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Abstract Acute intoxication with cholinesterase inhibiting organophosphates (OP) can produce life-threatening cholinergic crisis and status epilepticus (SE). Survivors often develop long-term neurological consequences, including spontaneous recurrent seizures (SRS) and impaired cognition. Numerous studies implicate OP-induced neuroinflammation as a pathogenic mechanism contributing to these chronic sequelae; however, little is known about the inflammatory phenotype of innate immune cells in the brain following acute OP intoxication. Thus, the aim of this study was to characterize the natural history of microglial and astrocytic inflammatory phenotypes following acute intoxication with the OP, diisopropylfluorophosphate (DFP). Adult male and female Sprague–Dawley rats were administered a single dose of DFP (4 mg/kg, sc) followed by standard medical countermeasures. Within minutes, animals developed benzodiazepine-resistant SE as determined by monitoring seizures using a modified Racine scale. At 1, 3, 7, 14, and 28 d post-exposure (DPE), neuroinflammation was assessed using translocator protein (TSPO) positron emission tomography (PET) and magnetic resonance imaging (MRI). In both sexes, we observed consistently elevated radiotracer uptake across all examined brain regions and time points. A separate group of animals was euthanized at these same time points to collect tissues for immunohistochemical analyses. Colocalization of IBA-1, a marker for microglia, with iNOS or Arg1 was used to identify pro- and anti-inflammatory microglia, respectively; colocalization of GFAP, a marker for astrocytes, with C3 or S100A10, pro- and anti-inflammatory astrocytes, respectively. We observed shifts in the inflammatory profiles of microglia and astrocyte populations during the first month post-intoxication, largely in hyperintense inflammatory lesions in the piriform cortex and amygdala regions. In these areas, iNOS+ proinflammatory microglial cell density peaked at 3 and 7 DPE, while anti-inflammatory Arg1+ microglia cell density peaked at 14 DPE. Pro- and anti-inflammatory astrocytes emerged within 7 DPE, and roughly equal ratios of C3+ pro-inflammatory and S100A10+ anti-inflammatory astrocytes persisted at 28 DPE. In summary, microglia and astrocytes adopted mixed inflammatory phenotypes post-OP intoxication, which evolved over one month post exposure. These activated cell populations were most prominent in the piriform and amygdala areas and were more abundant in males compared to females. The temporal relationship between microglial and astrocytic responses suggests that initial microglial activity may influence delayed, persistent astrocytic responses. Further, our findings identify putative windows for inhibition of OP-induced neuroinflammatory responses in both sexes to evaluate the therapeutic benefit of anti-inflammation in this context.

Abstract Climate change is currently one of humanity’s greatest threats. To help scholars understand the psychology of climate change, we conducted an online quasi-experimental survey on 59,508 participants from 63 countries (collected between July 2022 and July 2023). In a between-subjects design, we tested 11 interventions designed to promote climate change mitigation across four outcomes: climate change belief, support for climate policies, willingness to share information on social media, and performance on an effortful pro-environmental behavioural task. Participants also reported their demographic information (e.g., age, gender) and several other independent variables (e.g., political orientation, perceptions about the scientific consensus). In the no-intervention control group, we also measured important additional variables, such as environmentalist identity and trust in climate science. We report the collaboration procedure, study design, raw and cleaned data, all survey materials, relevant analysis scripts, and data visualisations. This dataset can be used to further the understanding of psychological, demographic, and national-level factors related to individual-level climate action and how these differ across countries.

Evidence increasingly demonstrates nature engagement benefits. However, little evidence shows nature engagement provides children with a reflective perception of biodiversity, nor whether perception influences children's wellbeing and resilience. We explored the impact of weekly nature engagement in schoolgrounds on 509 eight-to-eleven-year-olds' biodiversity perception, wellbeing, and resilience. At the start and end of the academic year, wellbeing and resilience questionnaires were completed, and biodiversity perception was assessed by children drawing what they thought was in their schoolgrounds. Children initially perceived few organisms within easily visible taxa, and perceived more vertebrates compared to invertebrate species. After, children were more aware of taxa, resulting in a more reflective biodiversity perception. Children with initially low scores in wellbeing and resilience increased in these measures, and a positive association was found between increased invertebrates and vertebrates perception and improved resilience. Nature engagement within curriculum could reduce children's extinction of experience and improve wellbeing and resilience.

Abstract Accurate and scalable quantification of amyloid-β (Aβ) pathology is crucial for deeper disease phenotyping and furthering research in Alzheimer Disease (AD). This multidisciplinary study addresses the current limitations on neuropathology by leveraging a machine learning (ML) pipeline to perform a granular quantification of Aβ deposits and assess their distribution in the temporal lobe. Utilizing 131 whole-slide-images from consecutive autopsied cases at the University of California Davis Alzheimer Disease Research Center, our objectives were threefold: (1) Validate an automatic workflow for Aβ deposit quantification in white matter (WM) and gray matter (GM); (2) define the distributions of different Aβ deposit types in GM and WM, and (3) investigate correlates of Aβ deposits with dementia status and the presence of mixed pathology. Our methodology highlights the robustness and efficacy of the ML pipeline, demonstrating proficiency akin to experts’ evaluations. We provide comprehensive insights into the quantification and distribution of Aβ deposits in the temporal GM and WM revealing a progressive increase in tandem with the severity of established diagnostic criteria (NIA-AA). We also present correlations of Aβ load with clinical diagnosis as well as presence/absence of mixed pathology. This study introduces a reproducible workflow, showcasing the practical use of ML approaches in the field of neuropathology, and use of the output data for correlative analyses. Acknowledging limitations, such as potential biases in the ML model and current ML classifications, we propose avenues for future research to refine and expand the methodology. We hope to contribute to the broader landscape of neuropathology advancements, ML applications, and precision medicine, paving the way for deep phenotyping of AD brain cases and establishing a foundation for further advancements in neuropathological research.

Abstract Biological sex differences exist for many airway diseases in which females have either worse or better health outcomes. Inflammatory airway diseases such as cystic fibrosis (CF) and asthma display a clear male advantage in post-puberty while a female benefit is observed in asthma during the pre-puberty years. The influence of menstrual cycle stage and pregnancy on the frequency and severity of pulmonary exacerbations in CF and asthma point to a role for sex steroid hormones, particularly estrogen, in underpinning biological sex differences in these diseases. There are many ways by which estrogen may aggravate asthma and CF involving disturbances in airway surface liquid (ASL) dynamics, inappropriate hyper-immune and allergenic responses, as well as exacerbation of pathogen virulence. The deleterious effect of estrogen on pulmonary function in CF and asthma contrasts with the female advantage observed in airway diseases characterised by pulmonary edema such as pneumonia, acute respiratory distress syndrome (ARDS) and COVID-19. Airway surface liquid hypersecretion and alveolar flooding are hallmarks of ARDS and COVID-19, and contribute to the morbidity and mortality of severe forms of these diseases. ASL dynamics encompasses the intrinsic features of the thin lining of fluid covering the airway epithelium which regulate mucociliary clearance (ciliary beat, ASL height, volume, pH, viscosity, mucins, and channel activating proteases) in addition to innate defence mechanisms (pathogen virulence, cytokines, defensins, specialised pro-resolution lipid mediators, and metabolism). Estrogen regulation of ASL dynamics contributing to biological sex differences in CF, asthma and COVID-19 is a major focus of this review. Graphical Abstract

