Controversies Incorporated: Accepting Androgyny; Women Composers Today: A Personal View; View from the Industrial North; Performance, Notation, Time

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Economic and Practical Factors in Diagnosing HNPCC Using Clinical Criteria, Immunohistochemistry and Microsatellite Instability Analysis

Aim: To determine a cost-efficient strategy for HNPCC molecular diagnostic testing. Methods: 138 families referred to a Regional Genetics Service had hMLH1 and hMSH2 mutation analysis. The sensitivity and specificity of clinical selection criteria with or without immunohistochemistry (IHC) and microsatellite instability (MSI) analysis to further refine case selection and the effect of these approaches on the cost of mutation analysis were examined. Results: Clearly deleterious mutations were identified in 49/138 (35.5%) of all families tested. The most sensitive criteria for identifying families with MMR mutations were the full Bethesda guidelines but these have poor specificity. IHC and MSI were useful pre-screening tools. Conclusion: A cost-efficient approach in laboratories where IHC and/or MSI analysis are available, is to use inclusive (non-specific) criteria to select cases, followed by IHC and then MSI. Where one or both results are abnormal, proceed to further mutation analysis. Where MSI or IHC or tumour blocks are not available, more restrictive clinical criteria may be more appropriate for cost-efficient case selection

The Effect of Hair Color on the Incorporation of Codeine into Human Hair

The influence of melanin on the binding of xenobiotics in hair will impact the interpretation of drug concentrations determined by hair testing. The purpose of this study was to determine if codeine, as a model compound of abused drugs, would be incorporated into black, brown, blond, or red hair as a function of melanin concentration. Such data would assist in the interpretation of codeine concentrations in hair and help elucidate the potential influence of hair color on incorporation of drugs. Male and female Caucasians with black (n = 6), brown (n = 12), blond (n = 8), or red hair (n = 6) and non-Caucasians with black hair (n = 12) aged 21-40 years were enrolled in the study. Each subject was administered oral codeine phosphate syrup in a dosage of 30 mg three times a day for five days. Twenty-four hours after the end of the treatment period, a 30-mg codeine dose was administered and the subject's plasma area under the concentration time curve (AUC) for codeine was determined. Codeine and melanin were measured in the first 3 cm of hair closest to the vertex region of the scalp prior to and 1, 4, 5, 6, and 7 weeks after dosing. The quantitative and qualitative melanin profiles were determined for each subjects hair to provide an objective measure of hair color. The plasma concentrations of codeine were measured to eliminate differences in the bioavailability and clearance of codeine as factors that might account for the differences in codeine hair concentrations. The subjects were asked not to cut their hair in the vertex region of the scalp or to use any form of chemical treatment on their hair, but otherwise normal hygienic measures were permitted. The mean (± SE) hair codeine concentrations 5 weeks after dosing were 1429 (± 249) pg/mg in black hair; 208 (± 17) pg/mg in brown hair; 99 (± 10) pg/mg in blond hair; and 69 (± 11) in red hair pg/mg. In black hair, codeine concentrations were 2564 (± 170) pg/mg for Asians and 865 (± 162) pg/mg for Caucasians. Similar concentration relationships were observed at weeks 4, 6, and 7. A strong relationship between the hair concentrations of codeine and melanin (R2 = 0.73) was observed. Normalization of the codeine concentration with the melanin concentration reduced the hair color differences observed. These data demonstrate that the interpretation and reporting of hair test results for codeine are influenced by hair color. After this dosing protocol, the proposed federal guideline cutoff of 200 pg/mg of codeine would result in 100% of subjects with black hair and 50% of subjects with brown hair being reported as positive, and subjects with blond or red hair would be reported as negative. The incorporation of these drugs into hair should be studied carefully in humans to ensure the appropriate interpretation of drug concentration

Translation of liver stage activity of M5717, a Plasmodium elongation factor 2 inhibitor: from bench to bedside

