The Australian Work Exposures Study: Prevalence of Occupational Exposure to Respirable Crystalline Silica

Background: Respirable crystalline silica (RCS) is a biologically active dust that can accumulate in the lung and induce silicosis and lung cancer. Despite occupational exposure being the predominant source, no study has described current occupational RCS exposure on a national scale in Australia. The aim of this study is to estimate the characteristics of those exposed and the circumstances of RCS exposure in Australian workplaces. Methods: A cross-sectional survey of the Australian working population (18–65 years old) was conducted. Information about the respondents’ current job and their demographic characteristics was collected in a telephone interview. Occupational exposure to RCS was determined based on preprogrammed decision rules regarding potential levels of exposure associated with self-reported tasks. Results: Overall, 6.4% of respondents were deemed exposed to RCS at work in 2012 (3.3% were exposed at a high level). The exposure varied with sex, state of residence, and socioeconomic status. Miners and construction workers were most likely to be highly exposed to RCS when performing tasks with concrete or cement or working near crushers that create RCS-containing dusts. When extrapolated to the entire Australian working population, 6.6% of Australian workers were exposed to RCS and 3.7% were highly exposed when carrying out tasks at work. Conclusion: This is the first study investigating occupational RCS exposure in an entire national working population. The information about occupational tasks that lead to high level RCS exposure provided by this study will inform the direction of occupational interventions and policies

Optical tools for visualizing and controlling human GLP-1 receptor activation with high spatiotemporal resolution

The glucagon-like peptide-1 receptor (GLP1R) is a broadly expressed target of peptide hormones with essential roles in energy and glucose homeostasis, as well as of the blockbuster weight-loss drugs semaglutide and liraglutide. Despite its large clinical relevance, tools to investigate the precise activation dynamics of this receptor with high spatiotemporal resolution are limited. Here, we introduce a novel genetically encoded sensor based on the engineering of a circularly permuted green fluorescent protein into the human GLP1R, named GLPLight1. We demonstrate that fluorescence signal from GLPLight1 accurately reports the expected receptor conformational activation in response to pharmacological ligands with high sensitivity (max ΔF/F$_{0}$=528%) and temporal resolution (τ$_{ON}$ = 4.7 s). We further demonstrated that GLPLight1 shows comparable responses to glucagon-like peptide-1 (GLP-1) derivatives as observed for the native receptor. Using GLPLight1, we established an all-optical assay to characterize a novel photocaged GLP-1 derivative (photo-GLP1) and to demonstrate optical control of GLP1R activation. Thus, the new all-optical toolkit introduced here enhances our ability to study GLP1R activation with high spatiotemporal resolution

Parametricity and Dependent Types

Reynolds' abstraction theorem shows how a typing judgement in System F can be translated into a relational statement (in second order predicate logic) about inhabitants of the type. We (in second order predicate logic) about inhabitants of the type. We obtain a similar result for a single lambda calculus (a pure type system), in which terms, types and their relations are expressed. Working within a single system dispenses with the need for an interpretation layer, allowing for an unusually simple presentation. While the unification puts some constraints on the type system (which we spell out), the result applies to many interesting cases, including dependently-typed ones

Safety and efficacy of ganaxolone in patients with CDKL5 deficiency disorder: results from the double-blind phase of a randomised, placebo-controlled, phase 3 trial

