Developing screening tools to identify novel, resistance breaking pesticides.

Pesticide resistance is estimated to cost the USA $1.4 billion annually. Not only is there a huge economic cost, but the loss of crop yield and higher doses of pesticides needed to control pests damages the ecosystem 1,2. The development of resistance to chemicals is a universal phenomenon and within insect pests more than 440 species are now resistant to one or more pesticidal compound 3,4. As increasing levels of resistance arise and new molecular tools become available the understanding of resistance mechanisms grows and the limitations of pesticides are clarified 5,6. Understanding resistance is vital to counter it 5,7,8. Still facing high levels of pesticide resistance and the damaging effects of the remaining effective compounds, I here look to identify a novel pesticidal compound to overcome current resistance mechanisms 9. Synthetic compounds made by industrial partner Darr House M.I. were tested for activity against Drosophila melanogaster and Myzus persicae. The first 18 compounds were expected to act on the nicotinic acetylcholine receptor using imidacloprid as a positive control. Four competitively active compounds were found but, following a ban on neonicotinoids in the EU in 2018 and a knock-on lack of interest on the part of major agrochemical companies in novel nAChR compounds, this part of the project was pursued no further 10,11. The next 30 compounds were then tested for activity against the neurotransmitter gamma-aminobutyric acid (GABA) receptor. Here activity was only found against Drosophila not Myzus. Five compounds showed activity against D. melanogaster susceptible strain Canton-S, four then showed activity against metabolic resistant strain Hikone-R with compound 47 being close to resistance breaking. While synthetic compounds are popular, natural sources are not only a source of inspiration for synthetic products but natural products used for pest control have advantages of being environmentally friendly and constantly evolving with their pests. I tested 9 botanical sources for insecticidal and repellent activity against D. melanogaster and the Peach potato aphid M. persicae. Extracts from samples were taken using a methanol extraction technique. Rosemary extract results suggest potential lethal effects on Drosophila but development of this product would be required to concentrate the lethal effects above 40%. All extracts: basil, chilli, garlic, lemongrass, nasturtium leaves, flowers and seeds and rosemary showed repellent activity against Myzus except dill extract which had no effect. An increase in nymph droppings was seen for Myzus treated with basil suggesting possible problems for use of this compound as aphid control. To address the problem of cost and identification of novel active pesticides a Fly-Tox panel was developed using D. melanogaster as a model screening tool containing metabolic P450 resistance genes from multiple economically important pests and pollinator species. In this thesis four lines were developed containing Cyp6cm1, Cyp6bq23, Cyp6bq9 and Cyp337b3 but conferral of resistance was unsuccessful. Alternative lines from the published Fly-Tox panel were used to test the use of the screening tool with novel insecticides from chapter 2 and 3; one nAChR and one GABA targeting compound. These novel compounds were compared against positive controls; imidacloprid and fipronil, and showed a successful test run of a section of the screening tool. No resistance breaking bee-safe compounds were identified in this thesis but there was a successful trial of the Fly-Tox screening tool of transgenic Drosophila showing the value of this new resource in pesticidal discovery science. There were also findings of broad metabolic capabilities of the gene Cyp6er1, known to metabolise neonicotinoids, but also found to be active against suspected GABA targeting novel compound 47.European Commission BBSR

Fly-Tox: A panel of transgenic flies expressing pest and pollinator cytochrome P450s

This is the final version. Available from the publisher via the DOI in this record.There is an on-going need to develop new insecticides that are not compromised by resistance and that have improved environmental profiles. However, the cost of developing novel compounds has increased significantly over the last two decades. This is in part due to increased regulatory requirements, including the need to screen both pest and pollinator insect species to ensure that pre-existing resistance will not hamper the efficacy of a new insecticide via cross-resistance, or adversely affect non-target insect species. To add to this problem the collection and maintenance of toxicologically relevant pest and pollinator species and strains is costly and often difficult. Here we present Fly-Tox, a panel of publicly available transgenic Drosophila melanogaster lines each containing one or more pest or pollinator P450 genes that have been previously shown to metabolise insecticides. We describe the range of ways these tools can be used, including in predictive screens to avoid pre-existing cross-resistance, to identify potential resistance-breaking inhibitors, in the initial assessment of potential insecticide toxicity to bee pollinators, and identifying harmful pesticide-pesticide interactions.European Research Council (ERC)European Union's Horizon 2020 research and innovation programmeBiotechnology and Biological Sciences Research Council (BBSRC