Background: In the phase III SYNAPSE study, mepolizumab plus standard of care reduced total endoscopic nasal polyp score (NPS) versus that with placebo in patients with chronic rhinosinusitis with nasal polyps. Objective: Our aim was to investigate relationships between NPS and (1) peak nasal inspiratory flow (PNIF) and (2) patient-reported outcomes. Methods: In this post hoc analysis, patients randomized 1:1 received mepolizumab, 100 mg, or placebo subcutaneously every 4 weeks (plus standard of care). Changes from baseline in PNIF (week 52), visual analog scale scores (overall symptoms, nasal obstruction, and loss of smell [weeks 49-52]), and total 22-Item Sino-Nasal Outcome Test score (week 52) were assessed in patients with or without improvements in NPS (improvement of ≥1 point) or without (improvement of

Abstract Producing quantitative volcanic ash forecasts is challenging due to multiple sources of uncertainty. Careful consideration of this uncertainty is required to produce timely and robust hazard warnings. Structural uncertainty occurs when a model fails to produce accurate forecasts, despite good knowledge of the eruption source parameters, meteorological conditions and suitable parameterizations of transport and deposition processes. This uncertainty is frequently overlooked in forecasting practices. Using a Lagrangian particle dispersion model, simulations with varied output spatial resolution, temporal averaging period and particle release rate are performed to quantify the impact of these structural choices. This experiment reveals that, for the 2019 Raikoke eruption, structural choices give measurements of peak ash concentration spanning an order of magnitude, significantly impacting decision‐relevant thresholds used in aviation flight planning. Conversely, along‐flight dosage estimates exhibit less sensitivity to structural choices, suggesting it is a more robust metric to use in flight planning. Uncertainty can be reduced by eliminating structural choices that do not result in a favourable level of agreement with a high‐resolution reference simulation. Reliable forecasts require output spatial resolution ≤ 80 km, temporal averaging periods ≤ 3 h and particle release rates ≥ 5000 particles/h. This suggests that simulations with relatively small numbers of particles could be used to produce a large ensemble of simulations without significant loss of accuracy. Comparison with previous Raikoke simulations indicates that the uncertainty associated with these constrained structural choices is smaller than those associated with satellite constrained eruption source parameter and internal model parameter uncertainties. Thus, given suitable structural choices, other epistemic sources of uncertainty are likely to dominate. This insight is useful for the design of ensemble methodologies which are required to enable a shift from deterministic to probabilistic forecasting. The results are applicable to other long‐range dispersion problems and to Eulerian dispersion models.

Abstract Background Sarcoptic mange is a serious animal welfare concern in bare-nosed wombats (Vombatus ursinus). Fluralaner (Bravecto®) is a novel acaricide that has recently been utilised for treating mange in wombats. The topical ‘spot-on’ formulation of fluralaner can limit treatment delivery options in situ, but dilution to a volume for ‘pour-on’ delivery is one practicable solution. This study investigated the in vitro acaricidal activity of Bravecto, a proposed essential oil-based diluent (Orange Power®), and two of its active constituents, limonene and citral, against Sarcoptes scabiei. Methods Sarcoptes scabiei were sourced from experimentally infested pigs. In vitro assays were performed to determine the lethal concentration (LC50) and survival time of the mites when exposed to varying concentrations of the test solutions. Results All compounds were highly effective at killing mites in vitro. The LC50 values of Bravecto, Orange Power, limonene and citral at 1 h were 14.61 mg/ml, 4.50%, 26.53% and 0.76%, respectively. The median survival times of mites exposed to undiluted Bravecto, Orange Power and their combination were 15, 5 and 10 min, respectively. A pilot survival assay of mites collected from a mange-affected wombat showed survival times of

Abstract There has been huge recent interest in the potential of making operational weather forecasts using machine learning techniques. As they become a part of the weather forecasting toolbox, there is a pressing need to understand how well current machine learning models can simulate high-impact weather events. We compare short to medium-range forecasts of Storm Ciarán, a European windstorm that caused sixteen deaths and extensive damage in Northern Europe, made by machine learning and numerical weather prediction models. The four machine learning models considered (FourCastNet, Pangu-Weather, GraphCast and FourCastNet-v2) produce forecasts that accurately capture the synoptic-scale structure of the cyclone including the position of the cloud head, shape of the warm sector and location of the warm conveyor belt jet, and the large-scale dynamical drivers important for the rapid storm development such as the position of the storm relative to the upper-level jet exit. However, their ability to resolve the more detailed structures important for issuing weather warnings is more mixed. All of the machine learning models underestimate the peak amplitude of winds associated with the storm, only some machine learning models resolve the warm core seclusion and none of the machine learning models capture the sharp bent-back warm frontal gradient. Our study shows there is a great deal about the performance and properties of machine learning weather forecasts that can be derived from case studies of high-impact weather events such as Storm Ciarán.

Abstract Background Kinetic modeling of 18F-florbetaben provides important quantification of brain amyloid deposition in research and clinical settings but its use is limited by the requirement of arterial blood data for quantitative PET. The total-body EXPLORER PET scanner supports the dynamic acquisition of a full human body simultaneously and permits noninvasive image-derived input functions (IDIFs) as an alternative to arterial blood sampling. This study quantified brain amyloid burden with kinetic modeling, leveraging dynamic 18F-florbetaben PET in aorta IDIFs and the brain in an elderly cohort. Methods 18F-florbetaben dynamic PET imaging was performed on the EXPLORER system with tracer injection (300 MBq) in 3 individuals with Alzheimer’s disease (AD), 3 with mild cognitive impairment, and 9 healthy controls. Image-derived input functions were extracted from the descending aorta with manual regions of interest based on the first 30 s after injection. Dynamic time-activity curves (TACs) for 110 min were fitted to the two-tissue compartment model (2TCM) using population-based metabolite corrected IDIFs to calculate total and specific distribution volumes (VT, Vs) in key brain regions with early amyloid accumulation. Non-displaceable binding potential ( $$ {BP}_{ND})$$ was also calculated from the multi-reference tissue model (MRTM). Results Amyloid-positive (AD) patients showed the highest VT and VS in anterior cingulate, posterior cingulate, and precuneus, consistent with $$ {BP}_{ND}$$ analysis. $$ {BP}_{ND} $$ and VT from kinetic models were correlated (r² = 0.46, P

Abstract The iconic European stag beetle (Lucanus cervus) (Coleoptera: Lucanidae) is one of the largest terrestrial beetles in Europe. Due to decreasing population numbers, thought to be a consequence of habitat loss, this beetle has become a near-threatened species across much of Europe, and a reliable monitoring system is required to measure its future population trends. As part of a programme aimed at conserving UK populations, we have investigated the chemical ecology of the beetle, with a view to developing an efficient semiochemical-based monitoring system. Such a scheme will be beneficial not only in the UK but across the European range of the species, where the beetle is of conservation concern. Here, we report on a surprising discovery of a male-produced pheromone, which provokes initial sexual receptivity in females, and which has not been previously identified in the animal kingdom. Furthermore, we assign sex pheromone function to a previously described female-specific compound.

