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Background: The identification of people at risk of cognitive impairment is essential for improving recruitment in secondary prevention trials of Alzheimer's disease. We aimed to test and qualify a biomarker risk assignment algorithm (BRAA) to identify participants at risk of developing mild cognitive impairment due to Alzheimer's disease within 5 years, and to evaluate the safety and efficacy of low-dose pioglitazone to delay onset of mild cognitive impairment in these at-risk participants. Methods: In this phase 3, multicentre, randomised, double-blind, placebo-controlled, parallel-group study, we enrolled cognitively healthy, community living participants aged 65–83 years from 57 academic affiliated and private research clinics in Australia, Germany, Switzerland, the UK, and the USA. By use of the BRAA, participants were grouped as high risk or low risk. Participants at high risk were randomly assigned 1:1 to receive oral pioglitazone (0·8 mg/day sustained release) or placebo, and all low-risk participants received placebo. Study investigators, site staff, sponsor personnel, and study participants were masked to genotype, risk assignment, and treatment assignment. The planned study duration was the time to accumulate 202 events of mild cognitive impairment due to Alzheimer's disease in White participants who were at high risk (the population on whom the genetic analyses that informed the BRAA development was done). Primary endpoints were time-to-event comparisons between participants at high risk and low risk given placebo (for the BRAA objective), and between participants at high risk given pioglitazone or placebo (for the efficacy objective). The primary analysis included all participants who were randomly assigned, received at least one dose of study drug, and had at least one valid post-baseline visit, with significance set at p=0·01. The safety analysis included all participants who were randomly assigned and received at least one dose of study medication. An efficacy futility analysis was planned for when approximately 33% of the anticipated events occurred in the high-risk, White, non-Hispanic or Latino group. This trial is registered with ClinicalTrials.gov, NCT01931566. Findings: Between Aug 28, 2013, and Dec 21, 2015, we enrolled 3494 participants (3061 at high risk and 433 at low risk). Of those participants, 1545 were randomly assigned to pioglitazone and 1516 to placebo. 1104 participants discontinued treatment (464 assigned to the pioglitazone group, 501 in the placebo high risk group, and 139 in the placebo low risk group). 3399 participants had at least one dose of study drug or placebo and at least one post-baseline follow-up visit, and were included in the efficacy analysis. 3465 participants were included in the safety analysis (1531 assigned to the pioglitazone group, 1507 in the placebo high risk group, and 427 in the placebo low risk group). In the full analysis set, 46 (3·3%) of 1406 participants at high risk given placebo had mild cognitive impairment due to Alzheimer's disease, versus four (1·0%) of 402 participants at low risk given placebo (hazard ratio 3·26, 99% CI 0·85–12·45; p=0·023). 39 (2·7%) of 1430 participants at high risk given pioglitazone had mild cognitive impairment, versus 46 (3·3%) of 1406 participants at high risk given placebo (hazard ratio 0·80, 99% CI 0·45–1·40; p=0·307). In the safety analysis set, seven (0·5%) of 1531 participants at high risk given pioglitazone died versus 21 (1·4%) of 1507 participants at high risk given placebo. There were no other notable differences in adverse events between groups. The study was terminated in January, 2018, after failing to meet the non-futility threshold. Interpretation: Pioglitazone did not delay the onset of mild cognitive impairment. The biomarker algorithm demonstrated a 3 times enrichment of events in the high risk placebo group compared with the low risk placebo group, but did not reach the pre-specified significance threshold. Because we did not complete the study as planned, findings can only be considered exploratory. The conduct of this study could prove useful to future clinical development strategies for Alzheimer's disease prevention studies. Funding: Takeda and Zinfandel.