© The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativeco mmons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.Background: Targeting the asymptomatic liver stage of Plasmodium infection through chemoprevention could become a key intervention to reduce malaria-associated incidence and mortality. Methods: M5717, a Plasmodium elongation factor 2 inhibitor, was assessed in vitro and in vivo with readily accessible Plasmodium berghei parasites. In an animal refinement, reduction, replacement approach, the in vitro IC99 value was used to feed a Population Pharmacokinetics modelling and simulation approach to determine meaningful effective doses for a subsequent Plasmodium sporozoite-induced volunteer infection study. Results: Doses of 100 and 200 mg would provide exposures exceeding IC99 in 96 and 100% of the simulated population, respectively. Conclusions: This approach has the potential to accelerate the search for new anti-malarials, to reduce the number of healthy volunteers needed in a clinical study and decrease and refine the animal use in the preclinical phase.This work was funded by the healthcare business of Merck KGaA, Darmstadt, Germany (CrossRef Funder ID: https://doi.org/10.13039/100009945). F.A. is the recipient of an individual Ph.D. fellowship funded by FCT (PD/BD/128371/2017).info:eu-repo/semantics/publishedVersio

Pharmacokinetics and Safety of Prolonged Paracetamol Treatment in Neonates: An Interventional Cohort Study

Aims To investigate the pharmacokinetics and safety of prolonged paracetamol use (\u3e72 h) for neonatal pain. Methods Neonates were included if they received paracetamol orally or intravenously for pain treatment. A total of 126 samples were collected. Alanine aminotransferase and bilirubin were measured as surrogate liver safety markers. Paracetamol and metabolites were measured in plasma. Pharmacokinetic parameters for the parent compound were estimated with a nonlinear mixed-effects model. Results Forty-eight neonates were enrolled (38 received paracetamol for \u3e72 h). Median gestational age was 38 weeks (range 25–42), and bodyweight at inclusion was 2954 g (range 713–4750). Neonates received 16 doses (range 4–55) over 4.1 days (range 1–13.8). The median (range) dose was 10.1 mg/kg (2.9–20.3). The median oxidative metabolite concentration was 14.6 μmol/L (range 0.12–113.5) and measurable \u3e30 h after dose. There was no significant difference (P \u3e .05) between alanine aminotransferase and bilirubin measures at \u3c72 h or \u3e72 h of paracetamol treatment or the start and end of the study. Volume of distribution and paracetamol clearance for a 2.81-kg neonate were 2.99 L (% residual standard error = 8, 95% confidence interval 2.44–3.55) and 0.497 L/h (% residual standard error = 7, 95% confidence interval 0.425–0.570), respectively. Median steady-state concentration from the parent model was 50.3 μmol/L (range 30.6–92.5), and the half-life was 3.55 h (range 2.41–5.65). Conclusion Our study did not provide evidence of paracetamol-induced liver injury nor changes in metabolism in prolonged paracetamol administration in neonates

Evaluating risk factor assumptions: a simulation-based approach

<p>Abstract</p> <p>Background</p> <p>Microsimulation models are an important tool for estimating the comparative effectiveness of interventions through prediction of individual-level disease outcomes for a hypothetical population. To estimate the effectiveness of interventions targeted toward high risk groups, the mechanism by which risk factors influence the natural history of disease must be specified. We propose a method for evaluating these risk factor assumptions as part of model-building.</p> <p>Methods</p> <p>We used simulation studies to examine the impact of risk factor assumptions on the relative rate (RR) of colorectal cancer (CRC) incidence and mortality for a cohort with a risk factor compared to a cohort without the risk factor using an extension of the CRC-SPIN model for colorectal cancer. We also compared the impact of changing age at initiation of screening colonoscopy for different risk mechanisms.</p> <p>Results</p> <p>Across CRC-specific risk factor mechanisms, the RR of CRC incidence and mortality decreased (towards one) with increasing age. The rate of change in RRs across age groups depended on both the risk factor mechanism and the strength of the risk factor effect. Increased non-CRC mortality attenuated the effect of CRC-specific risk factors on the RR of CRC when both were present. For each risk factor mechanism, earlier initiation of screening resulted in more life years gained, though the magnitude of life years gained varied across risk mechanisms.</p> <p>Conclusions</p> <p>Simulation studies can provide insight into both the effect of risk factor assumptions on model predictions and the type of data needed to calibrate risk factor models.</p