Understanding the impacts of changing climate and disturbance regimes on forest ecosystems is greatly aided by the use of process-based models. Such models simulate processes based on first principles of ecology, which requires parameterization. Parameterization is an important step in model development and application, defining the characteristics of trees and their responses to the environment, i.e., their traits. For species-specific models, parameterization is usually done at the level of individual species. Parameterization is indispensable for accurately modeling demographic processes, including growth, mortality, and regeneration of trees, along with their intra- and inter-specific interactions. As it is time-demanding to compile the parameters required to simulate forest ecosystems in complex models, simulations are often restricted to the most common tree species, genera, or plant-functional types. Yet, as tree species composition might change in the future, it is important to account for a broad range of species and their individual responses to drivers of change explicitly in simulations. Thus, species-specific parameterization is a critical task for making accurate projections about future forest trajectories, yet species parameters often remain poorly documented in simulation studies.We compiled and harmonized all existing tree species parameters available for the individual-based forest landscape and disturbance model (iLand). Since its first publication in 2012, iLand has been applied in 50 peer-reviewed publications across three continents throughout the Northern Hemisphere (i.e., Europe, North America, and Asia). The model operates at individual-tree level and simulates ecosystem processes at multiple spatial scales, making it a capable process-based model for studying forest change. However, the extensive number of processes and their interactions as well as the wide range of spatio-temporal scales considered in iLand require intensive parameterization, with tree species characterized by 66 unique parameters in the model. The database presented here includes parameters for 150 temperate and boreal tree species and provenances (i.e., regional variations). Excluding missing values, the database includes a total of 9,249 individual parameter entries. In addition, we provide parameters for the individual susceptibility of tree species to wind disturbance (five parameters) for a subset of 104 tree species and provenances (498 parameter entries). To guide further model parameterization efforts, we provide an estimate of uncertainty for each species based on how thoroughly simulations with the respective parameters were evaluated against independent data.Our dataset aids the future parameterization and application of iLand, and sets a new standard in documenting parameters used in process-based forest simulations. This dataset will support model application in previously unstudied areas and can facilitate the investigation of new tree species being introduced to well-studied systems (e.g., simulating assisted migration in the context of rapid climate change). Given that many process-based models rely on similar underlying processes our harmonized parameter set will be of relevance beyond the iLand community. Our work could catalyze further research into improving the parameterization of process-based forest models, increasing the robustness of projections of climate change impacts and adaptation strategies.

Abstract Forests are a large carbon sink and could serve as natural climate solutions that help moderate future warming. Thus, establishing forest carbon baselines is essential for tracking climate‐mitigation targets. Western US forests are natural climate solution hotspots but are profoundly threatened by drought and altered disturbance regimes. How these factors shape spatial patterns of carbon storage and carbon change over time is poorly resolved. Here, we estimate live and dead forest carbon density in 19 forested western US ecoregions with national inventory data (2005–2019) to determine: (a) current carbon distributions, (b) underpinning drivers, and (c) recent trends. Potential drivers of current carbon included harvest, wildfire, insect and disease, topography, and climate. Using random forests, we evaluated driver importance and relationships with current live and dead carbon within ecoregions. We assessed trends using linear models. Pacific Northwest (PNW) and Southwest (SW) ecoregions were most and least carbon dense, respectively. Climate was an important carbon driver in the SW and Lower Rockies. Fire reduced live and increased dead carbon, and was most important in the Upper Rockies and California. No ecoregion was unaffected by fire. Harvest and private ownership reduced carbon, particularly in the PNW. Since 2005, live carbon declined across much of the western US, likely from drought and fire. Carbon has increased in PNW ecoregions, likely recovering from past harvest, but recent record fire years may alter trajectories. Our results provide insight into western US forest carbon function and future vulnerabilities, which is vital for effective climate change mitigation strategies.

Abstract As wildfire activity increases and fire‐size distributions potentially shift in many forested regions worldwide, anticipating the spatial patterns of burn severity expected with future fire activity is critical for ecological understanding and informing management and policy. Because spatial patterns of burn severity are influenced by a complex mixture of drivers, they remain difficult to predict for any given burned landscape. At broader extents, however, spatial scaling relationships relating high‐severity patch size and shape to overall fire size, when combined with scenarios regarding regional area burned and fire‐size distributions, offer a means to anticipate the spatial configuration of burn severity in future fires. Here, leveraging a satellite burn‐severity dataset for 1615 fire events occurring across the northwest United States between 1985 and 2020, we present an approach for simulating expected patch‐level burn‐severity patterns at the scale of a region or fire regime of interest. We demonstrate this approach in a historically climate‐limited fire regime within the Pacific Northwest, USA, where relatively infrequent but large and severe fires shape biomass‐rich forests, and where fire potential is projected to increase as summer fire seasons become warmer and drier. We quantify how, for a given total burned area, the range of cumulative burn‐severity patterns is expected to vary with the size distributions of fire events. Our results illustrate how shifts in fire‐size distributions toward larger fire events will lead to increasingly large high‐severity burn patches with interior areas that are increasingly far from unburned seed sources following fire. In contrast, the same total area burned in more numerous but smaller fire events will result in qualitatively different cumulative patterns of burn severity, characterized by smaller high‐severity patches and closer proximity to postfire seed sources across burned landscapes. These results have important implications in forested regions, informing management actions ranging from prefire planning (e.g., fire response preparedness) to real‐time decision‐making (e.g., fire suppression vs. managed wildfire use) and postfire responses (e.g., replanting to restore tree cover and/or promoting early‐seral habitat). The approach we present is generalizable and can be applied across regions and fire regimes to anticipate potential future fire effects.

Permafrost cores provide physical samples that can be used to measure the characteristics of frozen ground. Measurements of core physical properties, however, are typically destructive and time intensive. In this study, multi-sensor core logging (MSCL) is used to provide a rapid (∼2–3 cm core depth per minute), high-resolution, non-destructive method to image and collect the physical properties of permafrost cores, allowing for the visualization of cryostructures and estimation of frozen bulk density, magnetic susceptibility, and volumetric ice content. Six permafrost cores with differing properties were analyzed using MSCL and compared with established destructive analyses to assess the potential of this instrument both in terms of accuracy and relative rate of data acquisition. A calibration procedure is presented for gamma ray attenuation from a 137Cs source that is specific to frozen-core materials. This accurately estimates frozen bulk density over the wide range of material densities found in permafrost. MSCL frozen bulk density data show agreement with destructive analyses based on discrete-sample measurements, with an RMSE of 0.067 g cm−3. Frozen bulk density data from the gamma attenuation, along with soil dry bulk density measurements for different sediment types, are used to estimate volumetric ice content. This approach does require an estimation of the soil dry bulk density and assumption of air content. However, the averaged results for this method show good agreement with an RMSE of 6.7 %, illustrating MSCL can provide non-destructive estimates of volumetric ice contents and a digital archive of permafrost cores for future applications.