The share of biofuels in the transportation sector is increasing. Previous studies revealed that the use of biofuels decreases the size of particles (which is linked to an increase in particulate toxicity). Current emission regulations do not consider small particles (sub-23 nm); however, there is a focus in future emissions regulations on small particles. These and the fact that within cold-start emissions are higher than during the warmed-up operation highlight the importance of a research that studies particulate matter emissions during cold-start. This research investigates the influence of biofuel on PN and PM concentration, size distribution, median diameter and cumulative share at different size ranges (including sub-23 nm and nucleation mode) during cold-start and warm-up operations using diesel and 10, 15 and 20% mixture (coconut biofuel blended with diesel). During cold-start, between 19 and 29% of total PN and less than 0.8% of total PM were related to the nucleation mode (sub-50 nm). Out of that, the share of sub-23 nm was up to 9% for PN while less than 0.02% for PM. By using biofuel, PN increased between 27 and 57% at cold-start; while, the increase was between 4 and 19% during hot-operation. The median diameter also decreased at cold-start and the nucleation mode particles (including sub-23 nm particles) significantly increased. This is an important observation because using biofuel can have a more adverse impact within cold-start period which is inevitable in most vehicles’ daily driving schedules.

Functional neurological disorder (FND) is a common and disabling disorder that is often considered difficult to treat, particularly in adults. Psychological therapies are often recommended for FND. Outcome research on psychological therapies for FND has grown in recent years but has not been systematically evaluated since 2005. This study aims to build on that by systematically reviewing the evidence-base for individual outpatient cognitive behavioural and psychodynamic psychotherapies for FND. Medical databases were systematically searched for prospective studies of individual outpatient psychotherapy for FND with at least five adult participants. Studies were assessed for methodological quality using a standardised assessment tool. Results were synthesised, and effect sizes calculated for illustrative purposes. The search strategy identified 131 relevant studies, of which 19 were eligible for inclusion: 12 examining cognitive behavioural therapy (CBT) and 7 investigating psychodynamic therapy (PDT). Eleven were pre–post studies and eight were randomised controlled trials. Most studies recruited a single symptom-based subtype rather than all presentations of FND. Effect sizes, where calculable, showed generally medium-sized benefits for physical symptoms, mental health, well-being, function and resource use for both CBT and PDT. Outcomes were broadly comparable across the two therapy types, although a lack of high-quality controlled trials of PDT is a significant limitation, as is the lack of long-term follow-up data in the majority of identified CBT trials. In conclusion, both CBT and PDT appear to potentially offer some benefit for FND, although better quality studies are needed.

Estimation of attenuation from positron emission tomography (PET) data only is of interest for hybrid PET-MR and systems where CT is not available or recommended. However, when using data from a single energy window, emission-based non-time-of-flight (TOF) PET attenuation correction (AC) methods suffer from “cross-talk” artifacts. Based on earlier work, this article explores the hypothesis that cross-talk can be reduced by using more than one energy window. We propose an algorithm for the simultaneous estimation of both activity and attenuation images, as well as, the scatter component of the measured data from a PET acquisition, using multiple energy windows. The model for the measurements is 3-D and accounts for the finite energy resolution of PET detectors; it is restricted to single scatter. The proposed energy-based simultaneous maximum likelihood reconstruction of activity and attenuation with photopeak scatter re-estimation algorithm is compared with simultaneous estimation from a single energy window simultaneous maximum likelihood reconstruction of activity and attenuation with photopeak scatter re-estimation. The evaluation is based on simulations using the characteristics of the Siemens mMR scanner. Phantoms of different complexity were investigated. In particular, a 3-D XCAT torso phantom was used to assess the inpainting of attenuation values within the lung region. Results show that the cross-talk present in non-TOF maximum likelihood reconstruction of activity and attenuation reconstructions is significantly reduced when using multiple energy windows and indicate that the proposed approach warrants further investigation.