Crop Updates 2001 - Weeds

This session covers forty six papers from different authors: 1. INTRODUCTION, Vanessa Stewart, Agriculture Western Australia PLENARY 2. Wild radish – the implications for our rotations, David Bowran, Centre for Cropping Systems INTEGRATED WEED MANAGEMENT IWM system studies/demonstration sites 3. Integrated weed management: Cadoux, Alexandra Wallace, Agriculture Western Australia 4. A system approach to managing resistant ryegrass, Bill Roy, Agricultural Consulting and Research Services Pty Ltd, York 5. Long term herbicide resistance demonstration, Peter Newman, Agriculture Western Australia, Cameron Weeks, Tony Blake and Dave Nicholson 6. Integrated weed management: Katanning, Alexandra Wallace, Agriculture Western Australia 7. Integrated weed management: Merredin, Vanessa Stewart, Agriculture Western Australia 8. Short term pasture phases for weed control, Clinton Revell and Candy Hudson, Agriculture Western Australia Weed biology – implications for IWM 9. Competitivness of wild radish in a wheat-lupin rotation , Abul Hashem, Nerys Wilkins, and Terry Piper, Agriculture Western Australia 10. Population explosion and persistence of wild radish in a wheat-lupin rotation, Abul Hashem, Nerys Wilkins, Aik Cheam and Terry Piper , Agriculture Western Australia 11. Variation is seed dormancy and management of annual ryegrass, Amanda Ellery and Ross Chapman, CSIRO 12. Can we eradicate barley grass, Sally Peltzer, Agriculture Western Australia Adoption and modelling 13. Where to with RIM? Vanessa Stewart1 and Robert Barrett-Lennard2, 1Agriculture Western Australia, 2Western Australian Herbicide Resistance Initiative (WAHRI) 14. Multi-species RIM model, Marta Monjardino1,2, David Pannell2 and Stephen Powles1 1Western Australian Herbicide Resistance Initiative (WAHRI), 2ARE, University of Western Australia 15. What causes WA grain growers to adopt IWM practices? Rick Llewellyn, WAHRI/ARE, Faculty of Agriculture, University of WA New options for IWM? 16. Fuzzy tramlines for more yield and less weeds, Paul Blackwell Agriculture Western Australia, and Maurice Black, Harbour Lights Estate, Geraldton 17. Inter-row knockdowns for profitable lupins, Paul Blackwell, Agriculture Western Australia and Miles Obst, Farmer Mingenew 18. Row cropping and weed control in lupins, Mike Collins and Julie Roche, Agriculture Western Australia 19. Cross seedimg suppresses annual ryegrass and increases wheat yield, Abul Hashem, Dave Nicholson and Nerys Wilkins Agriculture Western Australia 20. Weed control by chaff burial, Mike Collins, Agriculture Western Australia HERBICIDE RESISTANCE 21. Resistance in wild oats to Fop and Dim herbicides in Western Australia, Abul Hashem and Harmohinder Dhammu, Agriculture Western Australia 22. Triazine and diflufenican resistance in wild radish: what it means to the lupin industry, Aik Cheam, Siew Lee, David Nicholson and Peter Newman, Agriculture Western Australia 23. Comparison if in situ v seed testing for determining herbicide resistance, Bill Roy, Agricultural Consulting and Research Services Pty Ltd, York HERBICIDE TOLERANCE 24. Phenoxy herbicide tolerance of wheat, Peter Newman and Dave Nicholson, Agriculture Western Australia 25. Tolerance of wheat to phenoxy herbicides, Harmohinder S. Dhammu, Terry Piper and Mario F. D\u27Antuono, Agriculture Western Australia 26. Herbicide tolerance of new wheats, Harmohinder S. Dhammu, Terry Piper and David F. Nicholson, Agriculture Western Australia 27. Herbicide tolerance of durum wheats, Harmohinder S. Dhammu, Terry Piper and David F. Nicholson, Agriculture Western Australia 28. Herbicide tolerance of new field pea varieties, Harmohinder S. Dhammu, Terry Piper, David F. Nicholson, and Mario F. D\u27Antuono, Agriculture Western Australia 29. Herbicide tolerance of Cooke field peas on marginal soil, Harmohinder S. Dhammu, Terry Piper, David F. Nicholson, and Mario F. D\u27Antuono, Agriculture Western Australia 30. Herbicide tolerance of some annual pasture legumes adapted to coarse textured sandy soils, Clinton Revell and Ian Rose, Agriculture Western Australia 31 Herbicide tolerance of some annual pasture legumes adapted to fine textured clay soils, Clinton Revell and Ian Rose, Agriculture Western Australia WEED CONTROL IN LUCERNE 32. Management of weeds for Lucerne establishment, Diana Fedorenko, Clayton Butterly, Stuart McAlpine, Terry Piper and David Bowran, Centre for Cropping Systems, Agriculture Western Australia 33. Management of weeds in the second year of Lucerne, Diana Fedorenko, Clayton Butterly, Stuart McAlpine, Terry Piper and David Bowran, Centre for Cropping Systems, Agriculture Western Australia 34. Residual effects of weed management in the third year of Lucerne, Diana Fedorenko, Clayton Butterly, Stuart McAlpine, Terry Piper and David Bowran, Centre for Cropping Systems, Agriculture Western Australia 35. Herbicide tolerance and weed control in Lucerne, Peter Newman, Dave Nicholson and Keith Devenish Agriculture Western Australia HERBICIDES – NEW PRODUCTS/PRODUCE USES; USE New products or product use 36. New herbicide options for canola, John Moore and Paul Matson, Agriculture Western Australia 37. Chemical broadleaf weed management in Peaola, Shannon Barraclough and Lionel Martin, Muresk Institute of Agriculture, Curtin University of Technology 38. Balance® - a new broad leaf herbicide for the chickpea industry, Mike Clarke, Jonas Hodgson and Lawrence Price, Aventis CropScience 39. Marshmallow – robust herbicide strategies, Craig Brown, IAMA Agribusiness 40. Affinity DF – a prospective option for selective in-crop marshmallow control, Gordon Cumming, Technical Officer, Crop Care Australasia 41. A new formulation of Carfentrazone-ethyl for pre-seeding knockdown control of broadleaved weeds including Marshmallow, Gordon Cumming, Technical Officer, Crop Care Australasia Herbicide use 42. Autumn applied trifluralin can be effective! Bill Crabtree, Scientific Officer, Western Australian No-Tillage Farmers Association 43. Which knockdown herbicide for small ryegrass? Peter Newman and Dave Nicholson, Agriculture Western Australia 44. Poor radish control with Group D herbicides in lupins, Peter Newman and Dave Nicholson, Agriculture Western Australia WEED ISSUES 45. Distribution and incidence of aphids and barley yellow dwarf virus in over-summering grasses in the WA wheatbelt, Jenny Hawkes and Roger Jones, CLIMA and Agriculture Western Australia 46. e-weed, Vanessa Stewart, Agriculture Western Australia CONTRIBUTING AUTHOR CONTACT DETAIL

