Holocene slip rate variability along the Pernicana fault system (Mt. Etna, Italy): Evidence from offset lava flows

The eastern flank of the Mount Etna stratovolcano is affected by extension and is slowly sliding eastward into the Ionian Sea. The Pernicana fault system forms the border of the northern part of this sliding area. It consists of three E-W−oriented fault sectors that are seismically active and characterized by earthquakes up to 4.7 in magnitude (M) capable of producing ground rupture and damage located mainly along the western and central sectors, and by continuous creep on the eastern sector. A new topographic study of the central sector of the Pernicana fault system shows an overall bell-shaped profile, with maximum scarp height of 35 m in the center of the sector, and two local minima that are probably due to the complex morphological relation between fault scarp and lava flows. We determined the ages of lava flows cut by the Pernicana fault system at 12 sites using cosmogenic 3He and 40Ar/39Ar techniques in order to determine the recent slip history of the fault. From the displacement-age relations, we estimate an average throw rate of ∼2.5 mm/yr over the last 15 k.y. The slip rate appears to have accelerated during the last 3.5 k.y., with displacement rates of up to ∼15 mm/yr, whereas between 3.5 and 15 ka, the throw rate averaged ∼1 mm/yr. This increase in slip rate resulted in significant changes in seismicity rates, for instance, decreasing the mean recurrence time of M ≥ 4.7 earthquakes from ∼200 to ∼20 yr. Based on empirical relationships, we attribute the variation in seismic activity on the Pernicana fault system to factors intrinsic to the system that are likely related to changes in the volcanic system. These internal factors could be fault interdependencies (such as those across the Taupo Rift, New Zealand) or they could represent interactions among magmatic, tectonic, and gravitational processes (e.g., Kīlauea volcano, Hawaii). Given their effect on earthquake recurrence intervals, these interactions need to be fully assessed in seismic hazard evaluations

Post-collisional shift from polygenetic to monogenetic volcanism revealed by new 40Ar/39Ar ages in the southern Lesser Caucasus (Armenia)

The post-collisional Syunik and Vardenis volcanic highlands, located in the southern Lesser Caucasus mountains (part of the Arabia-Eurasia collision zone) are host to over 200 monogenetic volcanoes, as well as 2 large Quaternary polygenetic volcanoes in the Syunik highland. The latter are overlain by lavas from the monogenetic volcanoes, suggesting there was a transition in the style of volcanic activity from large-volume central vent eruptions to dispersed small-volume eruptions. 12 new high quality 40Ar/39Ar ages are presented here, with 11 ages calculated by step-heating experiments on groundmass separates, and the final age obtained from total fusions of a population of sanidines. All the ages were younger than 1.5 Ma, except for one ignimbrite deposit whose sanidines gave an age of 6 Ma. While the bulk of the exposed products of post-collisional volcanism relate to Pleistocene activity, it is clear there has been active volcanism in the region since at least the late Miocene. All ages for monogenetic volcanoes in the Syunik highland are younger than 1 Ma, but to the north in Vardenis there is geochronological evidence of monogenetic volcanism at 1.4 and 1.3 Ma. An age of 1.3 Ma is determined for a lava flow from one of the polygenetic volcanoes- Tskhouk, and when combined with other ages helps constrain the timing of the polygenetic to monogenetic transition to around 1 Ma. The new ages illustrate a degree of spatio-temporal coupling in the formation of new vents, which could be related to pull-apart basins focussing ascending magmas. This coupling means that future eruptions are particularly likely to occur close to the sites of the most recent Holocene activity. The polygenetic to monogenetic transition is argued to be the result of a decreasing magma supply based on: (i) volume estimates for Holocene eruptions and for all monogenetic volcanoes and their lava flows in Syunik; and (ii) the volcanic stratigraphy of the Lesser Caucasus region which shows late Pliocene- early Pleistocene continental flood basalts being succeeded by a few large andesite-dacite volcanoes and then the most recent deposits consisting of small-volume scoria cones. The Syunik highland has the highest density of monogenetic centres in the Lesser Caucasus, which is taken to indicate this region has the highest magma flux, and was therefore the last location to transition to monogenetic volcanism, which is why the transition is most clearly seen there. There is no evidence from Sr-Nd-B isotope measurements for the exhaustion of fusible slab components in the mantle source, showing that an inherited slab signature can survive for millions of years after the end of subduction. Although volcanism in the Lesser Caucasus is currently waning, a future pulse of activity is possible

Reduced level of arousal and increased mortality in adult acute medical admissions: a systematic review and meta-analysis

Abstract Background Reduced level of arousal is commonly observed in medical admissions and may predict in-hospital mortality. Delirium and reduced level of arousal are closely related. We systematically reviewed and conducted a meta-analysis of studies in adult acute medical patients of the relationship between reduced level of arousal on admission and in-hospital mortality. Methods We conducted a systematic review (PROSPERO: CRD42016022048), searching MEDLINE and EMBASE. We included studies of adult patients admitted with acute medical illness with level of arousal assessed on admission and mortality rates reported. We performed meta-analysis using a random effects model. Results From 23,941 studies we included 21 with 14 included in the meta-analysis. Mean age range was 33.4 - 83.8 years. Studies considered unselected general medical admissions (8 studies, n=13,039) or specific medical conditions (13 studies, n=38,882). Methods of evaluating level of arousal varied. The prevalence of reduced level of arousal was 3.1%-76.9% (median 13.5%). Mortality rates were 1.7%-58% (median 15.9%). Reduced level of arousal was associated with higher in-hospital mortality (pooled OR 5.71; 95% CI 4.21-7.74; low quality evidence: high risk of bias, clinical heterogeneity and possible publication bias). Conclusions Reduced level of arousal on hospital admission may be a strong predictor of in-hospital mortality. Most evidence was of low quality. Reduced level of arousal is highly specific to delirium, better formal detection of hypoactive delirium and implementation of care pathways may improve outcomes. Future studies to assess the impact of interventions on in-hospital mortality should use validated assessments of both level of arousal and delirium

The kinetics of antibody binding to Plasmodium falciparum VAR2CSA PfEMP1 antigen and modelling of PfEMP1 antigen packing on the membrane knobs

<p>Abstract</p> <p>Background</p> <p>Infected humans make protective antibody responses to the PfEMP1 adhesion antigens exported by <it>Plasmodium falciparum </it>parasites to the erythrocyte membrane, but little is known about the kinetics of this antibody-receptor binding reaction or how the topology of PfEMP1 on the parasitized erythrocyte membrane influences antibody association with, and dissociation from, its antigenic target.</p> <p>Methods</p> <p>A Quartz Crystal Microbalance biosensor was used to measure the association and dissociation kinetics of VAR2CSA PfEMP1 binding to human monoclonal antibodies. Immuno-fluorescence microscopy was used to visualize antibody-mediated adhesion between the surfaces of live infected erythrocytes and atomic force microscopy was used to obtain higher resolution images of the membrane knobs on the infected erythrocyte to estimate knob surface areas and model VAR2CSA packing density on the knob.</p> <p>Results</p> <p>Kinetic analysis indicates that antibody dissociation from the VAR2CSA PfEMP1 antigen is extremely slow when there is a high avidity interaction. High avidity binding to PfEMP1 antigens on the surface of <it>P. falciparum</it>-infected erythrocytes in turn requires bivalent cross-linking of epitopes positioned within the distance that can be bridged by antibody. Calculations of the surface area of the knobs and the possible densities of PfEMP1 packing on the knobs indicate that high-avidity cross-linking antibody reactions are constrained by the architecture of the knobs and the large size of PfEMP1 molecules.</p> <p>Conclusions</p> <p>High avidity is required to achieve the strongest binding to VAR2CSA PfEMP1, but the structures that display PfEMP1 also tend to inhibit cross-linking between PfEMP1 antigens, by holding many binding epitopes at distances beyond the 15-18 nm sweep radius of an antibody. The large size of PfEMP1 will also constrain intra-knob cross-linking interactions. This analysis indicates that effective vaccines targeting the parasite's vulnerable adhesion receptors should primarily induce strongly adhering, high avidity antibodies whose association rate constant is less important than their dissociation rate constant.</p

Functional comparison of blood-stage Plasmodium falciparum malaria vaccine candidate antigens

The malaria genome encodes over 5,000 proteins and many of these have also been proposed to be potential vaccine candidates, although few of these have been tested clinically. RH5 is one of the leading blood-stage Plasmodium falciparum malaria vaccine antigens and Phase I/II clinical trials of vaccines containing this antigen are currently underway. Its likely mechanism of action is to elicit antibodies that can neutralize merozoites by blocking their invasion of red blood cells (RBC). However, many other antigens could also elicit neutralizing antibodies against the merozoite, and most of these have never been compared directly to RH5. The objective of this study was to compare a range of blood-stage antigens to RH5, to identify any antigens that outperform or synergize with anti-RH5 antibodies. We selected 55 gene products, covering 15 candidate antigens that have been described in the literature and 40 genes selected on the basis of bioinformatics functional prediction. We were able to make 20 protein-in-adjuvant vaccines from the original selection. Of these, S-antigen and CyRPA robustly elicited antibodies with neutralizing properties. Anti-CyRPA IgG generally showed additive GIA with anti-RH5 IgG, although high levels of anti-CyRPA-specific rabbit polyclonal IgG were required to achieve 50% GIA. Our data suggest that further vaccine antigen screening efforts are required to identify a second merozoite target with similar antibody-susceptibility to RH5

Antibodies to a Full-Length VAR2CSA Immunogen Are Broadly Strain-Transcendent but Do Not Cross-Inhibit Different Placental-Type Parasite Isolates

The high molecular weight, multidomain VAR2CSA protein mediating adhesion of Plasmodium falciparum-infected erythrocytes in the placenta is the leading candidate for a pregnancy malaria vaccine. However, it has been difficult so far to generate strong and consistent adhesion blocking antibody responses against most single-domain VAR2CSA immunogens. Recent advances in expression of the full-length recombinant protein showed it binds with much greater specificity and affinity to chondroitin sulphate A (CSA) than individual VAR2CSA domains. This raises the possibility that a specific CSA binding pocket(s) is formed in the full length antigen and could be an important target for vaccine development. In this study, we compared the immunogenicity of a full-length VAR2CSA recombinant protein containing all six Duffy binding-like (DBL) domains to that of a three-domain construct (DBL4-6) in mice and rabbits. Animals immunized with either immunogen acquired antibodies reacting with several VAR2CSA individual domains by ELISA, but antibody responses against the highly conserved DBL4 domain were weaker in animals immunized with full-length DBL1-6 recombinant protein compared to DBL4-6 recombinant protein. Both immunogens induced cross-reactive antibodies to several heterologous CSA-binding parasite lines expressing different VAR2CSA orthologues. However, antibodies that inhibited adhesion of parasites to CSA were only elicited in rabbits immunized with full-length immunogen and inhibition was restricted to the homologous CSA-binding parasite. These findings demonstrate that partial and full-length VAR2CSA immunogens induce cross-reactive antibodies, but inhibitory antibody responses to full-length immunogen were highly allele-specific and variable between animal species

Interaction between drug and placebo effects: a cross-over balanced placebo design trial

<p>Abstract</p> <p>Background</p> <p>The total effect of a medication is the sum of its drug effect, placebo effect (meaning response), and their possible interaction. Current interpretation of clinical trials' results assumes no interaction. Demonstrating such an interaction has been difficult due to lack of an appropriate study design.</p> <p>Methods</p> <p>180 adults were randomized to caffeine (300 mg) or placebo groups. Each group received the assigned intervention described by the investigators as caffeine or placebo, in a randomized crossover design. 4-hour-area-under-the-curve of energy, sleepiness, nausea (on 100 mm visual analog scales), and systolic blood pressure levels as well as caffeine pharmacokinetics (in 22 volunteers nested in the caffeine group) were determined. Caffeine drug, placebo, placebo-plus-interaction, and total effects were estimated by comparing outcomes after, receiving caffeine described as placebo to receiving placebo described as placebo, receiving placebo described as caffeine or placebo, receiving caffeine described as caffeine or placebo, and receiving caffeine described as caffeine to receiving placebo described as placebo, respectively.</p> <p>Results</p> <p>The placebo effect on area-under-the-curve of energy (mean difference) and sleepiness (geometric mean ratio) was larger than placebo-plus-interaction effect (16.6 [95% CI, 4.1 to 29.0] vs. 8.4 [-4.2 to 21.0] mm*hr and 0.58 [0.39 to 0.86] vs. 0.69 [0.49 to 0.97], respectively), similar in size to drug effect (20.8 [3.8 to 37.8] mm*hr and 0.49 [0.30 to 0.91], respectively), and its combination with the later was larger than total caffeine effect (29.5 [11.9 to 47.1] mm*hr and 0.37 [0.22 to 0.64]). Placebo-plus-interaction effect increased caffeine terminal half-life by 0.40 [0.12 to 0.68] hr (P = 0.007).</p> <p>Conclusions</p> <p>Drug and placebo effects of a medication may be less than additive, which influences the interpretation of clinical trials. The placebo effect may increase active drug terminal half-life, a novel mechanism of placebo action.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov identification number - NCT00426010.</p

Estimation of the severity of breathlessness in the emergency department: a dyspnea score

BACKGROUND: Dyspnea is a frequent complaint in emergency departments (ED). It has a significant amount of subjective and affective components, therefore the dyspnea scores, based on the patients' rating, can be ambiguous. Our purpose was to develop and validate a simple scoring system to evaluate the severity of dyspnea in emergency care, based on objectively measured parameters. METHODS: We performed a double center, prospective, observational study including 350 patients who were admitted in EDs with dyspnea. We evaluated the patients' subjective feeling about dyspnea and applied our Dyspnea Severity Score (DSS), rating the dyspnea in 7 Dimensions from 0 to 3 points. The DSS was validated using the deterioration of pH, base-excess and lactate levels in the blood gas samples (Objective Classification Scale (OCS) 9 points and 13 points groups). RESULTS: All of the Dimensions correlated closely with the OCS values and with the subjective feeling of the dyspnea. Using multiple linear regression analysis we were able to decrease the numbers of Dimensions from seven to four without causing a significant change in the determination coefficient in any OCS groups. This reduced DSS values (exercise tolerance, cooperation, cyanosis, SpO2 value) showed high sensitivity and specificity to predict the values of OCS groups (the ranges: AUC 0.77-0.99, sensitivity 65-100%, specificity 64-99%). There was a close correlation between the subjective dyspnea scores and the OCS point values (p /=7 points without correction factors) can be useful at the triage or in pre-hospital care

Human vaccination against RH5 induces neutralizing antimalarial antibodies that inhibit RH5 invasion complex interactions.

The development of a highly effective vaccine remains a key strategic goal to aid the control and eventual eradication of Plasmodium falciparum malaria. In recent years, the reticulocyte-binding protein homolog 5 (RH5) has emerged as the most promising blood-stage P. falciparum candidate antigen to date, capable of conferring protection against stringent challenge in Aotus monkeys. We report on the first clinical trial to our knowledge to assess the RH5 antigen - a dose-escalation phase Ia study in 24 healthy, malaria-naive adult volunteers. We utilized established viral vectors, the replication-deficient chimpanzee adenovirus serotype 63 (ChAd63), and the attenuated orthopoxvirus modified vaccinia virus Ankara (MVA), encoding RH5 from the 3D7 clone of P. falciparum. Vaccines were administered i.m. in a heterologous prime-boost regimen using an 8-week interval and were well tolerated. Vaccine-induced anti-RH5 serum antibodies exhibited cross-strain functional growth inhibition activity (GIA) in vitro, targeted linear and conformational epitopes within RH5, and inhibited key interactions within the RH5 invasion complex. This is the first time to our knowledge that substantial RH5-specific responses have been induced by immunization in humans, with levels greatly exceeding the serum antibody responses observed in African adults following years of natural malaria exposure. These data support the progression of RH5-based vaccines to human efficacy testing

Comparing microbiotas in the upper aerodigestive and lower respiratory tracts of lambs

Abstract Background Recently, the importance of the lung microbiota during health and disease has been examined in humans and in small animal models. Whilst sheep have been proposed as an appropriate large animal model for studying the pathophysiology of a number of important human respiratory diseases, it is clearly important to continually define the limits of agreement between these systems as new concepts emerge. In humans, it has recently been established that the lung microbiota is seeded by microbes from the oral cavity. We sought to determine whether the same was true in sheep. Results We took lung fluid and upper aerodigestive tract (oropharyngeal) swab samples from 40 lambs (7 weeks old). DNA extraction was performed, and the V2-V3 region of the 16S rRNA gene was amplified by PCR then sequenced via Illumina Miseq. Oropharyngeal swabs were either dominated by bacteria commonly associated with the rumen or by bacteria commonly associated with the upper aerodigestive tract. Lung microbiota samples did not resemble either the upper aerodigestive tract samples or reagent-only controls. Some rumen-associated bacteria were found in lung fluids, indicating that inhalation of ruminal bacteria does occur. We also identified several bacteria which were significantly more abundant in lung fluids than in the upper aerodigestive tract swabs, the most predominant of which was classified as Staphylococcus equorum. Conclusions In contrast to humans, we found that the lung microbiota of lambs is dissimilar to that of the upper aerodigestive tract, and we suggest that this may be related to physiological and anatomical differences between sheep and humans. Understanding the comparative physiology and anatomy underlying differences in lung microbiota between species will provide a foundation upon which to interpret changes associated with disease and/or environment