Abstract Background Evidence-based interventions to protect against cognitive decline among older adults at risk for Alzheimer’s disease and related dementias (ADRD) are urgently needed. Rehabilitation approaches to support memory and behavioral/lifestyle interventions are recognized as promising strategies for preserving or improving cognitive health, although few previous interventions have combined both approaches. This paper describes the protocol of the Brain Boosters intervention, which synergistically combines training in compensatory and healthy lifestyle behaviors and supports implementation and tracking of new behaviors with a digital application. Methods The study utilizes a single-site, single-blinded, randomized controlled design to compare a structured lifestyle and compensatory aid intervention to an education-only self-guided intervention. We plan to enroll 225 community-dwelling adults (25% from underrepresented groups) aged 65 + who endorse subjective cognitive decline (SCD) and low baseline levels of healthy lifestyle behaviors. Both interventions will be administered in group format, consisting of 15 two-hour classes that occur weekly for ten weeks and taper to bi-monthly and monthly, for an intervention duration of 6 months. Participants in both interventions will receive education about a variety of memory support strategies and healthy lifestyle behaviors, focusing on physical and cognitive activity and stress management. The structured intervention will also receive support in adopting new behaviors and tracking set goals aided by the Electronic Memory and Management Aid (EMMA) digital application. Primary outcomes include global cognition (composite of memory, attention, and executive function tests) and everyday function (Everyday Cognition Questionnaire). Data will be collected at baseline and outcome visits, at approximately 6, 12, and 18 months. Qualitative interviews, self-report surveys (e.g., indicators of self-determination, health literacy) and EMMA data metrics will also be used to identify what components of the intervention are most effective and for whom they work. Discussion Successful project completion will provide valuable information about how individuals with SCD respond to a compensation and preventative lifestyle intervention assisted by a digital application, including an understanding of factors that may impact outcomes, treatment uptake, and adherence. The work will also inform development, scaling, and personalization of future interventions that can delay disability in individuals at risk for ADRD. Trial Registration ClinicalTrials.gov. (NCT05027789, posted 8/30/2021).

Abstract Background Anorexia nervosa (AN) has amongst the highest mortality rates and the highest treatment costs of any psychiatric disorder. Recently, interest in non-invasive brain stimulation as a novel treatment for AN has grown. These include repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS). Methods This double-blind, randomised sham-controlled trial will compare the relative acceptability and efficacy of tDCS and rTMS in people with AN. 70 participants will be randomised to active or sham tDCS, or active or sham rTMS treatment (2:1:2:1 ratio) over an 8-week treatment period. Participants will receive treatment as usual across the study duration. The primary outcomes are change on the Eating Disorder Examination Questionnaire and treatment acceptability. Secondary outcomes will include change in weight, cognition, mood, interpersonal functioning, and quality of life. Following the 8-week assessment, all participants will have the option of receiving an additional 12 weeks of at-home tDCS. A follow-up assessment will be conducted at 20 weeks post treatment. Discussion Research into non-invasive brain stimulation as treatments for AN has potential to improve clinical outcomes for patients by comparing the relative efficacy and acceptability of both treatment modalities in the inpatient and at-home setting (i.e., for at-home tDCS) results from this study will provide important information for informing future larger clinical trials of these treatments for AN. Trial registration ClinicalTrials.gov Identifier: NCT05788042.

This study examines how higher education professionals navigate intersectional failures in institutional, state, and federal support as advocates for undocumented students. Semi-structured interviews with these professionals reveal that they rely on college interventionists to fill the gaps in undocumented student support on their college campuses. Recommendations for scholarship and practitioners include additional interventions for addressing the precarity faced by undocumented students and the personnel who serve them in higher education.

IntroductionThe role of lipopolysaccharide binding protein (LBP), an inflammation marker of bacterial translocation from the gastrointestinal tract, in Alzheimer’s disease (AD) is not clearly understood.MethodsIn this study the concentrations of LBP were measured in n = 79 individuals: 20 apolipoprotein E (APOE)3/E3 carriers with and 20 without AD dementia, and 19 APOE3/E4 carriers with and 20 without AD dementia. LBP was found to be enriched in the 1.21–1.25 g/mL density fraction of plasma, which has previously been shown to be enriched in intestinally derived high-density lipoproteins (HDL). LBP concentrations were measured by ELISA.ResultsLBP was significantly increased within the 1.21–1.25 g/mL density fraction of plasma in APOE3/E3 AD patients compared to controls, but not APOE3/E4 patients. LBP was positively correlated with Clinical Dementia Rating (CDR) and exhibited an inverse relationship with Verbal Memory Score (VMS).DiscussionThese results underscore the potential contribution of gut permeability to bacterial toxins, measured as LBP, as an inflammatory mediator in the development of AD, particularly in individuals with the APOE3/E3 genotype, who are genetically at 4-12-fold lower risk of AD than individuals who express APOE4.

Tree establishment following severe or stand-replacing disturbance is critical for achieving U.S. climate change mitigation goals and for maintaining the co-benefits of intact forest ecosystems. In many contexts, natural post-fire tree regeneration is sufficient to maintain forest cover and associated ecosystem services, but increasingly the pattern and scale of disturbance exceeds ecological thresholds and active reforestation may be warranted. Our capacity to plant trees, however, is not keeping pace with reforestation needs. This shortfall is uniquely apparent in the western U.S., where wildfire size and severity have increased in recent decades and long-term divestment in the reforestation supply chain has limited our ability to respond to existing needs. Here we present an analysis of key facets of both the supply and demand side of reforestation in the western U.S. and address six questions: (1) What is the current backlog of potential reforestation needs driven by high-severity wildfire?; (2) How will increasing wildfire activity through the end of the century affect potential reforestation needs?; (3) What is our capacity to meet current and future reforestation needs?; (4) How can we scale the reforestation supply chain to meet current and future demands?; (5) What approaches to reforestation can promote forest resilience to climate change and wildfire?; and (6) Where are opportunities emerging from recent policy initiatives, innovative public-private partnerships, and natural capital markets for scaling reforestation? Between 1984 and 2000, annual tree planting capacity met post-fire needs but cumulatively over the last two decades (2000 to 2021) it has fallen short of fire-driven needs by an estimated 1.5 million ha (ca. 3.8 million ac). We anticipate this gap will increase 2 to 3 fold by 2050. Scaling up reforestation efforts to close this gap will require increased investment across all facets of the reforestation supply chain, public-private partnerships, and novel approaches to reforestation that increase the resilience of western forests to drought and wildfire. We highlight emerging opportunities from recent policy initiatives and conservation finance for expanding reforestation efforts.

Acute intoxication with high levels of organophosphate (OP) cholinesterase inhibitors can cause cholinergic crisis, which is associated with acute, life-threatening parasympathomimetic symptoms, respiratory depression and seizures that can rapidly progress to status epilepticus (SE). Clinical and experimental data demonstrate that individuals who survive these acute neurotoxic effects often develop significant chronic morbidity, including behavioral deficits. The pathogenic mechanism(s) that link acute OP intoxication to chronic neurological deficits remain speculative. Cellular senescence has been linked to behavioral deficits associated with aging and neurodegenerative disease, but whether acute OP intoxication triggers cellular senescence in the brain has not been investigated. Here, we test this hypothesis in a rat model of acute intoxication with the OP diisopropylfluorophosphate (DFP). Adult male Sprague-Dawley rats were administered DFP (4 mg/kg, s.c.). Control animals were administered an equal volume (300 µL) of sterile phosphate-buffered saline (s.c.). Both groups were subsequently injected with atropine sulfate (2 mg/kg, i.m.) and 2-pralidoxime (25 mg/kg, i.m.). DFP triggered seizure activity within minutes that rapidly progressed to SE, as determined using behavioral seizure criteria. Brains were collected from animals at 1, 3, and 6 months post-exposure for immunohistochemical analyses of p16, a biomarker of cellular senescence. While there was no immunohistochemical evidence of cellular senescence at 1-month post-exposure, at 3- and 6-months post-exposure, p16 immunoreactivity was significantly increased in the CA3 and dentate gyrus of the hippocampus, amygdala, piriform cortex and thalamus, but not the CA1 region of the hippocampus or the somatosensory cortex. Co-localization of p16 immunoreactivity with cell-specific biomarkers, specifically, NeuN, GFAP, S100β, IBA1 and CD31, revealed that p16 expression in the brain of DFP animals is neuron-specific. The spatial distribution of p16-immunopositive cells overlapped with expression of senescence associated β-galactosidase and with degenerating neurons identified by FluoroJade-C (FJC) staining. The co-occurrence of p16 and FJC was positively correlated. This study implicates cellular senescence as a novel pathogenic mechanism underlying the chronic neurological deficits observed in individuals who survive OP-induced cholinergic crisis.