Pyroclastic deposits of the Holocene Igwisi Hills kimberlite volcanoes, Tanzania, preserve unequivocal evidence for rapid, syn-eruptive agglutination. The unusual pyroclasts are composed of ash-sized particles agglutinated to each other by thin necks. The textures suggest the magma was disrupted into droplets during ascent. Collisions between particles occurred within a volcanic plume and on deposition within the conduit to form a weakly agglutinated, porous pyroclastic deposit. Theoretical considerations indicate that agglutination occurred over short timescales. Agglutinated clasts were entrained into weak volcanic plumes and deposited around the craters. Our results support the notion that agglutination can occur during kimberlite eruptions, and that some coherent, dense rocks in ancient kimberlite pipes interpreted as intrusive rocks could instead represent agglutinated pyroclastic rocks. Differentiating between agglutinated pyroclastic rocks and effusive or intrusive rocks in kimberlite pipes is important because of the potential effects that pyroclastic processes might have on diamond concentrations in deposits.

BVD is funded by the Natural Environment Research Council through the EnvEast Doctoral Training partnership (grant number NE/1002582/1)., Proximal deposits of small-volume trachytic eruptions are an under-studied record of eruption dynamics despite being common across a range of settings. The 59 ± 4 ka Echo Canyon deposits, Ascension Island, resulted from a small-volume explosiveeffusive trachytic eruption. Variations in juvenile clast texture reveal changes in ascent dynamics and transitions in eruption style. Five dominant textural types are identified within the pumice lapilli population. Early Strombolian-Vulcanian eruption phases are typified by macro- and micro-vesicular equant clast types. Sheared clasts are most abundant at the eruption peak, transitioning to dense clasts in later phases due to shear-induced coalescence, outgassing and vesicle collapse. Melt densification and outgassing via tuffisite veins increased plume density, contributing to partial column collapse and the explosive-effusive transition. Bulk vesicularity distributions indicate a shift in dominant fragmentation mechanism during the eruption, from early-stage bubble interference and rupture to late-stage transient fragmentation, with a transient peak of Plinian activity. Dome and lava groundmass crystallinities of up to 70% indicate near-complete degassing during effusive phases, followed by shallow over pressurisation and a final less explosive phase. We provide textural evidence for high-intensity explosive phases and rapid transitions in eruptive style during small-volume trachytic eruptions and consider the impact of trachytic melt compositions on underlying dynamics of these short-lived, explosive events. This analysis demonstrates the value of detailed stratigraphy in understanding critical changes in eruption dynamics and the timescales over which they may occur which is of particular value in anticipating future eruptions of this type., Natural Environment Research Council through the EnvEast Doctoral Training partnership NE/1002582/1

PurposeAssessment of psychotherapeutic competence is increasingly regarded as important in the delivery of psychological services and training programmes. This article reviews tools designed to assess clinical competence in psychodynamic, interpersonal, and relational models of therapy.MethodsPsycINFO, CINAHL, and Web of Science online databases were reviewed using terms relating to competence, psychotherapy, and measurement. Titles and abstracts of all articles were screened, and full texts of remaining articles were read. Reference lists of included articles were also screened. Papers that described a measure of psychotherapeutic competence in a psychodynamic, interpersonal, or relational model, and reported at least one assessment of the reliability and/or validity of the measure, were included. The quality of the studies was evaluated, and the quality of individual measures was summarized.ResultsFourteen studies met the inclusion criteria, examining 13 competence measures for 12 specific models of therapy. Competence measures were not found for several NICE‐recommended models of therapy. Some measures demonstrated strengths in certain areas of reliability and validity; however, there were a number of quality issues in development and psychometric properties that suggest none of the measures are currently proven for widespread use.ConclusionsFurther research is required to refine currently existing measures and develop new measures for key NICE‐recommended models of therapy.Practitioner pointsAssessment and improvement of therapist competence is key to provision of high‐quality psychotherapeutic interventions.This review shows there are few measures of competence in relational therapy models and several NICE‐recommended models do not have corresponding competence measures.Measures that do exist are mixed in terms of their validity and reliability and should therefore be used with caution.