Is telemedicine the answer to rural expansion of medication treatment for opioid use disorder? Early experiences in the feasibility study phase of a National Drug Abuse Treatment Clinical Trials Network Trial

Telemedicine (TM) enabled by digital health technologies to provide medical services has been considered a key solution to increasing health care access in rural communities. With the immediate need for remote care due to the COVID-19 pandemic, many health care systems have rapidly incorporated digital technologies to support the delivery of remote care options, including medication treatment for individuals with opioid use disorder (OUD). In responding to the opioid crisis and the COVID-19 pandemic, public health officials and scientific communities strongly support and advocate for greater use of TM-based medication treatment for opioid use disorder (MOUD) to improve access to care and have suggested that broad use of TM during the pandemic should be sustained. Nevertheless, research on the implementation and effectiveness of TM-based MOUD has been limited. To address this knowledge gap, the National Drug Abuse Treatment Clinical Trials Network (CTN) funded (via the NIH HEAL Initiative) a study on Rural Expansion of Medication Treatment for Opioid Use Disorder (Rural MOUD; CTN-0102) to investigate the implementation and effectiveness of adding TM-based MOUD to rural primary care for expanding access to MOUD. In preparation for this large-scale, randomized controlled trial incorporating TM in rural primary care, a feasibility study is being conducted to develop and pilot test implementation procedures. In this commentary, we share some of our experiences, which include several challenges, during the initial two-month period of the feasibility study phase. While these challenges could be due, at least in part, to adjusting to the COVID-19 pandemic and new workflows to accommodate the study, they are notable and could have a substantial impact on the larger, planned pragmatic trial and on TM-based MOUD more broadly. Challenges include low rates of identification of risk for OUD from screening, low rates of referral to TM, digital device and internet access issues, workflow and capacity barriers, and insurance coverage. These challenges also highlight the lack of empirical guidance for best TM practice and quality remote care models. With TM expanding rapidly, understanding implementation and demonstrating what TM approaches are effective are critical for ensuring the best care for persons with OUD

The Feasibility and Utility of Harnessing Digital Health to Understand Clinical Trajectories in Medication Treatment for Opioid Use Disorder: D-TECT Study Design and Methodological Considerations

Introduction: Across the U.S., the prevalence of opioid use disorder (OUD) and the rates of opioid overdoses have risen precipitously in recent years. Several effective medications for OUD (MOUD) exist and have been shown to be life-saving. A large volume of research has identified a confluence of factors that predict attrition and continued substance use during substance use disorder treatment. However, much of this literature has examined a small set of potential moderators or mediators of outcomes in MOUD treatment and may lead to over-simplified accounts of treatment non-adherence. Digital health methodologies offer great promise for capturing intensive, longitudinal ecologically-valid data from individuals in MOUD treatment to extend our understanding of factors that impact treatment engagement and outcomes. Methods: This paper describes the protocol (including the study design and methodological considerations) from a novel study supported by the National Drug Abuse Treatment Clinical Trials Network at the National Institute on Drug Abuse (NIDA). This study (D-TECT) primarily seeks to evaluate the feasibility of collecting ecological momentary assessment (EMA), smartphone and smartwatch sensor data, and social media data among patients in outpatient MOUD treatment. It secondarily seeks to examine the utility of EMA, digital sensing, and social media data (separately and compared to one another) in predicting MOUD treatment retention, opioid use events, and medication adherence [as captured in electronic health records (EHR) and EMA data]. To our knowledge, this is the first project to include all three sources of digitally derived data (EMA, digital sensing, and social media) in understanding the clinical trajectories of patients in MOUD treatment. These multiple data streams will allow us to understand the relative and combined utility of collecting digital data from these diverse data sources. The inclusion of EHR data allows us to focus on the utility of digital health data in predicting objectively measured clinical outcomes. Discussion: Results may be useful in elucidating novel relations between digital data sources and OUD treatment outcomes. It may also inform approaches to enhancing outcomes measurement in clinical trials by allowing for the assessment of dynamic interactions between individuals\u27 daily lives and their MOUD treatment response. Clinical Trial Registration: Identifier: NCT04535583