The Maternally Expressed WRKY Transcription Factor TTG2 Controls Lethality in Interploidy Crosses of Arabidopsis

The molecular mechanisms underlying lethality of F1 hybrids between diverged parents are one target of speciation research. Crosses between diploid and tetraploid individuals of the same genotype can result in F1 lethality, and this dosage-sensitive incompatibility plays a role in polyploid speciation. We have identified variation in F1 lethality in interploidy crosses of Arabidopsis thaliana and determined the genetic architecture of the maternally expressed variation via QTL mapping. A single large-effect QTL, DR. STRANGELOVE 1 (DSL1), was identified as well as two QTL with epistatic relationships to DSL1. DSL1 affects the rate of postzygotic lethality via expression in the maternal sporophyte. Fine mapping placed DSL1 in an interval encoding the maternal effect transcription factor TTG2. Maternal parents carrying loss-of-function mutations in TTG2 suppressed the F1 lethality caused by paternal excess interploidy crosses. The frequency of cellularization in the endosperm was similarly affected by both natural variation and ttg2 loss-of-function mutants. The simple genetic basis of the natural variation and effects of single-gene mutations suggests that F1 lethality in polyploids could evolve rapidly. Furthermore, the role of the sporophytically active TTG2 gene in interploidy crosses indicates that the developmental programming of the mother regulates the viability of interploidy hybrid offspring