Diesel particulate filters (DPF) are widely adopted in diesel vehicles to meet the increasingly stringent emission regulations, which require continuous passive regenerations or/and periodic active regenerations to burn off the accumulated particulate matter (PM). In spite of many laboratory studies using DPF benches and engine/chassis dynamometers, there is currently a lack of investigation on DPF regeneration under real-world conditions. Therefore, this study was conducted to investigate the impact of active DPF regenerations on the fuel consumption and gaseous and particulate emissions performance of a diesel light goods vehicle under real-driving conditions by using the state-of-the-art portable emission measurement system. In total, 60 real-driving emission (RDE) tests (∼1200 km in total) were performed on the same route during the same periods of a day, to minimise the effect of uncontrollable real-world factors on the performance evaluation. The results showed that real-world active DPF regenerations occurred every 130 km for the studied vehicle. Although they did not occur frequently, DPF regenerations increased the trip-averaged fuel consumption rate by 13% on average. CO and THC emission factors tended to increase with DPF regenerations because the post combustion used to achieve the high exhaust temperature for regeneration of the filter occurred under oxygen-lean conditions. Total NOx emissions were not affected but NO2/NOx ratio was greatly reduced by DPF regeneration due to lower NO oxidation by the diesel oxidation catalyst and higher NO2 reduction by the DPF. Finally, DPF regenerations sharply increased PM emission factors by 27 times compared with a trip without DPF regeneration, resulting in significant exceedance of the emission limit.

Objectives: There has been extensive research in evaluating chronic pain in the context of litigation while considering the implications that it can have on healthcare outcomes and rehabilitation progress. The aim of this article is to present retrospective observational data about the levels of disability and distress reported by patients with ongoing litigation at the start and following a UK-based multi-disciplinary pain management programme (PMP) when compared with those without litigation. Method: Between June 2014 and September 2017, 859 patients attended and completed a 16-day PMP at a tertiary-level National Health Service (UK) pain clinic. Patients were split into two groups: (1) litigation (n = 110) and (2) non-litigation (n = 749). As a part of the assessment procedure, the patients were given a battery of psychological and physical measures to complete over two time points. Results: Patients with litigation are statistically significantly more distressed at assessment but make comparable clinically meaningful change in PMP intervention when compared with a non-litigation sample. A very small proportion of the variance in depression scores post-treatment is accounted for by the context of litigation (0.5%), which may be accounted for by employment status. There was no effect of litigation on physical outcome post-intervention. Discussion: This article concludes that it is not appropriate to merely assume that the context of litigation results in limited positive psychological and physical outcomes post-PMP. There are some limitations to the clinical sample presented in respect to the conclusions.

Volcanism on Earth and on other planets and satellites is dominated by the eruption of low viscosity magmas. During explosive eruption, high melt temperatures and the inherent low viscosity of the fluidal pyroclasts allow for substantial post-fragmentation modification during transport obscuring the record of primary, magmatic fragmentation processes. Here, we show these syn-eruption modifications, in the form of melt stripping and agglutination, to be advantageous for providing fundamental insights into lava fountain and jet dynamics, including eruption velocities, grain size distributions and melt physical properties. We show how enigmatic, complex pyroclasts termed pelletal lapilli form by a two-stage process operating above the magmatic fragmentation surface. Melt stripping from pyroclast surfaces creates a spray of fine melt droplets whilst sustained transport in the fountain allows for agglutination and droplet scavenging, thereby coarsening the grain size distribution. We conclude with a set of universal regime diagrams, applicable for all fluidal fountain products, that link fundamental physical processes to eruption conditions and melt physical properties.

