Cholinesterase Research Outreach Project (CROP): measuring cholinesterase activity and pesticide use in an agricultural community

BACKGROUND: Australian farmers and their workers are exposed to a wide variety of pesticides. Organophosphate (OP) insecticides are a widely used class of pesticide used for animal husbandry practices (Naphthalophos for sheep dipping, jetting and drench), crop production for pest control (Dimethoate) and in public health (Maldison for head lice). Acute poisonings with this class of insecticide are reported among agricultural workers and children around the globe, due to the inhibition of acetylcholinesterase (AChE). Less is known about chronic exposures. Regular monitoring of erythrocyte AChE will enable farmers to identify potential exposure to organophosphate insecticides and take action to reduce exposures and improve their health and safety practices. This study aims to assess and improve the integration of AChE monitoring into routine point of care health clinics, and provide farming and non-farming people with a link between their AChE activity and their household chemical and agrichemical use. METHODS/DESIGN: The research will target individuals who work on mixed farming enterprises and routinely using OPs (n = 50) and non-farmers (n = 30). Baseline data are collected regarding demographic, health conditions and behaviours, Kessler 10 (K10) scores, chemical use and personal protection. Baseline anthropometric measures include height, weight, hip and waist circumference, body fat analysis and, biochemical analysis of fasted total serum cholesterol, triglycerides, low-density cholesterol (LDL), high-density cholesterol (HDL) and blood glucose. Analysis of erythrocyte cholinesterase (EAChE) activity is also conducted using a finger prick test. Testing of EAChE is then repeated in all participants every 3 weeks for a maximum of three times over a period 10 weeks. Participants are provided with full feedback and counselling about their EAChE activity after each reading and a detailed summary provided to all participants at the completion of the study. Data will be analysed using repeated measures within a general linear model. DISCUSSION: This work will provide an evidence base and recommendations for the integration of EAChE monitoring into Australian rural health clinics, leading to research which will further quantify pesticide exposure both on the farm and in the home, highlighting the importance of sustaining and providing a safe work and home environment for farming communities. TRIAL REGISTRATION: ACTRN12613001256763

Geomorphology and palaeoecology of late Holocene floodplain environments in the river Irthing, Cumbria, UK

PhD ThesisPalaeochannel development along the middle reaches of the River Irthing valley floor, Cumbria, UK, has been reconstructed via a range of palaeoenvironmental techniques. This has enabled the analysis of interactions between the geomorphological, hydrological and ecological components of the floodplain system during the mid to late Holocene. Geornorphological mapping, surveying and lithostratigraphic analysis of palaeochannel fills along a 2.5 kilometre reach of the valley floor has determined the character of Holocene channel and floodplain evolution and the physical context for palaeochannel habitat development. Chronological controls have been provided by historical map analysis and radiocarbon dating. The River Irthing valley floor experienced net fluvial incision from the Pleistocene-Holocene boundary up until the mid Holocene, while late Holocene floodplain evolution has been characterised by a series of channel avulsion and limited floodplain reworking. Periods of channel incision and planform change have been dated to 2440-1920 cal. BC, 670-970 cal. AD, 1410-1620 cal. AD and the late eighteenth to early nineteenth century AD. Five palaeochannel reaches with well-preserved organic rich channel fill sediments were selected for detailed lithostratigraphic analyses (by multiple core transects) and plant macrofossil analyses. Channel fills provide evidence of rapid biotic response to channel abandonment and subsequent changes to the physical characteristics and trophic status of the habitat. Hydroseral sequences from aquatic to wetland to floodplain woodland communities and the affects of human activity on palaeochannel development are also evident. The results indicate high magnitude flood inundation significantly affects vegetation succession and highlight the importance of physical processes and the landscape context in determining the characteristics of palaeochannel development. The research emphasises the application of plant macrofossil analysis to organic rich alluvial sediments.University of Newcastle, Small Research Grant

