibility (CSR). The empirical analysis is based on a sample of 379 firms that made up the Standard &amp; Poor’s 500 Index over the period 2010-2015. In order to take into account the endogeneity problem between board gender diversity and ESG disclosure, a fixed effect model with lagged board variables is used. Findings Two main results arise from this study. First, no significant relationship is found between board gender diversity and ESG disclosure. Second, the evidence also partially confirms critical mass theory, as below three female directors the relationship between board gender diversity and ESG disclosure is not statistically significant. However, beyond that, no significant relationship was found. Research limitations/implications Reasonable theoretical arguments drawn from stakeholder theory suggest that board gender diversity may have a positive effect on ESG disclosure. The empirical evidence presented neither supports, nor denies stakeholder theory. However, the results may be improved by enlarging the frontiers of this research in time and space, increasing the perimeter of qualitative data integrated in this investigation. Practical implications This paper offers theoretical and empirical arguments for the feminization of corporate boards, not only in the name of equality between women and men and organizational justice, but also in the light of organizational performance (examined through the prism of governance). Transparency, analyzed using the proxy of ESG disclosure, is strongly and positively correlated with a feminization of boards, if the proportion of women is significant and sufficient to be able to prevent and surpass the “invisibilization” phenomenon, which is based on the marginalization of passive ultra-minorities, reduction to silence, marginalization (disqualification of women voice or exit strategy), assimilation or the endorsement of stigma. Originality/value First, this makes a theoretical contribution to the diversity and governance literature by examining the effect of WOCB on ESG disclosure through the stakeholder theory (Freeman, 2010). Second, the authors contribute to the CSR literature (cf. Byron and Post, 2016) by documenting specifically the effect of board gender diversity on CSR disclosures through ESG. Indeed, ESG research mainly concentrates on firm financial performance (Galbreath, 2013). No study has examined the relationship between WOCB and ESG disclosure. Finally, from an empirical standpoint, an FE model with lagged board variables (Liu et al. , 2014) is used to fully address the endogeneity problems in the relationship between WOCB and ESG disclosure that may occur because of differences in unobservable characteristics across firms or reverse causality (Boulouta, 2013).

A bstract Although collisions with motorized ships are a recognized source of whale mortality, little has been done to compile information on the frequency of their occurrence or contributing factors. We searched historical records and computerized stranding databases for evidence of ship strikes involving great whales ( i. e. , baleen whales and the sperm whale). Historical records suggest that ship strikes fatal to whales first occurred late in the 1800s as ships began to reach speeds of 13‐15 kn, remained infrequent until about 1950, and then increased during the 1950s‐1970s as the number and speed of ships increased. Of 11 species known to be hit by ships, fin whales ( Balaenoptera physalus ) are struck most frequently; right whales ( Eubalaena glacialis and E. australis ), humpback whales ( Megaptera novaeangliae ), sperm whales ( Physeter catodon ), and gray whales ( Escbricbtius robustus ) are hit commonly. In some areas, one‐third of all fin whale and right whale strandings appear to involve ship strikes. To assess contributing factors, we compiled descriptions of 58 collisions. They indicate that all sizes and types of vessels can hit whales; most lethal or severe injuries are caused by ships 80 m or longer; whales usually are not seen beforehand or are seen too late to be avoided; and most lethal or severe injuries involve ships travelling 14 kn or faster. Ship strikes can significantly affect small populations of whales, such as northern right whales in the western North Atlantic. In areas where special caution is needed to avoid such events, measures to reduce the vessel speed below 14 kn may be beneficial.

ou non, manant des tablissements d'enseignement et de recherche franais ou trangers, des laboratoires publics ou privs.

This study evaluated by immunohistochemistry (IHC) immune cell response during neoadjuvant primary systemic therapy (PST) with trastuzumab in patients with HER2-positive primary breast cancer. In all, 23 patients with IHC 3+ primary breast cancer were treated with trastuzumab plus docetaxel. Pathological complete and partial responses were documented for nine (39%) and 14 (61%) patients, respectively. Case-matched controls comprised patients treated with docetaxel-based PST without trastuzumab (D; n=23) or PST without docetaxel or trastuzumab (non-taxane, non-trastuzumab, NT-NT; n=23). All surgical specimens were blind-analysed by two independent pathologists, with immunohistochemical evaluation of B and T lymphocytes, macrophages, dendritic cells and natural killer (NK) cells. Potential cytolytic cells were stained for Granzyme B and TiA1. HER2 expression was also evaluated in residual tumour cells. Trastuzumab treatment was associated with significantly increased numbers of tumour-associated NK cells and increased lymphocyte expression of Granzyme B and TiA1 compared with controls. This study supports an in vivo role for immune (particularly NK cell) responses in the mechanism of trastuzumab action in breast cancer. These results suggest that trastuzumab plus taxanes lead to enhanced NK cell activity, which may partially account for the synergistic activity of trastuzumab and docetaxel in breast cancer.