The development of subsurface microstructural alterations known as dark etching regions (DERs) and white etching bands (WEBs) in rolling element bearings due to rolling contact fatigue have been investigated for the past eight decades, focusing on their initiation and formation mechanisms. They have only recently been shown to be driven by repetitive cycles of energy build-up due to micro-plastic deformation and energy release through recrystallization and recovery, which results in the formation of equiaxed and elongated ferrite grains, as well as lenticular carbides. These features develop within the bearing subsurface from DER to WEBs during bearing operation at moderate to high loads, but little evidence has been presented in the literature to understand links between DER and WEBs and the nucleation and growth of subsurface cracks. This investigation examines WEBs, including low angle bands (LABs) and high angle bands (HABs), in detail especially focusing on their late stages to understand such links. A number of techniques, including optical microscopy, scanning electron microscopy (SEM) and Energy-dispersive X-ray spectroscopy (EDX) have been used to examine the features involved. Analysis on WEBs obtained through serial sectioning has revealed that voids initiating at the interface between lenticular carbides and equiaxed ferrite grain bands within WEBs have led to crack formation which can subsequently propagate to bearing surfaces. Interactions between WEBs and non-metallic inclusions (NMIs) are observed to lead to de-bonding of inclusions from their surrounding microstructure and void formation, which has also found to influence the integrity of the bearings at late stages. Alumina and Manganese sulphide (MnS) inclusions are the mostly observed NMIs that de-bond and develop microcracks when interacting with WEBs. These findings thus provide important insights into the link between inclusions and crack initiation and represent a further step towards a fundamental understanding of the rolling contact fatigue process.

Abstract The specific activity of the $$\beta $$ β decay of $$^{39}$$ 39 Ar in atmospheric argon is measured using the DEAP-3600 detector. DEAP-3600, located 2 km underground at SNOLAB, uses a total of (3269 ± 24) kg of liquid argon distilled from the atmosphere to search for dark matter. This detector is well-suited to measure the decay of $$^{39}$$ 39 Ar owing to its very low background levels. This is achieved in two ways: it uses low background construction materials; and it uses pulse-shape discrimination to differentiate between nuclear recoils and electron recoils. With 167 live-days of data, the measured specific activity at the time of atmospheric extraction is (0.964 ± 0.001 $$_\textrm{stat}$$ stat ± 0.024 $$_\textrm{sys}$$ sys ) Bq/kg $$_\textrm{atmAr}$$ atmAr , which is consistent with results from other experiments. A cross-check analysis using different event selection criteria and a different statistical method confirms the result.

Abstract The lack of psychometrically sound outcome measures has been a barrier to evaluating the efficacy of treatments proposed for core symptoms of intellectual disability (ID). Research on Expressive Language Sampling (ELS) procedures suggest it is a promising approach to measuring treatment efficacy. ELS entails collecting samples of a participant’s talk in interactions with an examiner that are naturalistic but sufficiently structured to ensure consistency and limit examiner effects on the language produced. In this study, we extended previous research on ELS by analyzing an existing dataset to determine whether psychometrically adequate composite scores reflecting multiple dimensions of language can be derived from ELS procedures administered to 6- to 23-year-olds with fragile X syndrome (n = 80) or Down syndrome (n = 78). Data came from ELS conversation and narration procedures administered twice in a 4-week test–retest interval. We found that several composites emerged from variables indexing syntax, vocabulary, planning processes, speech articulation, and talkativeness, although there were some differences in the composites for the two syndromes. Evidence of strong test–retest reliability and construct validity of two of three composites were obtained for each syndrome. Situations in which the composite scores would be useful in evaluating treatment efficacy are outlined.

Background:. Despite the large impact of hip fracture care on hospital budgets, accurate episode-of-care costs (EOCC) calculations for this injury remains a challenge. The objective of this article was to assess EOCC for geriatric patients with hip fractures using an activity-based costing methodology and identify intraoperative, perioperative, and patient-specific factors associated with higher EOCC. Material and Methods:. This is a retrospective cohort study involving a total of 109 consecutive patients with hip fracture treated surgically at a Canadian level-1 trauma center from April 2018 to February 2019. Clinical and demographic data were extracted through the institution's centralized data warehouse. Data acquisition also included direct and indirect costs per episode of care, adverse events, and precise temporal data. Results:. The median total EOCC was $13,113 (interquartile range 6658), excluding physician fees. Out of the total cost, 75% was attributed to direct costs, which represented a median expenditure of $9941. The median indirect cost of the EOCC was $3322. Based on the multivariate analysis, patients not operated within the 48 hours guidelines had an increased length of stay by 5.7 days (P = 0.003), representing an increase in EOCC of close to 5000$. Higher American Society of Anesthesiology (ASA) scores were associated with elevated EOCC. Conclusion:. The cost of managing a patient with geriatric hip fracture from arrival in the emergency department to discharge from surgical ward represented $13,113. Main factors influencing the EOCC included adherence to the 48-hour benchmark surgical delay and ASA score. High-quality costing data are vital in assessing health care spending, conducting cost effectiveness analyses, and ultimately in guiding policy decisions. Level of Evidence:. Level III (3), retrospective cohort study.

Radiocarbon dating marine sediments is complicated by the strongly heterogeneous age of ocean waters. Tephrochronology provides a well-established method to constrain the age of local radiocarbon reservoirs and more accurately calibrate dates. Numerous ultra-distal cryptotephra deposits (non-visible volcanic ash more than 3000 km from source) have been identified in peatlands and lake sediments across north-eastern North America and correlated with volcanic arcs in the Pacific north-west. Previously, however, these isochrons have not been identified in sediments from the north-west Atlantic Ocean. In this study, we report the presence of two ultra-distal cryptotephra deposits; Mazama Ash and White River Ash eastern lobe (WRAe), in Placentia Bay, North Atlantic Ocean. We use these well-dated isochrons to constrain the local marine radiocarbon reservoir offset (ΔR) and develop a robust Bayesian age–depth model with a ΔR that varies through time. Our results indicate that the marine radiocarbon offset in Placentia Bay was -126±151 years (relative to the Marine20 calibration curve) at the time of Mazama Ash deposition (7572 ± 18 yr BP) and −396 ± 144 years at the time of WRAe deposition (1098–1097 yr BP). Changes in ΔR appear to coincide with inferred shifts in relative influences of the inner Labrador Current and the Slopewater Current in the bay. An important conclusion is that single-offset models of ΔR are easiest to apply and often hard to disprove. However, such models may oversimplify reservoir effects in a core, even over relatively short timescales. Acknowledging potentially varying offsets is critical when ocean circulation and ventilation characteristics have differed over time. The addition of tephra isochrons permits the calculation of semi-independent reservoir corrections and verification of the single ΔR model.