BACKGROUND: CDKL5 deficiency disorder (CDD) is a rare, X-linked, developmental and epileptic encephalopathy characterised by severe global developmental impairment and seizures that can begin in the first few months after birth and are often treatment refractory. Ganaxolone, an investigational neuroactive steroid, reduced seizure frequency in an open-label, phase 2 trial that included patients with CDD. We aimed to further assess the efficacy and safety of ganaxolone in patients with CDD-associated refractory epilepsy. METHODS: In the double-blind phase of this randomised, placebo-controlled, phase 3 trial, done at 39 outpatient clinics in eight countries (Australia, France, Israel, Italy, Poland, Russia, the UK, and the USA), patients were eligible if they were aged 2-21 years with a pathogenic or probably pathogenic CDKL5 variant and at least 16 major motor seizures (defined as bilateral tonic, generalised tonic-clonic, bilateral clonic, atonic, or focal to bilateral tonic-clonic) per 28 days in each 4-week period of an 8-week historical period. After a 6-week prospective baseline period, patients were randomly assigned (1:1) via an interactive web response system to receive either enteral adjunctive ganaxolone or matching enteral adjunctive placebo (maximum dose 63 mg/kg per day for patients weighing ≤28 kg or 1800 mg/day for patients weighing >28 kg) for 17 weeks. Patients, caregivers, investigators (including those analysing data), trial staff, and the sponsor (other than the investigational product manager) were masked to treatment allocation. The primary efficacy endpoint was percentage change in median 28-day major motor seizure frequency from the baseline period to the 17-week double-blind phase and was analysed (using a Wilcoxon-rank sum test) in all patients who received at least one dose of trial treatment and for whom baseline data were available. Safety (compared descriptively across groups) was analysed in all patients who received at least one dose of trial treatment. This study is registered with ClinicalTrials.gov, NCT03572933, and the open-label extension phase is ongoing. FINDINGS: Between June 25, 2018, and July 2, 2020, 114 patients were screened for eligibility, of whom 101 (median age 6 years [IQR 3 to 10]) were randomly assigned to receive either ganaxolone (n=50) or placebo (n=51). All patients received at least one dose of a study drug, but seizure frequency for one patient in the ganaxolone group was not recorded at baseline and so the primary endpoint was analysed in a population of 100 patients. There was a median percentage change in 28-day major motor seizure frequency of -30·7% (IQR -49·5 to -1·9) in the ganaxolone group and of -6·9% (-24·1 to 39·7) in the placebo group (p=0·0036). The Hodges-Lehmann estimate of median difference in responses to ganaxolone versus placebo was -27·1% (95% CI -47·9 to - 9·6). Treatment-emergent adverse events occurred in 43 (86%) of 50 patients in the ganaxolone group and in 45 (88%) of 51 patients in the placebo group. Somnolence, pyrexia, and upper respiratory tract infections occurred in at least 10% of patients in the ganaxolone group and more frequently than in the placebo group. Serious adverse events occurred in six (12%) patients in the ganaxolone group and in five (10%) patients in the placebo group. Two (4%) patients in the ganaxolone group and four (8%) patients in the placebo group discontinued the trial. There were no deaths in the double-blind phase. INTERPRETATION: Ganaxolone significantly reduced the frequency of CDD-associated seizures compared with placebo and was generally well tolerated. Results from what is, to our knowledge, the first controlled trial in CDD suggest a potential treatment benefit for ganaxolone. Long-term treatment is being assessed in the ongoing open-label extension phase of this trial. FUNDING: Marinus Pharmaceuticals

Auditory hallucinations and migraine of possible brainstem origin

10.1007/s10194-011-0355-zJournal of Headache and Pain125573-57

Investigating harbor porpoise (Phocoena phocoena) population differentiation using RAD-tag genotyping by sequencing

The population status of the harbor porpoise ( Phocoena phocoena ) in the Baltic Sea and adjacent regions is still not fully resolved. Here, we present a pilot study using the double digest restriction-site associated DNA sequencing (ddRAD-seq) genotyping- by -sequencing method on specimens from the Baltic Sea, eastern North Sea, Spain and the Black Sea. From a single Illumina lane and a set of 49 individuals, w e obtained around 6000 SNPs. We used these markers to estimate population structure and differentiation, and identified splits between porpoises from the North Sea and the Baltic, and within regions in the Baltic Sea (between the Belt Sea and the Inner Baltic Sea). The SNP analysis confirms population structure elucidated by previous mtDNA/microsatellite studies. We demonstrate the feasibility of SNP analysis on opportunistically sampled cetacean samples, with varying DNA quality, for population diversity and divergence analysis

Functional traits of hyporheic and benthic invertebrates reveal importance of wood-driven geomorphological processes to rivers

1.Large wood (LW) is a natural element of river environments and an integral component of many river restoration schemes to promote biodiversity. It is an important habitat in itself, but it also induces a wide range of hydraulic, hydrological, geomorphological, and chemical conditions that influence the ecological community. However, the effects of hydro‐geomorphological processes induced by LW on local benthic and hyporheic invertebrates have not been well characterized. 2.A functional approach was applied to invertebrate data collected in a field survey at sites with LW and without LW (control), to investigate the response of hyporheic and benthic invertebrates’ trait profiles in response to local LW‐induced processes. 3.We hypothesized LW sites to be associated with different trait modalities than control sites in relation to wood‐induced processes and conditions (i.e. hyporheic exchange flow, oxygen availability, temporal stability, organic matter, denitrification, hydraulic conductivity). Multivariate analyses and Partial Least Squares (PLS) Path Modelling were used to detect the differences in trait profiles between LW and control sites and to study the variation of traits as a function of hydrological, sedimentological, physical and chemical variables. 4.Biological (i.e. aquatic stages, reproduction), physiological (i.e. dispersal, feeding habits) and behavioural (i.e. substrate preferences) trait utilization by the hyporheic meiofauna differed between LW and control sites. At LW sites, the hyporheic meiofaunal assemblage was significantly associated with aquatic active dispersal, aquatic eggs and hard substrate preferences. This trait category selection was linked to changes in physical‐sedimentological processes at LW sites when compared to control sites. Macrofaunal benthic and hyporheic functional traits did not differ significasignificantly between wood and control sites, suggesting similar functioning of these assemblages at the surface‐subsurface interface. 5.This study found that LW affects invertebrate traits by altering fluvial processes to produce, locally, a mosaic of habitats. Hyporheic meiofauna trait responses to LW‐processes have suggested (i) the crucial role of LW in supporting river benthic zone functioning, and thus (ii) a possible benefit to river restoration by enhancing functional interactions among different ecological niches