Prospective Investigation of Pesticide Applicators' Health (PIPAH) study: a cohort study of professional pesticide users in Great Britain

PURPOSE: The purpose of the study is to monitor the exposure and health of workers in Great Britain who use pesticides as a part of their job, and to gain a better understanding of the relationship between long-term exposure to pesticides and health. PARTICIPANTS: Study participants are professional pesticide users who are certified in the safe use of pesticides or who were born before 1965 and apply pesticides under 'grandfather rights'. Overall response rate was 20%; participants are mostly male (98%) and the average age is 54 years, ranging from 17 to over 80 years. FINDINGS TO DATE: Participants have completed a baseline general questionnaire and three follow-up questionnaires on the use of pesticides. These data will enable investigations into the relationship between occupational pesticide exposure and health outcomes taking into account non-occupational confounding factors. FUTURE PLANS: There is no set end date for data collection. Recruitment into the cohort will continue, and for the foreseeable future there will be annual pesticide use questionnaires and five yearly follow-up general questionnaires.The intention is to validate the pesticide use questionnaire, and to develop a crop/job exposure matrix (C/JEM) which can be updated regularly. This C/JEM will be able to look at general categories of pesticide, such as insecticides, structurally related pesticides, such as organochlorines, or individual active ingredients. Data collected on use of personal protective equipment and method of application will provide information on how potential exposure to pesticide during application may have been modified. The study will be able to estimate changes in individual pesticide use over time, and to examine the associations between pesticide use and both baseline and long-term health outcomes.The cohort members will be linked to national databases for notification of hospital episode statistics, cancer incidence and mortality for follow-up of health outcomes

A study of localisation in dual-phase high-strength steels under dynamic loading using digital image correlation and FE analysis

Tensile tests were conducted on dual-phase high-strength steel in a Split-Hopkinson Tension Bar at a strain-rate in the range of 150-600/s and in a servo-hydraulic testing machine at a strain-rate between 10-3 and 100/s. A novel specimen design was utilized for the Hopkinson bar tests of this sheet material. Digital image correlation was used together with high-speed photography to study strain localisation in the tensile specimens at high rates of strain. By using digital image correlation, it is possible to obtain in-plane displacement and strain fields during non-uniform deformation of the gauge section, and accordingly the strains associated with diffuse and localised necking may be determined. The full-field measurements in high strain-rate tests reveal that strain localisation started even before the maximum load was attained in the specimen. An elasto-viscoplastic constitutive model is used to predict the observed stress-strain behaviour and strain localisation for the dual-phase steel. Numerical simulations of dynamic tensile tests were performed using the non-linear explicit FE code LS-DYNA. Simulations were done with shell (plane stress) and brick elements. Good correlation between experiments and numerical predictions was achieved, in terms of engineering stress-strain behaviour, deformed geometry and strain fields. However, mesh density plays a role in the localisation of deformation in numerical simulations, particularly for the shell element analysis

Studying Millisecond Pulsars in X-rays

Millisecond pulsars represent an evolutionarily distinct group among rotation-powered pulsars. Outside the radio band, the soft X-ray range ($\sim 0.1$--10 keV) is most suitable for studying radiative mechanisms operating in these fascinating objects. X-ray observations revealed diverse properties of emission from millisecond pulsars. For the most of them, the bulk of radiation is of a thermal origin, emitted from small spots (polar caps) on the neutron star surface heated by relativistic particles produced in pulsar acceleration zones. On the other hand, a few other very fast rotating pulsars exhibit almost pure nonthermal emission generated, most probably, in pulsar magnetospheres. There are also examples of nonthermal emission detected from X-ray nebulae powered by millisecond pulsars, as well as from pulsar winds shocked in binary systems with millisecond pulsars as companions. These and other most important results obtained from X-ray observations of millisecond pulsars are reviewed in this paper, as well as results from the search for millisecond pulsations in X-ray flux of the radio-quite neutron star RX J1856.5-3754

Sodium selenate as a disease-modifying treatment for progressive supranuclear palsy: Protocol for a phase 2, randomised, double-blind, placebo-controlled trial