An autonomous robot offers a challenging and ideal field for the study of intelligent architectures. Autonomy within a rational be havior could be evaluated by the robot's effectiveness and robust ness in carrying out tasks in different and ill-known environments. It raises major requirements on the control architecture. Further more, a robot as a programmable machine brings up other archi tectural needs, such as the ease and quality of its specification and programming. This article describes an integrated architecture that allows a mobile robot to plan its tasks—taking into account temporal and domain constraints, to perform corresponding actions and to con trol their execution in real-time—while being reactive to possible events. The general architecture is composed of three levels: a de cision level, an execution level, and a functional level. The latter is composed of modules that embed the functions achieving sensor- data processing and effector control. The decision level is goal and event driven, and it may have several layers, according to the application; their basic structure is a planner/supervisor pair that enables the architecture to integrate deliberation and reaction. The proposed architecture relies naturally on several representa tions, programming paradigms, and processing approaches, which meet the precise requirements that are specified for each level. The authors have developed proper tools to meet these specifications and implement each level of the architecture: a temporal planner, IxTeT; a procedural system for task refinement and supervision, PRS; Kheops for the reactive control of the functional level, and G en oM for the specification and integration of modules at that level Validation of the temporal and logical properties of the reactive parts of the system, through these tools, are presented. Instances of the proposed architecture have been integrated into several indoor and outdoor robots. Examples from real-world ex perimentations are provided and analyzed.

IMPORTANCE: Monitoring of residual gastric volume is recommended to prevent ventilator-associated pneumonia (VAP) in patients receiving early enteral nutrition. However, studies have challenged the reliability and effectiveness of this measure. OBJECTIVE: To test the hypothesis that the risk of VAP is not increased when residual gastric volume is not monitored compared with routine residual gastric volume monitoring in patients receiving invasive mechanical ventilation and early enteral nutrition. DESIGN, SETTING, AND PATIENTS: Randomized, noninferiority, open-label, multicenter trial conducted from May 2010 through March 2011 in adults requiring invasive mechanical ventilation for more than 2 days and given enteral nutrition within 36 hours after intubation at 9 French intensive care units (ICUs); 452 patients were randomized and 449 included in the intention-to-treat analysis (3 withdrew initial consent). INTERVENTION: Absence of residual gastric volume monitoring. Intolerance to enteral nutrition was based only on regurgitation and vomiting in the intervention group and based on residual gastric volume greater than 250 mL at any of the 6 hourly measurements and regurgitation or vomiting in the control group. MAIN OUTCOME MEASURES: Proportion of patients with at least 1 VAP episode within 90 days after randomization, as assessed by an adjudication committee blinded to patient group. The prestated noninferiority margin was 10%. RESULTS: In the intention-to-treat population, VAP occurred in 38 of 227 patients (16.7%) in the intervention group and in 35 of 222 patients (15.8%) in the control group (difference, 0.9%; 90% CI, -4.8% to 6.7%). There were no significant between-group differences in other ICU-acquired infections, mechanical ventilation duration, ICU stay length, or mortality rates. The proportion of patients receiving 100% of their calorie goal was higher in the intervention group (odds ratio, 1.77; 90% CI, 1.25-2.51; P = .008). Similar results were obtained in the per-protocol population. CONCLUSION AND RELEVANCE: Among adults requiring mechanical ventilation and receiving early enteral nutrition, the absence of gastric volume monitoring was not inferior to routine residual gastric volume monitoring in terms of development of VAP. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01137487.

The expected changes over the past 500 million years in the principal astronomical frequencies influencing the Earth's climate may be strong enough to be detectable in the geological records, and such effects have been inferred in several cases. Calculations suggest that the shortening of the Earth-moon distance and of the length of the day back in time induced a shortening of the fundamental periods for the obliquity and climatic precession, from 54 to 35, 41 to 29, 23 to 19, and 19 to 16 thousand years over the last half-billion years. At the same time, the precessional constant increased from 50 to 61 arc seconds per year. The changes in the frequencies of the planetary system due to its chaotic motion are much smaller; their influence on the changes of the periods of climatic precession, obliquity, and eccentricity of the Earth's orbit around the sun can be neglected. Eccentricity periods used for Quaternary climate studies may therefore be considered to have been more or less constant for pre-Quaternary times.