Meeting the looming policy challenge of sea-level change and human migration

PRIFPRI3; ISI; 1 Fostering Climate-Resilient and Sustainable Food Supply; 5 Strengthening Institutions and GovernanceDSG

The application of digital health to the assessment and treatment of substance use disorders: The past, current, and future role of the National Drug Abuse Treatment Clinical Trials Network

The application of digital technologies to better assess, understand, and treat substance use disorders (SUDs) is a particularly promising and vibrant area of scientific research. The National Drug Abuse Treatment Clinical Trials Network (CTN), launched in 1999 by the U.S. National Institute on Drug Abuse, has supported a growing line of research that leverages digital technologies to glean new insights into SUDs and provide science-based therapeutic tools to a diverse array of persons with SUDs. This manuscript provides an overview of the breadth and impact of research conducted in the realm of digital health within the CTN. This work has included the CTN\u27s efforts to systematically embed digital screeners for SUDs into general medical settings to impact care models across the nation. This work has also included a pivotal multi-site clinical trial conducted on the CTN platform, whose data led to the very first “prescription digital therapeutic” authorized by the U.S. Food and Drug Administration (FDA) for the treatment of SUDs. Further CTN research includes the study of telehealth to increase capacity for science-based SUD treatment in rural and under-resourced communities. In addition, the CTN has supported an assessment of the feasibility of detecting cocaine-taking behavior via smartwatch sensing. And, the CTN has supported the conduct of clinical trials entirely online (including the recruitment of national and hard-to-reach/under-served participant samples online, with remote intervention delivery and data collection). Further, the CTN is supporting innovative work focused on the use of digital health technologies and data analytics to identify digital biomarkers and understand the clinical trajectories of individuals receiving medications for opioid use disorder (OUD). This manuscript concludes by outlining the many potential future opportunities to leverage the unique national CTN research network to scale-up the science on digital health to examine optimal strategies to increase the reach of science-based SUD service delivery models both within and outside of healthcare

Disruption, not displacement: Environmental variability and temporary migration in Bangladesh

Mass migration is one of the most concerning potential outcomes of global climate change. Recent research into environmentally induced migration suggests that relationship is much more complicated than originally posited by the ‘environmental refugee’ hypothesis. Climate change is likely to increase migration in some cases and reduce it in others, and these movements will more often be temporary and short term than permanent and long term. However, few large-sample studies have examined the evolution of temporary migration under changing environmental conditions. To address this gap, we measure the extent to which temperature, precipitation, and flooding can predict temporary migration in Matlab, Bangladesh. Our analysis incorporates high-frequency demographic surveillance data, a discrete time event history approach, and a range of sociodemographic and contextual controls. This approach reveals that migration declines immediately after flooding but quickly returns to normal. In contrast, optimal precipitation and high temperatures have sustained positive effects on temporary migration that persist over one to two year periods. Building on previous studies of long-term migration, these results challenge the common assumption that flooding, precipitation extremes and high temperatures will consistently increase temporary migration. Instead, our results are consistent with a livelihoods interpretation of environmental migration in which households draw on a range of strategies to cope with environmental variability

Assessing learning and memory in pigs

In recent years, there has been a surge of interest in (mini) pigs (Sus scrofa) as species for cognitive research. A major reason for this is their physiological and anatomical similarity with humans. For example, pigs possess a well-developed, large brain. Assessment of the learning and memory functions of pigs is not only relevant to human research but also to animal welfare, given the nature of current farming practices and the demands they make on animal health and behavior. In this article, we review studies of pig cognition, focusing on the underlying processes and mechanisms, with a view to identifying. Our goal is to aid the selection of appropriate cognitive tasks for research into pig cognition. To this end, we formulated several basic criteria for pig cognition tests and then applied these criteria and knowledge about pig-specific sensorimotor abilities and behavior to evaluate the merits, drawbacks, and limitations of the different types of tests used to date. While behavioral studies using (mini) pigs have shown that this species can perform learning and memory tasks, and much has been learned about pig cognition, results have not been replicated or proven replicable because of the lack of validated, translational behavioral paradigms that are specially suited to tap specific aspects of pig cognition. We identified several promising types of tasks for use in studies of pig cognition, such as versatile spatial free-choice type tasks that allow the simultaneous measurement of several behavioral domains. The use of appropriate tasks will facilitate the collection of reliable and valid data on pig cognition