Organophosphate exposure and the chronic effects on farmers: a narrative review

INTRODUCTION: Organophosphates are a class of insecticides used globally by the agricultural industry for insect control. Acute consequences of organophosphate exposures are well known, while there has been limited research on their long-term effects. The objective of this review was to discuss the health effects of chronic organophosphate exposure in farmers. METHODS: Medline, Scopus and Web of Science were searched to find the relevant articles. Articles published only in English and until December 2018 were reviewed. The selected articles were then categorised as neurological (neurobehaviour, neurodevelopmental, neurological signs and symptoms) or non-neurological subheadings. RESULTS: A total of 53 articles for neurological effects and 17 articles for non-neurological effects were identified. Chronic organophosphates exposure was associated with deficits in the neurobehaviour subsets of attention and short-term memory, increased incidence of neurodegenerative diseases and effects on peripheral nerves and neurodevelopment. However, research to support non-neurological effects such as respiratory symptoms, increased cancer risk, endocrine disruption, cardiac issues, chronic fatigue and infertility was limited. CONCLUSION: Chronic organophosphate exposure was found to affect four of the five areas of described neurological effects in the literature. A large proportion of the research in this area was not methodologically strong, therefore few recommendations can be conclusively made. Future research is warranted to investigate the non-neurological effects of chronic exposure to ensure the occupational risks of low-level chronic exposure are clearly communicated to farmers and farm workers

Cholinesterase research outreach project (CROP): point of care cholinesterase measurement in an Australian agricultural community

BackgroundAustralian farmers are routinely exposed to a wide variety of agrichemicals, including herbicides and insecticides. Organophosphate (OP) insecticides are widely used for agricultural production, horticulture and animal husbandry practices. Symptoms of OP toxicity are the results of inhibition of the enzyme acetylcholinesterase (AChE) which is found in many types of conducting tissue in human bodies such as nerve and muscle, central and peripheral tissues, motor and sensory fibres. Cholinesterase can be measured in red blood cells/erythrocytes (AChE) and plasma (PChE). This study aims to explore integration of AChE monitoring into routine health checks for those at risk and also to examine any association between AChE activity and agrichemical use in a Victorian farming community in Australia.MethodsThis was a prospective cohort study, where farmers and non-famers were compared on the levels of AChE at four time points of baseline, 3&ndash;4 weeks, 6-weeks and at 9-weeks. Study participants (N&thinsp;=&thinsp;55) were residents from South West Victoria, aged between 18 and 75 years, spoke English, and had not had a previous known acute chemical accident. A total of 41 farming (had been farming for more than 5 years) and a convenience sample of 14 non-farming individuals met the inclusion criteria. Testing of AChE was repeated for all participants with a maximum of three times over 10 weeks.ResultsThe integration of AChE monitoring was very well accepted by all participants. There was no significant difference in average AChE activity between farming and non-farming participants (one-way ANOVA p&thinsp;&gt;&thinsp;0.05) in this study. There was no significant difference between personal use of agricultural chemicals on farm and the levels of AChE at baseline (measurement 1) or any of the follow up periods (p&thinsp;&gt;&thinsp;0.05). However, the mean activity of AChE was significantly lower within follow up periods [F (2.633, 139.539)&thinsp;=&thinsp;14.967, p&thinsp;&lt;&thinsp;0.001]. There was a significant reduction of AChE between the follow up at 3-weeks and 6-weeks period (p&thinsp;=&thinsp;0.015).ConclusionsThe routine monitoring of AChE may allow for early recognition of chronic low-level exposure to OPs when they are used by farmers, provided a reasonable estimate of baseline AChE is available. This work provides an evidence for recommending the integration of AChE monitoring into point of care (POC) procedures in rural health clinics and quantifying pesticide exposure and personal protection both on the farm and in the home. Farmer engagement is crucial to the successful integration of AChE monitoring into rural health clinics in Australia.<br /

Comparison of Standard 1.5 T vs. 3 T Optimized Protocols in Patients Treated with Glatiramer Acetate. A Serial MRI Pilot Study

This study explored the effect of glatiramer acetate (GA, 20 mg) on lesion activity using the 1.5 T standard MRI protocol (single dose gadolinium [Gd] and 5-min delay) or optimized 3 T protocol (triple dose of Gd, 20-min delay and application of an off-resonance saturated magnetization transfer pulse). A 15-month, phase IV, open-label, single-blinded, prospective, observational study included 12 patients with relapsing-remitting multiple sclerosis who underwent serial MRI scans (Days −45, −20, 0; the minus ign indicates the number of days before GA treatment; and on Days 30, 60, 90, 120, 150, 180, 270 and 360 during GA treatment) on 1.5 T and 3 T protocols. Cumulative number and volume of Gd enhancing (Gd-E) and T2 lesions were calculated. At Days −45 and 0, there were higher number (p < 0.01) and volume (p < 0.05) of Gd-E lesions on 3 T optimized compared to 1.5 T standard protocol. However, at 180 and 360 days of the study, no significant differences in total and cumulative number of new Gd-E and T 2 lesions were found between the two protocols. Compared to pre-treatment period, at Days 180 and 360 a significantly greater decrease in the cumulative number of Gd-E lesions (p = 0.03 and 0.021, respectively) was found using the 3 T vs. the 1.5 T protocol (p = NS for both time points). This MRI mechanistic study suggests that GA may exert a greater effect on decreasing lesion activity as measured on 3 T optimized compared to 1.5 T standard protocol

Chronic comorbidities in children and adolescents with perinatally acquired HIV infection in sub-Saharan Africa in the era of antiretroviral therapy.