We present the most significant measurement of the cosmic microwave background (CMB) lensing potential to date (at a level of 40), using temperature and polarization data from the Planck 2015 full-mission release. Using a polarization-only estimator, we detect lensing at a significance of 5. We cross-check the accuracy of our measurement using the wide frequency coverage and complementarity of the temperature and polarization measurements. Public products based on this measurement include an estimate of the lensing potential over approximately 70% of the sky, an estimate of the lensing potential power spectrum in bandpowers for the multipole range 40 L 400, and an associated likelihood for cosmological parameter constraints. We find good agreement between our measurement of the lensing potential power spectrum and that found in the CDM model that best fits the Planck temperature and polarization power spectra. Using the lensing likelihood alone we obtain a percent-level measurement of the parameter combination 8 0.25 m = 0.591 0.021. We combine our determination of the lensing potential with the E-mode polarization, also measured by Planck, to generate an estimate of the lensing B-mode. We show that this lensing B-mode estimate is correlated with the B-modes observed directly by Planck at the expected level and with a statistical significance of 10, confirming Planck's sensitivity to this known sky signal. We also correlate our lensing potential estimate with the large-scale temperature anisotropies, detecting a cross-correlation at the 3 level, as expected because of dark energy in the concordance CDM model.

Late Cretaceous (Cenomanian) fossils discovered in the Kem Kem region of Morocco include large predatory dinosaurs that inhabited Africa as it drifted into geographic isolation. One, represented by a skull approximately 1.6 meters in length, is an advanced allosauroid referable to the African genus Carcharodontosaurus. Another, represented by a partial skeleton with slender proportions, is a new basal coelurosaur closely resembling the Egyptian genus Bahariasaurus. Comparisons with Cretaceous theropods from other continents reveal a previously unrecognized global radiation of carcharodontosaurid predators. Substantial geographic differentiation of dinosaurian faunas in response to continental drift appears to have arisen abruptly at the beginning of the Late Cretaceous.

ABSTRACT In this brief communication we provide the rationale for and the outcome of the International Astronomical Union (IAU) resolution vote at the XXIXth General Assembly in Honolulu, Hawaii, in 2015, on recommended nominal conversion constants for selected solar and planetary properties. The problem addressed by the resolution is a lack of established conversion constants between solar and planetary values and SI units: a missing standard has caused a proliferation of solar values (e.g., solar radius, solar irradiance, solar luminosity, solar effective temperature, and solar mass parameter) in the literature, with cited solar values typically based on best estimates at the time of paper writing. As precision of observations increases, a set of consistent values becomes increasingly important. To address this, an IAU Working Group on Nominal Units for Stellar and Planetary Astronomy formed in 2011, uniting experts from the solar, stellar, planetary, exoplanetary, and fundamental astronomy, as well as from general standards fields to converge on optimal values for nominal conversion constants. The effort resulted in the IAU 2015 Resolution B3, passed at the IAU General Assembly by a large majority. The resolution recommends the use of nominal solar and planetary values, which are by definition exact and are expressed in SI units. These nominal values should be understood as conversion factors only, not as the true solar/planetary properties or current best estimates. Authors and journal editors are urged to join in using the standard values set forth by this resolution in future work and publications to help minimize further confusion.

In addition to the graphic-editing facilities, the software tool Tina proposes the construction of a number of representations for the behaviour of Petri nets or Time Petri nets. Various techniques are used to extract views of the behaviour of nets, preserving certain classes of properties of their state spaces. For Petri nets, these abstractions help prevent combinatorial explosion, relying on so-called partial order techniques such as covering steps and/or persistent sets. For Time Petri nets, which have, in general, infinite state spaces, they provide a finite symbolic representation of their behaviour in terms of state classes.

PURPOSE: Antibiotic prophylaxis is given to children at risk for urinary tract infection. However, evidence concerning its effectiveness in grade I to III vesicoureteral reflux is lacking. The objective of this study was to determine whether antibiotic prophylaxis reduces the incidence of urinary tract infection in young children with low grade vesicoureteral reflux. MATERIALS AND METHODS: Children 1 month to 3 years old with grade I to III vesicoureteral reflux were assigned randomly to receive daily cotrimoxazole or no treatment, and followed for 18 months. A urinary tract infection constituted an exit criterion. Infection-free survival rates were calculated using the Kaplan-Meier method and compared using the log rank test. RESULTS: A total of 225 children were enrolled in the study. Distribution of gender, age at inclusion and reflux grade were similar between the 2 groups. There was no significant difference in the occurrence of urinary tract infection between the 2 groups (17% vs 26%, p = 0.2). However, a significant association was found between treatment and patient gender (p = 0.017). Prophylaxis significantly reduced urinary tract infection in boys (p = 0.013), most notably in boys with grade III vesicoureteral reflux (p = 0.042). CONCLUSIONS: These data suggest that antibiotic prophylaxis does not reduce the overall incidence of urinary tract infection in children with low grade vesicoureteral reflux. However, such a strategy may prevent further urinary tract infection in boys with grade III reflux.