Abstract Glycosylation has been found to be altered in the brains of individuals with Alzheimer’s disease (AD). However, it is unknown which specific glycosylation-related pathways are altered in AD dementia. Using publicly available RNA-seq datasets covering seven brain regions and including 1724 samples, we identified glycosylation-related genes ubiquitously changed in individuals with AD. Several differentially expressed glycosyltransferases found by RNA-seq were confirmed by qPCR in a different set of human medial temporal cortex (MTC) samples (n = 20 AD vs. 20 controls). N-glycan-related changes predicted by expression changes in these glycosyltransferases were confirmed by mass spectrometry (MS)-based N-glycan analysis in the MTC (n = 9 AD vs. 6 controls). About 80% of glycosylation-related genes were differentially expressed in at least one brain region of AD participants (adjusted p-values

Sarcoptes scabiei is the microscopic burrowing mite responsible for sarcoptic mange, which is reported in approximately 150 mammalian species. In Australia, sarcoptic mange affects a number of native and introduced wildlife species, is particularly severe in bare-nosed wombats (Vombatus ursinus) and an emerging issue in koala and quenda. There are a variety of acaricides available for the treatment of sarcoptic mange which are generally effective in eliminating mites from humans and animals in captivity. In wild populations, effective treatment is challenging, and concerns exist regarding safety, efficacy and the potential emergence of acaricide resistance. There are risks where acaricides are used intensively or inadequately, which could adversely affect treatment success rates as well as animal welfare. While reviews on epidemiology, treatment strategies, and pathogenesis of sarcoptic mange in wildlife are available, there is currently no review evaluating the use of specific acaricides in the context of their pharmacokinetic and pharmacodynamic properties, and subsequent likelihood of emerging drug resistance, particularly for Australian wildlife. This review critically evaluates acaricides that have been utilised to treat sarcoptic mange in wildlife, including dosage forms and routes, pharmacokinetics, mode of action and efficacy. We also highlight the reports of resistance of S. scabiei to acaricides, including clinical and in vitro observations.

High-density lipoproteins (HDLs) are key regulators of cellular cholesterol homeostasis but are functionally altered in many chronic diseases. The factors that cause HDL functional loss in chronic disease are not fully understood. It is also unknown what roles antioxidant carotenoids play in protecting HDL against functional loss. The aim of this study was to measure how various disease-associated chemical factors including exposure to (1) Cu2+ ions, (2) hypochlorous acid (HOCL), (3) hydrogen peroxide (H2O2), (4) sialidase, (5) glycosidase, (6) high glucose, (7) high fructose, and (8) acidic pH, and the carotenoid antioxidants (9) lutein and (10) zeaxanthin affect HDL functionality. We hypothesized that some of the modifications would have stronger impacts on HDL particle structure and function than others and that lutein and zeaxanthin would improve HDL function. HDL samples were isolated from generally healthy human plasma and incubated with the corresponding treatments listed above. Cholesterol efflux capacity (CEC), lecithin–cholesterol acyl transferase (LCAT) activity, and paraoxonase-1 (PON1) activity were measured in order to determine changes in HDL functionality. Median HDL particle diameter was increased by acidic pH treatment and reduced by HOCl, high glucose, high fructose, N-glycosidase, and lutein treatments. Acidic pH, oxidation, and fructosylation all reduced HDL CEC, whereas lutein, zeaxanthin, and sialidase treatment improved HDL CEC. LCAT activity was reduced by acidic pH, oxidation, high fructose treatments, and lutein. PON1 activity was reduced by sialidase, glycosidase, H2O2, and fructose and improved by zeaxanthin and lutein treatment. These results show that exposure to oxidizing agents, high fructose, and low pH directly impairs HDL functionality related to cholesterol efflux and particle maturation, whereas deglycosylation impairs HDL antioxidant capacity. On the other hand, the antioxidants lutein and zeaxanthin improve or preserve both HDL cholesterol efflux and antioxidant activity but have no effect on particle maturation.

Acute intoxication with organophosphorus (OP) cholinesterase inhibitors can produce seizures that rapidly progress to life-threatening status epilepticus. Significant research effort has been focused on investigating the involvement of muscarinic acetylcholine receptors (mAChRs) in OP-induced seizure activity. In contrast, there has been far less attention on nicotinic AChRs (nAChRs) in this context. Here, we address this data gap using a combination of in vitro and in vivo models. Pharmacological antagonism and genetic deletion of α4, but not α7, nAChR subunits prevented or significantly attenuated OP-induced electrical spike activity in acute hippocampal slices and seizure activity in mice, indicating that α4 nAChR activation is necessary for neuronal hyperexcitability triggered by acute OP exposures. These findings not only suggest that therapeutic strategies for inhibiting the α4 nAChR subunit warrant further investigation as prophylactic and immediate treatments for acute OP-induced seizures, but also provide mechanistic insight into the role of the nicotinic cholinergic system in seizure generation.

The weak acid sorbic acid is a common preservative used in soft drink beverages to control microbial spoilage. Consumers and industry are increasingly transitioning to low-sugar food formulations, but potential impacts of reduced sugar on sorbic acid efficacy are barely characterised. In this study, we report enhanced sorbic acid resistance of yeast in low-glucose conditions. We had anticipated that low glucose would induce respiratory metabolism, which was shown previously to be targeted by sorbic acid. However, a shift from respiratory to fermentative metabolism upon sorbic acid exposure of Saccharomyces cerevisiae was correlated with relative resistance to sorbic acid in low glucose. Fermentation-negative yeast species did not show the low-glucose resistance phenotype. Phenotypes observed for certain yeast deletion strains suggested roles for glucose signalling and repression pathways in the sorbic acid resistance at low glucose. This low-glucose induced sorbic acid resistance was reversed by supplementing yeast cultures with succinic acid, a metabolic intermediate of respiratory metabolism (and a food-safe additive) that promoted respiration. The results indicate that metabolic adaptation of yeast can promote sorbic acid resistance at low glucose, a consideration for the preservation of foodstuffs as both food producers and consumers move towards a reduced sugar landscape.

Acute organophosphate (OP) intoxication can trigger seizures that progress to status epilepticus (SE), and survivors often develop chronic morbidities, including spontaneous recurrent seizures (SRS). The pathogenic mechanisms underlying OP-induced SRS are unknown, but increased BBB permeability is hypothesized to be involved. Previous studies reported BBB leakage following OP-induced SE, but key information regarding time and regional distribution of BBB impairment during the epileptogenic period is missing. To address this data gap, we characterized the spatiotemporal progression of BBB impairment during the first week post-exposure in a rat model of diisopropylfluorophosphate-induced SE, using MRI and albumin immunohistochemistry. Increased BBB permeability, which was detected at 6 h and persisted up to 7 d post-exposure, was most severe and persistent in the piriform cortex and amygdala, moderate but persistent in the thalamus, and less severe and transient in the hippocampus and somatosensory cortex. The extent of BBB leakage was positively correlated with behavioral seizure severity, with the strongest association identified in the piriform cortex and amygdala. These findings provide evidence of the duration, magnitude and spatial breakdown of the BBB during the epileptogenic period following OP-induced SE and support BBB regulation as a viable therapeutic target for preventing SRS following acute OP intoxication.

