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A number of recent studies regress a "narratively" identified measure of a macroeconomic shock directly on an outcome variable. In this note, we argue that this approach can be viewed as the reduced-form regression of an instrumental variable approach in which the narrative time series is used as an instrument for an endogenous series of interest. This motivates evaluating the validity of narrative measures through the lens of a randomized experiment. We apply our framework to four recently constructed narrative measures of tax shocks by Romer and Romer (2010), Cloyne (2013), and Mertens and Ravn (2012). All of them turn out to be weak instruments for observable measures of taxes. After correcting for weak instruments, we find that using any of the considered narrative tax measures as an instrument for cyclically adjusted tax revenues yields tax multiplier estimates that are indistinguishable from zero. We conclude that the literature currently understates the uncertainty associated with quantifying the tax multiplier.
The Time Projection Chamber (TPC), a large gaseous detector, is the main particle identification device of the ALICE experiment at the CERN LHC. The desired performance of the TPC defines the requirements for the gas mixture used in the detector. The active volume was filled with either Ne-CO2 (90-10) or Ne-CO2-N2 (90-10-5) during the first LHC running period. For LHC Run 2 the gas mixture is changed to Ar-CO2. Calculations of relevant gas properties are performed for Ar-based gas mixtures and compared to Ne-based gas mixtures to identify the most suitable Ar mixture. The drift velocity of ions in Ar is lower than in Ne. The closing time of the gating grid has to be adjusted accordingly to avoid drift field distortions due to back-drifting ions. The drift times of ions in the TPC readout chambers are calculated for the respective gas mixtures to determine the time to collect all ions from the amplification region. For LHC Run 3 the TPC readout chambers will be upgraded. The Multiwire Proportional Chambers (MWPCs) will be replaced by readout chambers based on Gas Electron Multipliers (GEMs) which are operated in continuous mode. As a consequence an ion backflow of the order of 1% causes significant space-charge distortions in the TPC drift volume. Similar distortions are expected in data taken specifically for the study of space-charge effects at the end of Run 1. The gating grid of the MWPCs is operated in the open state allowing the ions from the amplification region to enter the drift volume. The magnitude of the distortions in this data is measured and compared to the expectations for the TPC upgrade and results from current simulations.
RUCAM (Roussel Uclaf Causality Assessment Method) or its previous synonym CIOMS (Council for International Organizations of Medical Sciences) is a well established tool in common use to quantitatively assess causality in cases of suspected drug induced liver injury (DILI) and herb induced liver injury (HILI). Historical background and the original work confirm the use of RUCAM as single term for future cases, dismissing now the term CIOMS for reasons of simplicity and clarity. RUCAM represents a structured, standardized, validated, and hepatotoxicity specific diagnostic approach that attributes scores to individual key items, providing final quantitative gradings of causality for each suspect drug/herb in a case report. Experts from Europe and the United States had previously established in consensus meetings the first criteria of RUCAM to meet the requirements of clinicians and practitioners in care for their patients with suspected DILI and HILI. RUCAM was completed by additional criteria and validated, assisting to establish the timely diagnosis with a high degree of certainty. In many countries and for more than two decades, physicians, regulatory agencies, case report authors, and pharmaceutical companies successfully applied RUCAM for suspected DILI and HILI. Their practical experience, emerging new data on DILI and HILI characteristics, and few ambiguous questions in domains such alcohol use and exclusions of non-drug causes led to the present update of RUCAM. The aim was to reduce interobserver and intraobserver variability, to provide accurately defined, objective core elements, and to simplify the handling of the items. We now present the update of the well accepted original RUCAM scale and recommend its use for clinical, regulatory, publication, and expert purposes to validly establish causality in cases of suspected DILI and HILI, facilitating a straightforward application and an internationally harmonized approach of causality assessment as a common basic tool.
A three-dimensional gridded climatology of carbon monoxide (CO) has been developed by trajectory mapping of global MOZAIC-IAGOS in situ measurements from commercial aircraft data. CO measurements made during aircraft ascent and descent, comprising nearly 41 200 profiles at 148 airports worldwide from December 2001 to December 2012 are used. Forward and backward trajectories are calculated from meteorological reanalysis data in order to map the CO measurements to other locations, and so to fill in the spatial domain. This domain-filling technique employs 15 800 000 calculated trajectories to map otherwise sparse MOZAIC-IAGOS data into a quasi-global field. The resulting trajectory-mapped CO dataset is archived monthly from 2001–2012 on a grid of 5° longitude × 5° latitude × 1 km altitude, from the surface to 14 km altitude.
The mapping product has been carefully evaluated, by comparing maps constructed using only forward trajectories and using only backward trajectories. The two methods show similar global CO distribution patterns. The magnitude of their differences is most commonly 10 % or less, and found to be less than 30 % for almost all cases. The trajectory-mapped CO dataset has also been validated by comparison profiles for individual airports with those produced by the mapping method when data from that site are excluded. While there are larger differences below 2 km, the two methods agree very well between 2 and 10 km with the magnitude of biases within 20 %.
Maps are also compared with Version 6 data from the Measurements Of Pollution In The Troposphere (MOPITT) satellite instrument. While agreement is good in the lowermost troposphere, the MOPITT CO profile shows negative biases of ∼ 20 % between 500 and 300 hPa. These upper troposphere biases are not related to the
mapping procedure, as almost identical differences are found with the original in situ MOZAIC-IAGOS data. The total CO trajectory-mapped MOZAIC-IAGOS climatology column agrees with the MOPITT CO total column within ±5 %, which is consistent with previous reports.
The maps clearly show major regional CO sources such as biomass burning in the central and southern Africa and anthropogenic emissions in eastern China. The dataset shows the seasonal CO cycle over different latitude bands and altitude ranges that are representative of the regions as well as long-term trends over latitude bands. We observe a decline in CO over the Northern Hemisphere extratropics and the tropics consistent with that reported by previous studies.
Similar maps have been made using the concurrent O3 measurements by MOZAICIAGOS, as the global variation of O3–CO correlations can be a useful tool for the evaluation of ozone sources and transport in chemical transport models. We anticipate use of the trajectory-mapped MOZAIC-IAGOS CO dataset as an a priori climatology for satellite retrieval, and for air quality model validation and initialization.
Cloud microphysical processes involving the ice phase in tropospheric clouds are among the major uncertainties in cloud formation, weather and General Circulation Models (GCMs). The simultaneous detection of aerosol particles, liquid droplets, and ice crystals, especially in the small cloud-particle size range below 50 µm, remains challenging in mixed phase, often unstable ice-water phase environments. The Cloud Aerosol Spectrometer with Polarisation (CASPOL) is an airborne instrument that has the ability to detect such small cloud particles and measure their effects on the backscatter polarisation state. Here we operate the versatile Cosmics-Leaving- OUtdoor-Droplets (CLOUD) chamber facility at the European Organisation for Nuclear Research (CERN) to produce controlled mixed phase and other clouds by adiabatic expansions in an ultraclean environment, and use the CASPOL to discriminate between different aerosols, water and ice particles. In this paper, optical property measurements of mixed phase clouds and viscous Secondary Organic Aerosol (SOA) are presented. We report observations of significant liquid – viscous SOA particle polarisation transitions under dry conditions using CASPOL. Cluster analysis techniques were subsequently used to classify different types of particles according to their polarisation ratios during phase transition. A classification map is presented for water droplets, organic aerosol (e.g., SOA and oxalic acid), crystalline substances such as ammonium sulphate, and volcanic ash. Finally, we discuss the benefits and limitations of this classi- fication approach for atmospherically relevant concentration and mixtures with respect to the CLOUD 8–9 campaigns and its potential contribution to Tropical Troposphere Layer (TTL) analysis.
There are strong indications that particles containing secondary organic aerosol (SOA) exhibit amorphous solid or semi-solid phase states in the atmosphere. This may facilitate deposition ice nucleation and thus influence cirrus cloud properties. However, experimental ice nucleation studies of biogenic SOA are scarce. Here, we investigated the ice nucleation ability of viscous SOA particles.
The SOA particles were produced from the ozone initiated oxidation of α-pinene in an aerosol chamber at temperatures in the range from −38 to −10 ◦C at 5–15 % relative humidity with respect to water to ensure their formation in a highly viscous phase state, i.e. semi-solid or glassy. The ice nucleation ability of SOA particles with different sizes was investigated with a new continuous flow diffusion chamber. For the first time, we observed heterogeneous ice nucleation of viscous α-pinene SOA in the deposition mode for ice saturation ratios between 1.3 and 1.4 significantly below the homogeneous freezing limit. The maximum frozen fractions found at temperatures between −36.5 and −38.3 °C ranged from 6 to 20 % and did not depend on the particle surface area. Global modelling of monoterpene SOA particles suggests that viscous biogenic SOA particles are indeed present in regions where cirrus cloud formation takes place. Hence, they could make up an important contribution to the global ice nuclei (IN) budget.
The human 5-lipoxygenase (5-LO), encoded by the ALOX5 gene, is the key enzyme in the formation of pro-inflammatory leukotrienes. ALOX5 gene transcription is strongly stimulated by calcitriol (1α, 25-dihydroxyvitamin D3) and TGFβ (transforming growth factor-β). Here, we investigated the influence of MLL (activator of transcript initiation), AF4 (activator of transcriptional elongation) as well as of the leukemogenic fusion proteins MLL-AF4 (ectopic activator of transcript initiation) and AF4-MLL (ectopic activator of transcriptional elongation) on calcitriol/TGFβ-dependent 5-LO transcript elongation. We present evidence that the AF4 complex directly interacts with the vitamin D receptor (VDR) and promotes calcitriol-dependent ALOX5 transcript elongation. Activation of transcript elongation was strongly enhanced by the AF4-MLL fusion protein but was sensitive to Flavopiridol. By contrast, MLL-AF4 displayed no effect on transcriptional elongation. Furthermore, HDAC class I inhibitors inhibited the ectopic effects caused by AF4-MLL on transcriptional elongation, suggesting that HDAC class I inhibitors are potential therapeutics for the treatment of t(4;11)(q21;q23) leukemia.
Models propose an auditory-motor mapping via a left-hemispheric dorsal speech-processing stream, yet its detailed contributions to speech perception and production are unclear. Using fMRI-navigated repetitive transcranial magnetic stimulation (rTMS), we virtually lesioned left dorsal stream components in healthy human subjects and probed the consequences on speech-related facilitation of articulatory motor cortex (M1) excitability, as indexed by increases in motor-evoked potential (MEP) amplitude of a lip muscle, and on speech processing performance in phonological tests. Speech-related MEP facilitation was disrupted by rTMS of the posterior superior temporal sulcus (pSTS), the sylvian parieto-temporal region (SPT), and by double-knock-out but not individual lesioning of pars opercularis of the inferior frontal gyrus (pIFG) and the dorsal premotor cortex (dPMC), and not by rTMS of the ventral speech-processing stream or an occipital control site. RTMS of the dorsal stream but not of the ventral stream or the occipital control site caused deficits specifically in the processing of fast transients of the acoustic speech signal. Performance of syllable and pseudoword repetition correlated with speech-related MEP facilitation, and this relation was abolished with rTMS of pSTS, SPT, and pIFG. Findings provide direct evidence that auditory-motor mapping in the left dorsal stream causes reliable and specific speech-related MEP facilitation in left articulatory M1. The left dorsal stream targets the articulatory M1 through pSTS and SPT constituting essential posterior input regions and parallel via frontal pathways through pIFG and dPMC. Finally, engagement of the left dorsal stream is necessary for processing of fast transients in the auditory signal.
BACKGROUND: Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has shown superior efficacy to etanercept with similar safety in moderate to severe plaque psoriasis (FIXTURE study).
OBJECTIVE: We sought to directly compare efficacy and safety of secukinumab versus ustekinumab.
METHODS: In this 52-week, double-blind study (NCT02074982), 676 subjects were randomized 1:1 to subcutaneous injection of secukinumab 300 mg or ustekinumab per label. Primary end point was 90% or more improvement from baseline Psoriasis Area and Severity Index (PASI) score (PASI 90) at week 16.
RESULTS: Secukinumab (79.0%) was superior to ustekinumab (57.6%) as assessed by PASI 90 response at week 16 (P < .0001). The 100% improvement from baseline PASI score at week 16 was also significantly greater with secukinumab (44.3%) than ustekinumab (28.4%) (P < .0001). The 75% or more improvement from baseline PASI score at week 4 was superior for secukinumab (50.0%) versus ustekinumab (20.6%) (P < .0001). Percentage of subjects with the Dermatology Life Quality Index score 0/1 (week 16) was significantly higher with secukinumab (71.9%) than ustekinumab (57.4%) (P < .0001). The safety profile of secukinumab was comparable with ustekinumab and consistent with pivotal phase III secukinumab studies.
LIMITATIONS: The study was not placebo-controlled and of short-term duration.
CONCLUSIONS: Secukinumab is superior to ustekinumab in clearing skin of subjects with moderate to severe psoriasis and improving health-related quality of life with a comparable safety profile over 16 weeks.