The antiozonant N-phenyl-N'-(1,3-dimethylbutyl)-p-phenylenediamine (6-PPD) is added to tires to increase their lifetime and is emitted with tire and road wear particles into the environment. Recently, one of its transformation products (TPs), 6-PPD quinone (6-PPDQ), has gained attention due to its toxicity towards coho salmon. In this study, the abiotic oxidative transformation of 6-PPD is investigated by a series of ozonation experiments in the lab followed by analysis of TPs using liquid chromatography-high resolution-mass spectrometry (LC-HRMS). A total of 38 TPs were detected and tentatively identified, which were formed either directly from 6-PPD or via 6-PPDQ as intermediate. A suspect screening by LC-HRMS showed 32 of these TPs to occur in snow collected from urban roads as surrogate of road-runoff, where 6-PPDQ, 4-aminodiphenylamine (4-ADPA), TP 213, and TP 249 were the most prominent besides 6-PPD. More than 90% of the total load of 6-PPD and its TPs was found in the particulate fraction of snow. Thus, retaining the particulate fraction of road runoff before its discharge into surface water would substantially reduce the emission of 6-PPD and many of its TPs. Some TPs prevailed in the water phase of the snow due to their higher polarity. A total of 13 TPs were detected by suspect screening in the dissolved phase of a wastewater treatment plant (WWTP) influent. Their total load was markedly enhanced during a day of snowmelt (approx. 1100 g/d) and rainfall (approx. 2000 g/d) compared to dry weather (approx. 190 g/d). 6-PPD and 6-PPDQ contributed to less than 1% to this total load in the water phase (estimated concentrations of max 0.1 µg/L). The elimination of the estimated total loads of 6-PPD related TPs from the water phase in WWTP ranged from 22 to 67% depending on weather conditions. Eventually TP 249, 4-ADPA and TP 259_2 dominated in WWTP effluent (estimated concentration from 0.5 up to 2 µg/L). Thus TP 249 and TP 259_2 are, likely, the most specific and stable TPs of 6-PPD to be determined in the environment.

Frontotemporal dementia (FTD), characterized by behavioural and language disorders, is a clinically, genetically and pathologically heterogeneous group of diseases. The most recently identified of the four known genes is GRN, associated with 17q-linked FTD with ubiquitin-immunoreactive inclusions. GRN was analysed in 502 probands with frontal variant FTD (fvFTD), FTD with motoneuron disease (FTD-MND), primary progressive aphasia (PPA) and corticobasal degeneration syndrome (CBDS). We studied the clinical, neuropsychological and brain perfusion characteristics of mutation carriers. Eighteen mutations, seven novel were found in 24 families including 32 symptomatic mutation carriers. No copy number variation was found. The phenotypes associated with GRN mutations vary greatly: 20/32 (63%) carriers had fvFTD, the other (12/32, 37%) had clinical diagnoses of PPA, CBDS, Lewy body dementia or Alzheimer's disease. Parkinsonism developed in 13/32 (41%), visual hallucinations in 8/32 (25%) and motor apraxia in 5/21 (24%). Constructional disorders were present in 10/21 (48%). Episodic memory disorders were frequent (16/18, 89%), consistent with hippocampal amnestic syndrome in 5/18 (28%). Hypoperfusion was observed in the hippocampus, parietal lobe and posterior cingulate gyrus, as well as the frontotemporal cortices. The frequency of mutations according to phenotype was 5.7% (20/352) in fvFTD, 17.9% (19/106) in familial forms, 4.4% in PPA (3/68), 3.3% in CBDS (1/30). Hallucinations, apraxia and amnestic syndrome may help differentiate GRN mutation carriers from others FTD patients. Variable phenotypes and neuropsychological profiles, as well as brain perfusion profiles associated with GRN mutations may reflect different patterns of neurodegeneration. Since all the mutations cause a progranulin haploinsufficiency, additional factors probably explain the variable clinical presentation of the disease.