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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.
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.
The CARIBIC (Civil Aircraft for the Regular Investigation of the Atmosphere Based on an Instrument Container) passenger aircraft observatory performed in situ measurements at 10–12 km altitude in the South Asian summer monsoon anticyclone between June and September 2008. These measurements enable us to investigate this atmospheric region, which so far has mostly been observed from satellites, using the broad suite of trace gases and aerosols measured by CARIBIC. Elevated levels of a range of atmospheric pollutants were recorded e.g. carbon monoxide, total reactive nitrogen oxides, aerosol particles and several volatile organic compounds. The measurements provide detailed information about the chemical composition of air in different parts of the monsoon anticyclone, particularly of ozone precursors. While covering a range of 3500 km inside the monsoon anticyclone, CARIBIC observations show remarkable consistency, i.e. with regular latitudinal patterns of trace gases during the entire monsoon period. Trajectory calculations indicate that these air masses originated mainly from South Asia and Mainland Southeast Asia.
Using the CARIBIC trace gas and aerosol measurements in combination with the Lagrangian particle dispersion model FLEXPART we investigated the characteristics of monsoon outflow and the chemical evolution of air masses during transport. Estimated photochemical ages of the air were found to agree well with transport times from a source region east of 95 ° E. The photochemical ages of the air in the southern part of the monsoon anticyclone were consistently younger (less than 7 days) and the air masses mostly in an ozone forming chemical regime. In its northern part the air masses were older (up to 13 days) and had unclear ozone formation or destruction potential. Based on analysis of forward trajectories several receptor regions were identified. In addition to predominantly westward transport, we found evidence for efficient transport (within 10 days) to the Pacific and North America, particularly during June and September, and also of cross-tropopause exchange, which was strongest during June and July. Westward transport to Africa and further to the Mediterranean was the main pathway during July.
During CNS development and adult neurogenesis, immature neurons travel from the germinal zones towards their final destination using cellular substrates for their migration. Classically, radial glia and neuronal axons have been shown to act as physical scaffolds to support neuroblast locomotion in processes known as gliophilic and neurophilic migration, respectively (Hatten, 1999; Marin and Rubenstein, 2003; Rakic, 2003). In adulthood, long distance neuronal migration occurs in a glial-independent manner since radial glia cells differentiate into astrocytes after birth. A series of studies highlight a novel mode of neuronal migration that uses blood vessels as scaffolds, the so-called vasophilic migration. This migration mode allows neuroblast navigation in physiological and also pathological conditions, such as neuronal precursor migration after ischemic stroke or cerebral invasion of glioma tumor cells. Here we review the current knowledge about how vessels pave the path for migrating neurons and how trophic factors derived by glio-vascular structures guide neuronal migration both during physiological as well as pathological processes
An accurate quantification of low viremic HCV RNA plasma samples has gained importance since the approval of direct acting antivirals and since only one single measurement predicts the necessity of a prolonged or shortened therapy. As reported previously, HCV quantification assays such as Abbott RealTime HCV and Roche COBAS AmpliPrep/COBAS TaqMan HCV version 2 (CTM v2) may vary in sensitivity and precision particularly in low-level viremia. Importantly, substantial variations were previously demonstrated between some of these assays compared to the Roche High Pure System/COBAS TaqMan assay (HPS) reference assay, which was used to establish the clinical decision points in clinical studies. In this study, the reproducibility of assay performances across several laboratories was assessed by analysing quantification results generated by six independent laboratories (3× RealTime, 3× CTM v2) in comparison with one HPS reference laboratory. The 4th WHO Standard was diluted to 100, 25 and 10 IU/ml, and aliquots were tested in triplicates in 5 independent runs by each assay in the different laboratories to assess assay precision and detection rates. In a second approach, 2 clinical samples (GT 1a & GT 1b) were diluted to 100 and 25 IU/ml and tested as described above. While the result range for WHO 100 IU/ml replicates across all laboratories was similar in this analysis, the CVs of each laboratory ranged from 19.3 to 25.6 % for RealTime laboratories and were lower than CVs of CTM v2 laboratories with a range of 26.1–47.3 %, respectively, and also in comparison with the CV of the HPS reference laboratory (34.9 %). At WHO standard dilution of 25 IU/ml, 24 replicates were quantified by RealTime compared to 8 replicates with CTM v2. Results of clinical samples again revealed a higher variation of CTM v2 results as compared to RealTime values. (CVs at 100 IU/ml: RealTime: 13.1–21.0 % and CTM v2: 15.0–32.3 %; CVs at 25 IU/ml: RealTime 17.6–34.9 % and CTM v2 28.2–54.9 %). These findings confirm the superior precision of RealTime versus CTM v2 at low-level viremia even across different laboratories including the new clinical decision point at 25 IU/ml. A highly precise monitoring of HCV viral load during therapy will remain crucial for patient management with regard to futility rules, therapy efficacy and SVR.
Abstract: The current Ebola outbreak poses a threat to individual and global public health. Although the disease has been of interest to the scientific community since 1976, an effective vaccination approach is still lacking. This fact questions past global public health strategies, which have not foreseen the possible impact of this infectious disease. To quantify the global research activity in this field, a scientometric investigation was conducted. We analyzed the research output of countries, individual institutions and their collaborative networks. The resulting research architecture indicated that American and European countries played a leading role regarding output activity, citations and multi- and bilateral cooperations. When related to population numbers, African countries, which usually do not dominate the global research in other medical fields, were among the most prolific nations. We conclude that the field of Ebola research is constantly progressing, and the research landscape is influenced by economical and infrastructural factors as well as historical relations between countries and outbreak events.
Author Summary: For the first time in the history of the disease, the Ebola virus left its local setting and affected people not only in isolated rural areas, but reached larger towns and cities leading to worldwide repercussions. This development prompted a joint global response to this health threat. This encompassed not only immediate relief efforts, but also an up search in global research work. In this study, the scientific output in Ebola research available in one of the mayor medical search platforms was characterized. We studied among others the origin of research, the collaboration between countries and the research topics. Partly, the obtained data was weighted against economic parameters. We attained a detailed map of the research activities from the discovery of Ebola in 1976 up to today. Our research provides the first overview of the worldwide Ebola research output. It might help stakeholders in Ebola research to better plan investigations with a global perspective.