Highlights • Novel methodology and software for MR-PET registration uncertainty analysis. • Registration software had the biggest effect on MR-PET registration precision, followed by reconstruction parameters (i.e., iterations, smoothing) and PET count level. • PVC can significantly improve the PET signal, but since it relies on precise MR-PET registration, it also increases PET signal variability and hence care should be taken when using it., Accurate regional brain quantitative PET measurements, particularly when using partial volume correction, rely on robust image registration between PET and MR images. We argue here that the precision, and hence the uncertainty, of MR-PET image registration is mainly driven by the registration implementation and the quality of PET images due to their lower resolution and higher noise compared to the structural MR images. We propose a dedicated uncertainty analysis for quantifying the precision of MR-PET registration, centred around the bootstrap resampling of PET list-mode events to generate multiple PET image realisations with different noise (count) levels. The effects of PET image reconstruction parameters, such as the use of attenuation and scatter corrections and different number of iterations, on the precision and accuracy of MR-PET registration were investigated. In addition, the performance of four software packages with their default settings for rigid inter-modality image registration were considered: NiftyReg, Vinci, FSL and SPM. Four distinct PET image distributions made of two early time frames (similar to cortical FDG) and two late frames using two amyloid PET dynamic acquisitions of one amyloid positive and one amyloid negative participants were investigated. For the investigated four PET frames, the biggest impact on the uncertainty was observed between registration software packages (up to 10-fold difference in precision) followed by the reconstruction parameters. On average, the lowest uncertainty for different PET frames and brain regions was observed with SPM and two iterations of fully quantitative image reconstruction. The observed uncertainty for the varying PET count-level (from 5% to 60%) was slightly lower than for the reconstruction parameters. We also observed that the registration uncertainty in quantitative PET analysis depends on amyloid status of the considered PET frames, with increased uncertainty (up to three times) when using post-reconstruction partial volume correction. This analysis is applicable for PET data obtained from either PET/MR or PET/CT scanners.

Identification of volcanic signals preserved in paleoenvironmental records can provide key insights into the timing and consequences of explosive volcanism. Yet the eruption record is incomplete and this confounds our ability to link volcanic eruptions to their impacts on climate and environments. Studies have suggested that stalagmite records can help to address these gaps, through the identification of transient geochemical variability associated with incorporation of elements derived from erupted material. However, the utility of stalagmites for tracing volcanism is poorly constrained globally. Here, we present a high-resolution geochemical dataset for stalagmite NIED08–05 from Niedźwiedzia Cave (Poland). We do this with two primary aims: (1) to test the suitability of NIED08–05 as a record of volcanism since 3 ka BP, and (2) to ascertain whether stalagmites grown in temperate regions preserve volcanic signals with success comparable to those grown in tropical regions. We find transient enrichments of 16 trace elements and the rare-earth-elements Y, La, Nd, which coincide with the timing of some known eruption events. Using Principal Component Analysis (PCA) we find that elements atypically incorporated into calcite (e.g., Fe) co-vary. Similarly, filtering PC1 (17% of the dataset variability) for high magnitude deviations from a baseline signal yields tentative agreement between PC scores and some known large eruptions with tephra found in Poland. We use our analysis to discuss the complexities involved in associating volcanic signals with stalagmite chemistry in temperate regions far from the source of large eruptions. The transport pathway from volcanic source to stalagmite growth surfaces includes the complex Niedźwiedzia Cave hydrological system and is influenced by dense forest above the cave site. Together these factors increase the potential for attenuation of volcanic-derived chemical signals prior to reaching the stalagmite, and so make it difficult to unambiguously link trace element enrichments in NIED08–05 to volcanic eruptions. Our results provide strong evidence that in a temperate depositional environment far from active volcanoes, climate and hydrology conspire to mute the strength of volcanic geochemical signals. Therefore, this work provides important incentives for future research in this area by highlighting that stalagmites grown in a comparatively simple hydrological regime and grown in caves overlain by thin vegetation and soil cover , may preserve volcanic signatures with greater success than those grown in temperate environments.