Abstract As we contemplate the future of forest landscapes under changing climate conditions and land‐use demands, there is increasing value in studying historic forest conditions and how these landscapes have changed following past disturbances. Historic landscape paintings are a potential source of data on preindustrial forests with highly detailed, full‐color depictions of overstory and understory environments. They display key details about forest community composition, microhabitat features, and structural complexity from a time well before the advent of color photography. Despite these paintings' potential, their scientific applications have been impeded by questions of validity. How truly accurate are the images portrayed in these paintings? How much of an image is an artist's manipulation of a scene to best illustrate an allegory or romanticized view of nature? Following an established assessment model from historical ecology for evaluating resource validity, we demonstrate how scholarship on art history can be integrated with ecological understanding of forest landscapes to follow this model and address these questions of image veracity in 19th century American art. Further, to illustrate the potential use of these historic images in ecological studies, we present in a case study assessing microhabitat features of 10 different paintings. While this paper explores 19th century landscape art broadly, we focus our art historical review in particular on Asher Durand, a prolific and influential artist associated with the so‐called “Hudson River School” in the mid‐1800s. Durand left clear records about his perspectives on accurately depicting nature, and from a review of images and writings of Durand, we find support for the potential use of many of his paintings and sketches in historic forest ecology research. However, we also identify important caveats regarding potential ecological interpretations from these images. More broadly, because 19th century landscape paintings are not always directly transcriptive, and because regional art cultures differed in the 1800s, we cannot within this paper speak about landscape image veracity across all 19th century landscape art. However, in following established methods in historical ecology and integrating tools from art history research, we show that one can identify accurate historic landscape paintings for application in scientific studies.

Abstract Background To evaluate the association between the dietary inflammatory index (DII®) and incident cardiovascular disease (CVD) in Hispanic women from the Women’s Health Initiative (WHI), and to determine if body mass index (BMI) interacted with the DII scores. Methods Secondary analysis of baseline dietary data and long-term CVD outcomes among 3,469 postmenopausal women who self-identified as Hispanic enrolled in WHI. DII scores were calculated from self-administered food frequency questionnaires. The CVD outcomes included coronary heart disease (CHD) and stroke. Stratified Cox regression models were used to assess the relationship between DII scores and CVD in women with and without obesity. Models were adjusted for age, lifestyle risk factors, known risk factors, and neighborhood socioeconomic status. Results The incidence of CHD was 3.4 and 2.8% for stroke after a median follow-up of 12.9 years. None of the DIIs were associated with CVD risk in this sample of Hispanic women. BMI interacted with the DII (p

Objective: Transsphenoidal surgery (TSS) is the first-line treatment for Cushing’s disease. The objectives of the study were to determine remission and recurrence rates after TSS for Cushing’s disease, identify factors that predict these outcomes, and define the threshold for postoperative morning serum cortisol (MSeC) that most accurately predicts sustained remission. Methods: Records were retrospectively reviewed for consecutive adults undergoing TSS for Cushing’s disease at a tertiary centre (1990–2019). Remission was defined as MSeC

IntroductionUne collaboration efficace et soutenue entre cliniciens et professionnels en santé publique peut améliorer la santé des individus et la santé de la population. Le concept de santé publique clinique favorise cette collaboration entre médecine clinique et santé publique et permet de relever des défis complexes en matière de santé.Dans ce commentaire, nous décrivons le concept de santé publique clinique, les types de problèmes complexes qui nécessitent une collaboration entre les professionnels responsables de la santé des individus et ceux responsables de la santé de la population, de même que les obstacles à la santé publique clinique et les applications de la santé publique clinique qui ont émergé pendant la pandémie de COVID-19. ArgumentaireIl existe une complémentarité entre la médecine clinique, qui est axée sur la santé des individus, et la santé publique, qui est axée sur la promotion et la protection de la santé des populations. Une collaboration entre ces deux disciplines est nécessaire pour résoudre les problèmes de santé complexes. Pour ce faire, toutefois, il convient de s’attaquer aux obstacles relatifs aux disciplines, ainsi qu’aux obstacles culturels et financiers qui empêchent une collaboration accrue et durable en la matière. Les succès récents, particulièrement durant la pandémie de COVID-19, constituent un modèle de collaboration de ce type entre cliniciens et praticiens en santé publique. ConclusionUne approche en matière de santé publique qui favorise une collaboration permanente entre cliniciens et professionnels en santé publique pour lutter contre des menaces sanitaires complexes aura plus d’impact que la somme de ses parties.

IntroductionEffective, sustained collaboration between clinical and public health professionals can lead to improved individual and population health. The concept of clinical public health promotes collaboration between clinical medicine and public health to address complex, real­world health challenges.In this commentary, we describe the concept of clinical public health, the types of complex problems that require collaboration between individual and population health, and the barriers towards and applications of clinical public health that have become evident during the COVID­19 pandemic. RationaleThe focus of clinical medicine on the health of individuals and the aims of public health to promote and protect the health of populations are complementary. Interdisciplinary collaborations at both levels of health interventions are needed to address complex health problems. However, there is a need to address the disciplinary, cultural and financial barriers to achieving greater and sustained collaboration. Recent successes, particularly during the COVID­19 pandemic, provide a model for such collaboration between clinicians and public health practitioners ConclusionA public health approach that fosters ongoing collaboration between clinical and public health professionals in the face of complex health threats will have greater impact than the sum of the parts.

Abstract Multiple preclinical studies have shown improved outcomes when radiation therapy is combined with immune modulating antibodies. However, to date, many of these promising results have failed to translate to successful clinical studies. This led us to explore additional checkpoint and co-stimulatory pathways that may be regulated by radiation therapy. Here, we demonstrate that radiation increases the expression of inducible T cell co-stimulator (ICOS) on both CD4 and CD8 T cells in the blood following treatment. Moreover, when we combined a novel ICOS agonist antibody with radiation we observed durable cures across multiple tumor models and mouse strains. Depletion studies revealed that CD8 T cells were ultimately required for treatment efficacy, but CD4 T cells and NK cells also partially contributed to tumor control. Phenotypic analysis showed that the combination therapy diminished the increased infiltration of regulatory T cells into the tumor that typically occurs following radiation alone. Finally, we demonstrate in a poorly immunogenic pancreatic tumor model which is resistant to combined radiation and anti-PD1 checkpoint blockade that the addition of this novel ICOS agonist antibody to the treatment regimen results in tumor control. These findings identify ICOS as part of a T cell pathway that is modulated by radiation and targeting this pathway with a novel ICOS antibody results in durable tumor control in preclinical models.