INTRODUCTION: Progressive supranuclear palsy (PSP) is a neurodegenerative disorder for which there are currently no disease-modifying therapies. The neuropathology of PSP is associated with the accumulation of hyperphosphorylated tau in the brain. We have previously shown that protein phosphatase 2 activity in the brain is upregulated by sodium selenate, which enhances dephosphorylation. Therefore, the objective of this study is to evaluate the efficacy and safety of sodium selenate as a disease-modifying therapy for PSP. METHODS AND ANALYSIS: This will be a multi-site, phase 2b, double-blind, placebo-controlled trial of sodium selenate. 70 patients will be recruited at six Australian academic hospitals and research institutes. Following the confirmation of eligibility at screening, participants will be randomised (1:1) to receive 52 weeks of active treatment (sodium selenate; 15 mg three times a day) or matching placebo. Regular safety and efficacy visits will be completed throughout the study period. The primary study outcome is change in an MRI volume composite (frontal lobe+midbrain-3rd ventricle) over the treatment period. Analysis will be with a general linear model (GLM) with the MRI composite at 52 weeks as the dependent variable, treatment group as an independent variable and baseline MRI composite as a covariate. Secondary outcomes are change in PSP rating scale, clinical global impression of change (clinician) and change in midbrain mean diffusivity. These outcomes will also be analysed with a GLM as above, with the corresponding baseline measure entered as a covariate. Secondary safety and tolerability outcomes are frequency of serious adverse events, frequency of down-titration occurrences and frequency of study discontinuation. Additional, as yet unplanned, exploratory outcomes will include analyses of other imaging, cognitive and biospecimen measures. ETHICS AND DISSEMINATION: The study was approved by the Alfred Health Ethics Committee (594/20). Each participant or their legally authorised representative and their study partner will provide written informed consent at trial commencement. The results of the study will be presented at national and international conferences and published in peer-reviewed journals. TRIAL REGISTRATION NUMBER: Australian New Zealand Clinical Trials Registry (ACTRN12620001254987).Lucy Vivash, Kelly L Bertram, Charles B Malpas, Cassandra Marotta, Ian H Harding, Scott Kolbe, Joanne Fielding, Meaghan Clough, Simon J G Lewis, Stephen Tisch, Andrew H Evans, John D O, Sullivan, Thomas Kimber, David Darby, Leonid Churilov, Meng Law, Christopher M Hovens, Dennis Velakoulis, Terence J O, Brie

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Central Nervous System Therapeutic Targets in Friedreich Ataxia

Friedreich ataxia (FRDA) is an autosomal recessive inherited multisystem disease, characterized by marked differences in the vulnerability of neuronal systems. In general, the proprioceptive system appears to be affected early, while later in the disease, the dentate nucleus of the cerebellum and, to some degree, the corticospinal tracts degenerate. In the current era of expanding therapeutic discovery in FRDA, including progress toward novel gene therapies, a deeper and more specific consideration of potential treatment targets in the nervous system is necessary. In this work, we have re-examined the neuropathology of FRDA, recognizing new issues superimposed on classical findings, and dissected the peripheral nervous system (PNS) and central nervous system (CNS) aspects of the disease and the affected cell types. Understanding the temporal course of neuropathological changes is needed to identify areas of modifiable disease progression and the CNS and PNS locations that can be targeted at different time points. As most major targets of long-term therapy are in the CNS, this review uses multiple tools for evaluation of the importance of specific CNS locations as targets. In addition to clinical observations, the conceptualizations in this study include physiological, pathological, and imaging approaches, and animal models. We believe that this review, through analysis of a more complete set of data derived from multiple techniques, provides a comprehensive summary of therapeutic targets in FRDA.SCOPUS: re.jDecretOANoAutActifinfo:eu-repo/semantics/publishe

The calculation of inter-atomic potentials using electron-gas models

3.00SIGLELD:9091.9F(AERE-R--10425). / BLDSC - British Library Document Supply CentreGBUnited Kingdo

Transportation Greenhouse Gas Emissions and its Relationship with Urban Form, Transit Accessibility and Emerging Green Technologies: A Montreal Case Study

This research aims at estimating a GHG emission inventory at the household level using completely disaggregate trip data and taking into account all emitting modes. The impact of urban form (UF) and transit accessibility (TA) characteristics on household level GHG emissions is then quantified and compared to the impact of the introduction of emerging green technologies. Using a large and representative sample of household diaries, trip-level GHG emissions are estimated by combining different sources of data (origin-destination (OD) survey data, vehicle fleet characteristics, transit ridership data, etc.) and by using modelling tools (traffic assignment and GHGs models). Moreover, UF and TA indicators are developed and combined to generate neighbourhood typologies. A simultaneous equation modelling framework is then implemented to investigate the link between UF, TA, socio-demographics, and travel GHGs, taking into account the well known “self-selection” issue. The potential impact of land use and transit supply strategies with emerging green technological scenarios is then compared. Our findings are consistent with the literature, more specifically we have found that the built environment (BE) attributes are statistically significant (10% increase in density, transit accessibility and land-use mix, results in 3.5%, 5.8% and 2.5% reduction in GHG respectively), number of workers and retirees at the household level play an important role in the contribution to GHG emissions (102% increase by adding one worker and 51% decrease by adding a retiree to the household). Moreover, neighbourhood types represented by the combined effects of UF and TS have important effects on GHGs. Also it is found that by replacing transit fleet by electric trains and hybrid buses, the share of transit GHGs would decrease by 32%. With respect to the private motor-vehicle fleet, if current trends persist, the constant improvement of car fuel consumption economy would reduce car GHGs by 7%. According to our results, the two most efficient strategies to reduce GHGs at the regional and household level seem to be the continuous fuel-efficiency improvement of the private motor-vehicle fleet and the increase of transit accessibility