Ocean island volcanism is generally considered to be dominated by basaltic eruptions, yet felsic products associated with more hazardous explosive eruptive events are also present in the geological record of many of these islands. Ascension Island, recently recognised as an active volcanic system, exhibits explosive felsic eruption deposits but their age, eruptive styles and stratigraphic association with mafic volcanism are thus far unclear. Here we present a felsic pyroclastic stratigraphy for Ascension Island, supplemented by 26 new 40Ar/39Ar ages and whole rock geochemical XRF data. More than 80 felsic pyroclastic eruptions have occurred over the last ~ 1 Myr, including subplinian and phreatomagmatic eruptions, which produced pumice fall and pyroclastic density current deposits. Detailed sampling suggests felsic events are unevenly distributed in space and time. Subaerial activity can be divided into four Periods: Period 1 (~1000 – 500 ka) felsic and mafic eruptions, with felsic explosive eruptions, linked to a Central Felsic Complex; Period 2 (~ 500 – 100 ka) mafic period; Period 3 (~ 100 – 50 ka) felsic eruptions associated with the Eastern Felsic Complex; Period 4 (< 50 ka) mafic eruptions. The last explosive eruption occurred at ~ 60 ka. This work highlights the cyclical nature of ocean island volcanism and the timescales over which changes between predominantly mafic and felsic volcanism occur. The prevalence of past felsic explosive eruptions on Ascension highlights the need to consider the possibility of future subplinian or phreatomagmatic events in hazard management plans, with any potential risk compounded by Ascension’s small size and remote location.

Volcanic ash and pyroclasts can weld when deposited hot by pyroclastic density currents, in near-vent fall deposits, or in fractures in volcano interiors. Welding progressively decreases the permeability of the particle packs, influencing a range of magmatic and volcanic processes, including magma outgassing, which is an important control on eruption dynamics. Consequently, there is a need for a quantitative model for permeability evolution during welding of ash and pyroclasts under the range of conditions encountered in nature. Here we present in situ experiments in which hydrous, crystal-free, glassy pyroclasts are imaged via x-ray tomography during welding at high temperature. For each 3D dataset acquired, we determine the porosity, Darcian gas permeability, specific surface area, and pore connectivity. We find that all of these quantities decrease as a critical percolation threshold is approached. We develop a constitutive mathematical model for the evolution of permeability in welding volcanic systems based on percolation theory, and validate the model against our experimental data. Importantly, our model accounts for polydispersivity of the grainsize in the particle pack, the pressures acting on the pack, and changes in particle viscosity arising from degassing of dissolved H2O during welding. Our model is theoretically grounded and has no fitting parameters, hence it should be valid across all magma compositions. The model can be used to predict whether a cooling pyroclast pack will have sufficient time to weld and to degas, the scenarios under which a final deposit will retain a permeable network, the timescales over which sealing occurs, and whether a welded deposit will have disequilibrium or equilibrium H2O content. A user-friendly implementation of the model is provided.

ObjectiveResponsiveness to direct verbal suggestions (suggestibility) has long been hypothesized to represent a predisposing factor for functional neurological disorder (FND) but previous research has yielded conflicting results. The aim of this study was to quantitatively evaluate whether FND patients display elevated suggestibility relative to controls via meta-analysis.MethodsFour electronic databases were searched in November 2019, with the search updated in April 2020, for original studies assessing suggestibility using standardized behavioural scales or suggestive symptom induction protocols in FND patients and controls. The meta-analysis followed Cochrane, PRISMA, and MOOSE guidelines. Data extraction and study quality coding were performed by two independent reviewers. Standardized suggestibility scores and responsiveness to symptom induction protocols were used to calculate standardized mean differences (SMDs) between groups.ResultsOf 26,643 search results, 19 articles presenting 11 standardized suggestibility datasets (FND: n = 316; control: n = 360) and 11 symptom suggestibility datasets (FND: n = 1285; control: n = 1409) were included in random-effects meta-analyses. Meta-analyses revealed that FND patients displayed greater suggestibility than controls on standardized behavioural scales (SMD, 0.48 [95% CI, 0.15, 0.81]) and greater responsiveness to suggestive symptom induction (SMD, 1.39 [95% CI, 0.92, 1.86]). Moderation analyses presented mixed evidence regarding the extent to which effect sizes covaried with methodological differences across studies. No evidence of publication bias was found.ConclusionsThese results corroborate the hypothesis that FND is characterized by heightened responsiveness to verbal suggestion. Atypical suggestibility may confer risk for FND and be a cognitive marker that can inform diagnosis and treatment of this condition.