Summary: The glycine receptor alpha 2 (GlyRα2) is a ligand-gated ion channel which upon activation induces a chloride conductance. Here, we investigated the role of GlyRα2 in dopamine-stimulated striatal cell activity and behavior. We show that depletion of GlyRα2 enhances dopamine-induced increases in the activity of putative dopamine D1 receptor-expressing striatal projection neurons, but does not alter midbrain dopamine neuron activity. We next show that the locomotor response to d-amphetamine is enhanced in GlyRα2 knockout animals, and that this increase correlates with c-fos expression in the dorsal striatum. 3-D modeling revealed an increase in the neuronal ensemble size in the striatum in response to D-amphetamine in GlyRα2 KO mice. Finally, we show enhanced appetitive conditioning in GlyRα2 KO animals that is likely due to increased motivation, but not changes in associative learning or hedonic response. Taken together, we show that GlyRα2 is an important regulator of dopamine-stimulated striatal activity and function.

Objectives This rapid review aimed to assess and collate intravenous-to-oral switch (IVOS) criteria from the literature to achieve safe and effective antimicrobial IVOS in the hospital inpatient adult population.Design The rapid review follows the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement.Data sources OVID Embase and Medline databases.Eligibility criteria Articles of adult populations published globally between 2017 and 2021 were included.Data extraction and synthesis An Excel spreadsheet was designed with specific column headings. IVOS criteria from UK hospital IVOS policies informed the framework synthesis.Results IVOS criteria from 45/164 (27%) local IVOS policies were categorised into a five-section framework: (1) timing of IV antimicrobial review, (2) clinical signs and symptoms, (3) infection markers, (4) enteral route and (5) infection exclusions. The literature search identified 477 papers, of which 16 were included. The most common timing for review was 48–72 hours from initiation of intravenous antimicrobial (n=5, 30%). Nine studies (56%) stated clinical signs and symptoms must be improving. Temperature was the most frequently mentioned infection marker (n=14, 88%). Endocarditis had the highest mention as an infection exclusion (n=12, 75%). Overall, 33 IVOS criteria were identified to go forward into the Delphi process.Conclusion Through the rapid review, 33 IVOS criteria were collated and presented within five distinct and comprehensive sections. The literature highlighted the possibility of reviewing IVOS before 48–72 hours and of presenting heart rate, blood pressure and respiratory rate as a combination early warning score criterion. The criteria identified can serve as a starting point of IVOS criteria review for any institution globally, as no country or region limits were applied. Further research is required to achieve consensus on IVOS criteria from healthcare professionals that manage patients with infections.PROSPERO registration number CRD42022320343.

The phenology of fungal fruiting has changed in the UK over the last 70 years, but whether the associated mycophagous insects are able to exploit 'out of season' fruit bodies is unknown. This study focused on whether fungal baits can be used as a proxy to examine changes in fungal fruiting on insect communities. Using Agaricus bisporus as a bait, mushrooms were placed into two separate woodlands monthly from November 2020 to July 2021. Megaselia rufipes (Phoridae) and Bradysia spp. (Sciaridae) were reared from both wild fungi and fungal baits at different times, making them appropriate species to consider for possible host tracking. Various factors affect an insect's ability to track a fungal host, these include host preference, season, period of fungal fruiting and age of mushroom. Increased fruiting of macrofungi in the future may benefit generalist mycophagous insects, by providing enhanced temporal and spatial resource opportunities. Using fungal baits as a proxy for the effects of climate change on fungal fruiting should be beneficial in uncovering the host preferences of mycophagous insects and may potentially indicate whether mycophagous insects can track fungal hosts across seasons.

Due to the remote location of many volcanoes, there is substantial uncertainty about the timing, amount and vertical distribution of volcanic ash released when they erupt. One approach to determine these properties is to combine prior estimates with satellite retrievals and simulations from atmospheric dispersion models to create posterior emission estimates, constrained by both the observations and the prior estimates, using a technique known as source inversion. However, the results are dependent not only on the accuracy of the prior assumptions, the atmospheric dispersion model and the observations used, but also on the accuracy of the meteorological data used in the dispersion simulations. In this study, we advance the source inversion approach by using an ensemble of meteorological data from the Met Office Global and Regional Ensemble Prediction System to represent the uncertainty in the meteorological data and apply it to the 2019 eruption of Raikoke. Retrievals from the Himawari-8 satellite are combined with NAME dispersion model simulations to create posterior emission estimates. The use of ensemble meteorology provides confidence in the posterior emission estimates and associated dispersion simulations that are used to produce ash forecasts. Prior mean estimates of fine volcanic ash emissions for the Raikoke eruption based on plume height observations are more than 15 times higher than any of the mean posterior ensemble estimates. In addition, the posterior estimates have a different vertical distribution, with 27 %–44 % of ash being emitted into the stratosphere compared to 8 % in the mean prior estimate. This has consequences for the long-range transport of ash, as deposition to the surface from this region of the atmosphere happens over long timescales. The posterior ensemble spread represents uncertainty in the inversion estimate of the ash emissions. For the first 48 h following the eruption, the prior ash column loadings lie outside an estimate of the error associated with a set of independent satellite retrievals, whereas the posterior ensemble column loadings do not. Applying a risk-based methodology to an ensemble of dispersion simulations using the posterior emissions shows that the area deemed to be of the highest risk to aviation, based on the fraction of ensemble members exceeding predefined ash concentration thresholds, is reduced by 49 %. This is compared to estimates using an ensemble of dispersion simulations using the prior emissions with ensemble meteorology. If source inversion had been used following the eruption of Raikoke, it would have had the potential to significantly reduce disruptions to aviation operations. The posterior inversion emission estimates are also sensitive to uncertainty in other eruption source parameters and internal dispersion model parameters. Extending the ensemble inversion methodology to account for uncertainty in these parameters would give a more complete picture of the emission uncertainty, further increasing confidence in these estimates.

Volcanic ash advisories are produced by specialised forecasters who combine several sources of observational data and volcanic ash dispersion model outputs based on their subjective expertise. These advisories are used by the aviation industry to make decisions about where it is safe to fly. However, both observations and dispersion model simulations are subject to various sources of uncertainties that are not represented in operational forecasts. Quantification and communication of these uncertainties are fundamental for making more informed decisions. Here, we develop a data assimilation method that combines satellite retrievals and volcanic ash transport and dispersion model (VATDM) output, considering uncertainties in both data sources. The methodology is applied to a case study of the 2019 Raikoke eruption. To represent uncertainty in the VATDM output, 1000 simulations are performed by simultaneously perturbing the eruption source parameters, meteorology, and internal model parameters (known as the prior ensemble). The ensemble members are filtered, based on their level of agreement with the ash column loading, and their uncertainty, of the Himawari–8 satellite retrievals, to produce a constrained posterior ensemble. For the Raikoke eruption, filtering the ensemble skews the values of mass eruption rate towards the lower values within the wider parameters ranges initially used in the prior ensemble (mean reduces from 1 to 0.1 Tg h−1). Furthermore, including satellite observations from subsequent times increasingly constrains the posterior ensemble. These results suggest that the prior ensemble leads to an overestimate of both the magnitude and uncertainty in ash column loadings. Based on the prior ensemble, flight operations would have been severely disrupted over the Pacific Ocean. Using the constrained posterior ensemble, the regions where the risk is overestimated are reduced, potentially resulting in fewer flight disruptions. The data assimilation methodology developed in this paper is easily generalisable to other short duration eruptions and to other VATDMs and retrievals of ash from other satellites.