Globally, 1·7 million children are living with HIV, of which 90% are in sub-Saharan Africa. The remarkable scale-up of combination antiretroviral therapy has resulted in increasing numbers of children with HIV surviving to adolescence. Unfortunately, in sub-Saharan Africa, HIV diagnosis is often delayed with children starting antiretroviral therapy late in childhood. There have been increasing reports from low-income settings of children with HIV who have multisystem chronic comorbidities despite antiretroviral therapy. Many of these chronic conditions show clinical phenotypes distinct from those in adults with HIV, and result in disability and reduced quality of life. In this Review, we discuss the spectrum and pathogenesis of comorbidities in children with HIV in sub-Saharan Africa. Prompt diagnosis and treatment of perinatally acquired HIV infection is a priority. Additionally, there is a need for increased awareness of the burden of chronic comorbidities. Diagnostic and therapeutic strategies need to be collectively developed if children with HIV are to achieve their full potential

Modeling of Intermediate Structures and Chain Conformation in Silica-Latex Nanocomposites Observed by SANS During Annealing

The evolution of the polymer structure during nanocomposite formation and annealing of silica-latex nanocomposites is studied using contrast-variation small angle neutron scattering. The experimental system is made of silica nanoparticles (Rsi \approx 8 nm) and a mixture of purpose-synthesized hydrogenated and deuterated nanolatex (Rlatex \approx 12.5 nm). The progressive disappearance of the latex beads by chain interdiffusion and release in the nanocomposites is analyzed quantitatively with a model for the scattered intensity of hairy latex beads and an RPA description of the free chains. In silica-free matrices and nanocomposites of low silica content (7%v), the annealing procedure over weeks at up to Tg + 85 K results in a molecular dispersion of chains, the radius of gyration of which is reported. At higher silica content (20%v), chain interdiffusion seems to be slowed down on time-scales of weeks, reaching a molecular dispersion only at the strongest annealing. Chain radii of gyration are found to be unaffected by the presence of the silica filler

Rhenium and yttrium ions as antimicrobial agents against multidrug resistant Klebsiella pneumoniae and Acinetobacter baumannii biofilms

© 2019 The Authors. Letters in Applied Microbiology published by John Wiley & Sons Ltd on behalf of Society for Applied Microbiology. Antimicrobial resistance presents major global concerns to patient health. In this study, metal ions of molybdenum, rhenium, yttrium and thallium were tested against bacteria in planktonic and biofilm form using one strain of Klebsiella pneumoniae and Acinetobacter baumannii. The antimicrobial efficacy of the metal ions was evaluated against the planktonic bacterial strains using minimum inhibitory concentrations (MICs) and minimum bactericidal concentrations, whilst the efficacy of the metal ions against biofilms was tested using a crystal violet biofilm assay. Live Dead staining was used to visualize the antimicrobial activity elicited by the metal ions on the bacterial cell. The results showed that higher concentrations of the metals were required to inhibit the growth of biofilms (72·9 mg l −1 to 416·7 mg l −1 ), in comparison to their planktonic counterparts. MICs of the metal ions (<46·9 mg l −1 ) (planktonic cells) did not affect biofilm formation. Overall, rhenium and yttrium were effective antimicrobial agents. Molybdenum demonstrated the greatest level of biotoxicity. When taking into account these results and the known toxicity of thallium, it is possible that rhenium or yttrium ions could be developed as effective biocidal formulations in order to prevent transmission in healthcare environments. Significance and Impact of the Study: The metal ions, molybdenum, rhenium, thallium and yttrium were tested against both Klebsiella pneumoniae and Acinetobacter baumannii in planktonic and biofilm forms. This research demonstrated that all the metal ions may be effective antimicrobial agents. However, molybdenum induced high levels of cytotoxicity, whilst, there was no significant difference in the toxicity of the other metal ions tested. When considering the results for the antimicrobial efficacy and biotoxicity of the metal ions, in conjunction with the known toxicity of thallium in certain chemical compositions, it was concluded that overall rhenium or yttrium ions may be effective antimicrobial agents, one potential application may be utilizing these metal ions in hospital surface cleaning formulations

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir