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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.

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.

On stage, and in real life, timing is critical for success. Theranostic cancer care epitomizes the central role of timing in the evolution of efficacious molecular targeted radioligand therapy and its incorporation into routine clinical practice of oncology. Nuclear medicine has returned to its therapeutic roots, having been founded as a medical specialty, over three-quarters of a century ago, with radioiodine therapy of thyroid cancer. The very recent oncologist acceptance of 68Ga/177Lu/225Ac-PSMA effectiveness in treating prostate cancer has re-established the role of the physician in nuclear medicine. This article addresses various important issues in respect of timing related to this resurgence. Training of the required new workforce in technical -omics expertise and physicianly virtues is an urgent priority. Precision in radioligand therapy requires definition of individual radiation absorbed dose (Gy) to tumor and to critical normal organs, preferably prospectively. It is time to abandon one-size-fits-all administration of fixed activities (GBq) in arbitrary cycle intervals and duration. The time has also come to design combination sequenced theranostic-immuno-chemotherapeutic approaches to metastatic cancer to address unmet needs, particularly in pancreatic carcinoma; exploiting the potential of new fibroblast activation protein inhibitor radioligands targeting the tumor microenvironment. Public perception of all things "nuclear," including nuclear medicine, has recently recovered from the general opprobrium and radiophobia of the last half-century. Nuclear is the new green. At last, there have arisen propitious circumstances for the future development of theranostics: The timing is right, now. [ABSTRACT FROM AUTHOR]

Patients with relapsed or refractory metastatic cancer unresponsive to standard therapies have motivated nuclear physicians to develop innovative radioligands, precisely targeted to tumor molecular receptors, for effective treatment of specific advanced malignancies. Individual practitioners in departments of nuclear medicine across the world have performed first-in-human studies on compassionate patient usage N-of-One protocols. These physician-sponsored studies then evolved into early-phase clinical trials and obtained real-world data to demonstrate real-world evidence of effectiveness in prolonging survival and enhancing quality of life of many so-called "End-Stage" cancer patients. Virtually all the therapeutic radiopharmaceuticals in current clinical oncology have been discovered and developed into effective specific treatments of targetable cancers by individual doctors in the course of their hospital practice. Pharma industry was not involved until many years later when performance of mandated Phase 3 randomized controlled trials became necessary to achieve regulatory agency approval. This article traces the history of several novel theranostic agents developed from compassionate N-of-One studies by hospital physicians over the past 36 years. It acknowledges the collegiality and collaboration of individual nuclear medicine specialists, worldwide, in pioneering effective humane therapy of particular advanced cancers unresponsive to conventional treatments. [ABSTRACT FROM AUTHOR]

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.

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.

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.

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.

Introduction: Localisation methods for surgical excision of impalpable breast lesions have advanced in recent years, with increasing utilization of new wire-free technologies. The Hologic LOCalizer™ radiofrequency identification (RFID) tag is one such device; however, as is the case when new technologies are first introduced, little is known about clinical experiences, potential complications, and learning used to overcome perioperative challenges when changing from guidewires to RFID tags. This study reports shared learning experiences of clinicians using the LOCalizer™ as part of the national iBRA-NET localisation study., Methods: This mixed-methods study captured shared-learning themes relating to LOCalizer™ usage as part of a multicentre prospective registry study, which collected data on each LOCalizer™ placement. Prospective, anonymized clinical and demographic data were collected and managed using a Research Electronic Data Capture (REDCap) database. Shared learning was captured prospectively as part of the registry study between January 2021 and July 2022, combined with a virtual qualitative webinar-style focus group. Learning events were then coded, grouped by theme, and suggestions for practice were produced., Results: Twenty-four UK breast units submitted data on 1188 patient records pertaining to RFID-guided localisation between January 2021 and July 2022, of which 59 (5.0%) included a shared-learning event. The virtual webinar was attended by 108 healthcare professionals, including oncoplastic breast surgeons and breast radiologists. Shared-learning themes were categorized into preoperative, intraoperative, and postoperative events., Conclusions: By sharing learning outcomes associated with localisation techniques in this paper, the aim is to shorten the learning curve and potential for adverse events for users new to the LOCalizer™ technique., (Copyright © 2024. Published by Elsevier Ltd.)

Objective: To assess if ventricular size before shunting is correlated with neurodevelopmental outcomes in children with postnatal myelomeningocele closure., Study Design: This retrospective review included children with postnatal surgical closure of myelomeningocele and neuropsychological testing between 2018 and 2023 at the University of California, San Francisco. Frontal-occipital horn ratio (FOHR) was measured immediately before shunt placement or on the first study that reported ventricular stability for nonshunted patients. The primary outcome was full scale IQ (FSIQ) on the Weschler Intelligence Scale. Secondary outcomes included indices of the Weschler scale, the Global Executive Composite from the Behavior Rating Inventory of Executive Function, and the general adaptive composite from the Adaptive Behavior Assessment Scale. Univariable and multivariable regression was used to determine if FOHR was correlated with neuropsychological scores., Results: Forty patients met the inclusion criteria; 26 (65%) had shunted hydrocephalus. Age at neuropsychological testing was 10.9 ± 0.6 years. FOHR was greater in the shunted group (0.64 vs 0.51; P < .001). There were no differences in neuropsychological results between shunted and nonshunted groups. On univariable analysis, greater FOHR was associated with lower FSIQ (P = .025) and lower Visual Spatial Index scores (P = .013), which remained significant on multivariable analysis after adjusting for gestational age at birth, lesion level, shunt status, and shunt revision status (P = .049 and P = .006, respectively). Separate analyses by shunt status revealed that these effects were driven by the shunted group., Conclusions: Greater FOHR before shunting was correlated with lower FSIQ and the Visual Spatial Index scores on the Weschler Intelligence Scales. Larger studies are needed to explore further the relationship between ventricle size, hydrocephalus, and neurodevelopmental outcomes., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest. Funding: There was no funding for this study., (Copyright © 2024 Elsevier Inc. All rights reserved.)

There is an unmet need to recognize and address the psychosocial and spiritual support of the rapidly growing population of cancer survivors living with advanced metastatic disease which is essentially incurable. Palliative chemotherapy may do more harm than good. The role of the physician in the provision of a supportive, compassionate relationship of mutual trust is critical in the exploration of spirituality and the meaning of life for each individual patient. The objective must be to enhance quality of life rather than prolong it at any cost. Nuclear physicians are now equipped to offer effective control of advanced metastatic cancer of prostate and neuroendocrine neoplasms without clinically evident toxicity. They also now have the potential to practice phronesis, and in so doing, to significantly ameliorate the quality of life of patients afflicted with these specific advanced cancers. During the time of prolonged symptom-free survival, these patients may be encouraged to find life's meaning and a peaceful acceptance of their inevitable demise.

Introduction: Radiotherapy plays a key role in the multidisciplinary management of oesophageal cancers across neoadjuvant, definitive and palliative settings. Improved precision in radiotherapy planning and delivery techniques have allowed treating disease with tighter margins reducing toxicity. In this study, we examine the appropriateness of current practice in defining the planning target volume (PTV)., Methods: This is a single institutional retrospective study of patients who received radiotherapy for oesophageal cancers using volumetric modulated arc therapy (VMAT) during 2020. All cone-beam computerised tomography (CBCT) scans were reviewed to assess whether PTV expansions appropriately accounted for tumour motion and interfractional variation., Results: Of the 27 patients, 2 (7%), 5 (19%) and 20 (74%) had cervical, thoracic and distal/gastro-oesophageal junction (GOJ) disease, respectively. 16 (59%) had adenocarcinoma and 9 (33%) had squamous cell carcinoma. 9 of 20 distal/GOJ patients were planned and treated according to the institutional stomach filling protocol. 521/528 (98.7%) CBCTs demonstrated adequate target coverage. Cervical, thoracic and GOJ regions demonstrated adequate target coverage in 57/58, 96/97 and 368/373 CBCTs with median PTV expansions of 5, 7 and 7 mm, respectively. In four patients with GOJ disease, CBCT review identified five episodes where the target volume was insufficiently covered during the treatment course., Conclusion: In this single institutional retrospective study, for the vast majority of patients, our institutional practice of defining PTV margins achieved satisfactory target treatment. The interfractional variations observed in patients with GOJ tumours due to target motion and variable gastric volume, highlights the role of further refinements to motion management techniques in this cohort., (© 2024 Royal Australian and New Zealand College of Radiologists.)

Introduction: The established link between DNA methylation and pathophysiology of dementia, along with its potential role as a molecular mediator of lifestyle and environmental influences, positions blood-derived DNA methylation as a promising tool for early dementia risk detection., Methods: In conjunction with an extensive array of machine learning techniques, we employed whole blood genome-wide DNA methylation data as a surrogate for 14 modifiable and non-modifiable factors in the assessment of dementia risk in independent dementia cohorts., Results: We established a multivariate methylation risk score (MMRS) for identifying mild cognitive impairment cross-sectionally, independent of age and sex (P = 2.0 × 10 -3 ). This score significantly predicted the prospective development of cognitive impairments in independent studies of Alzheimer's disease (hazard ratio for Rey's Auditory Verbal Learning Test (RAVLT)-Learning = 2.47) and Parkinson's disease (hazard ratio for MCI/dementia   = 2.59)., Discussion: Our work shows the potential of employing blood-derived DNA methylation data in the assessment of dementia risk., Highlights: We used whole blood DNA methylation as a surrogate for 14 dementia risk factors. Created a multivariate methylation risk score for predicting cognitive impairment. Emphasized the role of machine learning and omics data in predicting dementia. The score predicts cognitive impairment development at the population level., (© 2024 The Author(s). Alzheimer's & Dementia published by Wiley Periodicals LLC on behalf of Alzheimer's Association.)

Background: Patient satisfaction has been positively associated with adherence which is expected to impact outcomes. Although vital for successful implementation of biosimilar medicines, little is known about the patient perspective of transition., Aim: The aim of this study was to investigate clinical outcomes and patient experience of transitioning between reference adalimumab and a biosimilar (SB5)., Method: iBaSS is a phase IV single-centre, prospective, randomised, single-blind, cross-over study in adult subjects with Crohn's disease. Participants, stable on adalimumab before consent, received 24 weeks of treatment with both reference adalimumab and SB5. The primary outcome was the proportion of patients maintaining baseline clinical status throughout each treatment period, with patients' perspective of disease control and treatment satisfaction assessed as secondary outcomes., Results: A total of 112 participants, representative of the heterogeneous patient populations encountered in routine clinical practice, were enrolled. A similar proportion of participants maintained baseline clinical status through each treatment period: 81.8% with reference adalimumab and 79.5% with SB5. Patient reported outcomes (IBD-Control questionnaire (SB5: 15.5; reference adalimumab 15) and TSQM), adverse events and therapeutic drug monitoring remained consistent through both treatment periods, although a higher median injection pain VAS score was noted with SB5 (53/100 versus 6/100 with reference adalimumab). The number of switches undertaken in the study did not impact serum drug concentration or immunogenicity., Conclusion: This study, mimicking real world adalimumab transition, demonstrates that patients undertaking brand transition can be expected to have consistent clinical and satisfaction outcomes., Clinical Trial Registered With Eudract: Number 2018-004967-30., (© 2024. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

The carcinogenicity potency categorization approach (CPCA) derived and harmonized by Health Authorities was a significant milestone, as it defined molecular properties that allowed for the rapid evaluation of the chemical structures of N-nitrosamine drug substance related impurities (NDSRIs) and the assignment of associated lifetime Acceptable Intake (AI) limits to inform on appropriate impurity control strategies in certain drug products. Nonetheless, it is important to continue to refine and improve on the CPCA based upon data-derived evidence. Herein, we focus on the default CPCA AI for NDSRIs, which is largely based on the small molecule N-nitrosamines (NAs). Considering the carcinogenic potency of NAs with a molecular weight >200 Da (NDSRIs molecular weight is typically 200-600 Da), we propose that in the absence of any compound specific data, the lowest lifetime Acceptable Intake for NAs, such as NDSRIs, should be 10x less (i.e., 150 ng/day) than the ICH M7 Threshold of Toxicological Concern of 1500 ng/day, (even for NDSRIs that are considered CPCA Category 1 and 2) which would conservatively result in a theoretical cancer risk of <1 in 100,000., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests. Joel Bercu reports a relationship with Gilead that includes: employment and equity or stocks. Olivier Dirat reports a relationship with Pfizer Global Product Development that includes: employment and equity or stocks. Krista Dobo reports a relationship with Pfizer Research and Development that includes: employment and equity or stocks. Robert Jolly reports a relationship with Eli Lilly and Company that includes: employment and equity or stocks. Michelle Kenyon reports a relationship with Pfizer Research and Development that includes: employment and equity or stocks. James Harvey reports a relationship with GSK that includes: employment and equity or stocks.Raphael Nudelman reports a relationship with Teva Pharmaceutical Industries Ltd that includes: employment and equity or stocks. Graham Smith reports a relationship with AstraZeneca that includes: employment and equity or stocks. Alejandra Trejo-Martin reports a relationship with Gilead that includes: employment and equity or stocks. Michael Urquhart reports a relationship with GSK that includes: employment and equity or stocks., (Copyright © 2024. Published by Elsevier Inc.)

Background: Alternative education provision such as Pupil Referral Units support young people who have been excluded from mainstream school settings and often from disadvantaged backgrounds. However, there is limited research to date exploring educators' perceptions of the complex needs of young people in PRUs, and the extent to which PRUs as currently configured can meet such needs., Methods: Between March 2019 and October 2020 twenty-two participants holding various educational roles from five different Pupil Referral Units across London and Southeast England were interviewed. The interviews aimed to explore the participants' experiences of working with students in PRU's and examine some of the challenges that they might encounter. Semi-structured interviews were analysed using Reflexive thematic analysis., Results: The three identified themes and their sub-themes highlighted the complex needs of these young people and identified significant barriers to effective service provision. The first theme 'Complexities of PRU population' highlighted the challenges that young people in PRUs face and perceived systemic short falls in addressing such complexity. The second theme 'Challenges of the PRU environment' highlights the frustrations that educators experience when it comes to providing adequate support to young people in PRU's, the absence of agency support, and the uncertainty that these educational settings can bring. The third theme 'Peer Group Influences' highlights the impact of peer groups from beyond the classroom on engagement within the classroom., Conclusions: Despite the clear complex needs of young people in PRUs, staff reported feeling ill-equipped to support these individuals and lacked access to effective inter-agency support. Participants reported that pupils' mental health difficulties were exacerbated by exclusion and reintegration practices, an over-zealous focus on educational outcomes and the impact of gang influences on their school lives. Implications include more specific mental health training for staff working in PRU's, improved inter-agency working and the incorporation of trauma-informed approaches in educational practice., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Kaip et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Regulation of neutrophil activation is critical for disease control. Neutrophil extracellular traps (NETs), which are web-like structures composed of DNA and neutrophil-derived proteins, are formed following pro-inflammatory signals; however, if this process is uncontrolled, NETs contribute to disease pathogenesis, exacerbating inflammation and host tissue damage 1,2 . Here we show that myeloid inhibitory C-type lectin-like (MICL), an inhibitory C-type lectin receptor, directly recognizes DNA in NETs; this interaction is vital to regulate neutrophil activation. Loss or inhibition of MICL functionality leads to uncontrolled NET formation through the ROS-PAD4 pathway and the development of an auto-inflammatory feedback loop. We show that in the context of rheumatoid arthritis, such dysregulation leads to exacerbated pathology in both mouse models and in human patients, where autoantibodies to MICL inhibit key functions of this receptor. Of note, we also detect similarly inhibitory anti-MICL autoantibodies in patients with other diseases linked to aberrant NET formation, including lupus and severe COVID-19. By contrast, dysregulation of NET release is protective during systemic infection with the fungal pathogen Aspergillus fumigatus. Together, we show that the recognition of NETs by MICL represents a fundamental autoregulatory pathway that controls neutrophil activity and NET formation., (© 2024. The Author(s).)

Cardiac masses are rare and of the neoplastic group, myxomas are the most common. An elderly male with a background of multiple myeloma and previous autologous stem cell transplant presented with dyspnea and chest heaviness with a subsequent cardiac mass found. Multimodal imaging, including three-dimensional (3D) echocardiography and cardiac magnetic resonance (CMR) imaging, was utilized to guide the diagnostic process, particularly given the differential of a cardiac plasmacytoma in the setting of multiple myeloma. CMR was used to identify characteristic features of the mass and 3D echocardiography highlighted the anatomical relationships of the mass in relation to surrounding structures to complement surgical planning. The different imaging approaches and clinical decision-making were implemented to aid in definitive surgical management., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Lal et al.)

Increasing evidence suggests that alternative splicing plays an important role in Alzheimer's disease (AD) pathology. We used long-read sequencing in combination with a novel bioinformatics tool (FICLE) to profile transcript diversity in the entorhinal cortex of female transgenic (TG) mice harboring a mutant form of human tau. Our analyses revealed hundreds of novel isoforms and identified differentially expressed transcripts - including specific isoforms of Apoe, App, Cd33, Clu, Fyn and Trem2 - associated with the development of tau pathology in TG mice. Subsequent profiling of the human cortex from AD individuals and controls revealed similar patterns of transcript diversity, including the upregulation of the dominant TREM2 isoform in AD paralleling the increased expression of the homologous transcript in TG mice. Our results highlight the importance of differential transcript usage, even in the absence of gene-level expression alterations, as a mechanism underpinning gene regulation in the development of AD neuropathology., (© 2024. The Author(s).)

Background: Patients with large vessel occlusion (LVO) stroke presenting with milder baseline clinical severity are common and require endovascular thrombectomy. However, such patients are difficult to recognize using pre-hospital severity-based triage tools and therefore are likely to require a secondary inter-hospital transfer if transported to a non-thrombectomy center. Given the potential for milder severity to represent better underlying cerebrovascular collateral circulation, it is unknown whether transfer delays are still associated with poorer post-stroke outcomes in this patient group., Aims: We primarily aimed to examine whether the harmful effect of inter-hospital transfer delay for thrombectomy was different for LVO patients with mild or severe deficits. Secondarily, we also investigated whether imaging markers of collateral circulation were different between severity groups., Methods: Registry data from two large Australian thrombectomy centers were used to identify all directly presenting and secondarily transferred LVO patients undergoing thrombectomy, divided into those with lower (NIHSS < 10) and higher (NIHSS ⩾ 10) baseline deficits. The primary outcome was the functional independence or return to baseline defined as modified Rankin Scale 0-2 or baseline at 90 days. Patients with complete baseline CT-perfusion data were analyzed for imaging markers of collateral circulation by baseline severity group., Results: A total of 1210 LVO patients undergoing thrombectomy were included, of which 273 (22.6%) had lower baseline severity. Despite similar thrombolysis and recanalization rates, transferred patients had lower odds of achieving the primary outcome compared to the primary presentation to a thrombectomy center, where baseline severity was higher (adjusted odds ratio (aOR) 0.759 (95% CI 0.576-0.999)), but not when severity was lower (aOR 1.357 (95% CI 0.764-2.409), p-interaction = 0.122). In the imaging analysis of 436 patients, those with milder severity showed smaller median ischemic core volumes (12.6 (IQR 0.0-17.9) vs 27.5 (IQR 6.5-37.1) mL, p < 0.001)), higher median perfusion mismatch ratio (10.8 (IQR 4.8-54.5) vs 6.6 (IQR 3.5-16.5), p < 0.001), and lower median hypoperfusion intensity ratio (0.25 (IQR 0.18-0.38) vs 0.40 (IQR 0.22-0.57), p < 0.001)., Discussion: Patients receiving secondary inter-hospital transfer for thrombectomy had poorer outcomes compared to those presenting directly to a thrombectomy center if baseline deficits were severe, but this difference was not observed when baseline deficits were milder. This result may potentially be due to our secondary findings of significantly improved collateral circulation markers in lower-severity LVO patients. As such, failure of pre-hospital screening tools to detect lower-severity LVO patients for pre-hospital bypass to a thrombectomy center may not necessarily deleteriously affect outcome., Data Access Statement: Anonymized data not published within this article will be made available on request from any qualified investigator., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

The expansion of the world's merchant fleet poses a great threat to the ocean's biodiversity. Collisions between ships and marine megafauna can have population-level consequences for vulnerable species. The Endangered whale shark (Rhincodon typus) shares a circumglobal distribution with this expanding fleet and tracking of movement pathways has shown that large vessel collisions pose a major threat to the species. However, it is not yet known whether they are also at risk within aggregation sites, where up to 400 individuals can gather to feed on seasonal bursts of planktonic productivity. These "constellation" sites are of significant ecological, socio-economic and cultural value. Here, through expert elicitation, we gathered information from most known constellation sites for this species across the world (>50 constellations and >13,000 individual whale sharks). We defined the spatial boundaries of these sites and their overlap with shipping traffic. Sites were then ranked based on relative levels of potential collision danger posed to whale sharks in the area. Our results showed that researchers and resource managers may underestimate the threat posed by large ship collisions due to a lack of direct evidence, such as injuries or witness accounts, which are available for other, sub-lethal threat categories. We found that constellations in the Arabian Sea and adjacent waters, the Gulf of Mexico, the Gulf of California, and Southeast and East Asia, had the greatest level of collision threat. We also identified 39 sites where peaks in shipping activity coincided with peak seasonal occurrences of whale sharks, sometimes across several months. Simulated collision mitigation options estimated potentially minimal impact to industry, as most whale shark core habitat areas were small. Given the threat posed by vessel collisions, a coordinated, multi-national approach to mitigation is needed within priority whale shark habitats to ensure collision protection for the species., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Accumulation of hyper-phosphorylated tau and amyloid beta (Aβ) are key pathological hallmarks of Alzheimer's disease (AD). Increasing evidence indicates that in the early pre-clinical stages of AD, phosphorylation and build-up of tau drives impairments in hippocampal excitatory synaptic function, which ultimately leads to cognitive deficits. Consequently, limiting tau-related synaptic abnormalities may have beneficial effects in AD. There is now significant evidence that the hippocampus is an important brain target for the endocrine hormone leptin and that leptin has pro-cognitive properties, as activation of synaptic leptin receptors markedly influences higher cognitive processes including learning and memory. Clinical studies have identified a link between the circulating leptin levels and the risk of AD, such that AD risk is elevated when leptin levels fall outwith the physiological range. This has fuelled interest in targeting the leptin system therapeutically. Accumulating evidence supports this possibility, as numerous studies have shown that leptin has protective effects in a variety of models of AD. Recent findings have demonstrated that leptin has beneficial effects in the preclinical stages of AD, as leptin prevents the early synaptic impairments driven by tau protein and amyloid β. Here we review recent findings that implicate the leptin system as a potential novel therapeutic target in AD.

Purpose: There has been a UK national directive to ensure that patients are offered reconstructive surgical options. We aimed to assess any change in oncoplastic practice over a 10-year period., Methods: The surgical management of 7019 breast cancers was retrospectively assessed at Nightingale Breast Centre, Manchester University UK, from 2010 to 2019. The procedures were categorised into breast conservative surgery (BCS) and mastectomy ± immediate reconstruction. The data were analysed using inclusion and exclusion criteria., Results: The overall rates of BCS and mastectomy were 60.1% and 39.9% respectively. No statistically significant change in the overall rates of BCS or mastectomy was observed over the last decade (p = 0.08). The rate of simple wide local excision (WLE) decreased from 98.7% to 89.3% (p < 0.001), whilst the rate of therapeutic mammoplasty (TM) increased from 1.3% to 8% (p < 0.01). The rate of chest wall perforator flaps (CWPF) changed from zero to account for 2.7% of all BCS by 2019. The overall rate of immediate breast reconstruction (IBR) did not significantly change over the study period, but it consistently remained above the national average of 27%. The rate of implant-based IBR increased from 61.3% to 76.5% (p = 0.012), whilst the rate of Latissimus Dorsi (LD) reconstruction decreased from 26.7% to 5.1% (p < 0.05). Additionally, the rate of nipple-sparing mastectomy significantly increased from 5.2% to 24%., Conclusion: No significant changes in the overall rates of BCS was observed, the rates of advanced breast conservation techniques, nipple-sparing mastectomy, and implant-based IBR all have increased, whilst the use of LD reconstruction decreased., (© 2024. Crown.)

Background: Transplant surgery has historically been a less desirable fellowship among general surgery graduates. Limited work has been done to understand factors associated with residents' interest in transplantation. Using a multi-institutional cohort, we examined how the resident experience on transplant surgery may influence their decision to pursue transplant fellowship., Methods: Individual demographics, program characteristics, and transplant-specific case logs were collected for graduates from 2010 to 2020 at 20 general surgery residency programs within the US Resident OPerative Experience (ROPE) Consortium. Residents who pursued transplant surgery fellowship were compared to those who went directly into practice or pursued a non-transplant fellowship., Results: Among 1342 general surgery graduates, 52 (3.9%) pursued abdominal transplant fellowship. These residents completed more transplant (22 vs. 9), liver (14 vs. 9), pancreas (15 vs. 11), and vascular access operations (38 vs. 30) compared to residents who did not pursue transplant fellowship (all p < 0.05). Multivariable logistic regression found that residents underrepresented in medicine were three times more likely (95% CI 1.54-6.58, p < 0.01) and residents at a program co-located with a transplant fellowship six times more likely (95% CI 1.95-18.18, p < 0.01) to pursue transplant fellowship. Additionally, a resident's increasing total transplant operative volume was associated with an increased likelihood of pursuing a transplant fellowship (OR = 1.12, 95% CI 1.09-1.14, p < 0.01)., Conclusion: The findings from this multi-institutional study demonstrate that increased exposure to transplant operations and interaction within a transplant training program is associated with a resident's pursuit of transplant surgery fellowship. Efforts to increase operative exposure, case participation, and mentorship may optimize the resident experience and promote the transplant surgery pipeline., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The embryonic environment is critical in shaping developmental trajectories and consequently post-natal phenotypes. Exposure to elevated stress hormones during this developmental stage is known to alter a variety of post-natal phenotypic traits, and it has been suggested that pre-natal stress can have long term effects on the circadian rhythm of glucocorticoid hormone production. Despite the importance of the circadian system, the potential impact of developmental glucocorticoid exposure on circadian clock genes, has not yet been fully explored. Here, we showed that pre-natal exposure to corticosterone (CORT, a key glucocorticoid) resulted in a significant upregulation of two key hypothalamic circadian clock genes during the embryonic period in the Japanese quail (Coturnix japonica). Altered expression was still present 10 days into post-natal life for both genes, but then disappeared by post-natal day 28. At post-natal day 28, however, diel rhythms of eating and resting were influenced by exposure to pre-natal CORT. Males exposed to pre-natal CORT featured an earlier acrophase, alongside spending a higher proportion of time feeding. Females exposed to pre-natal CORT featured a less pronounced shift in acrophase and spent less time eating. Both males and females exposed to pre-natal CORT spent less time inactive during the day. Pre-natal CORT males appeared to feature a delay in peak activity levels. Our novel data suggest that these circadian clock genes and aspects of diurnal behaviours are highly susceptible to glucocorticoid disruption during embryonic development, and these effects are persistent across developmental stages, at least into early post-natal life., Competing Interests: Declaration of competing interest There are no conflicts of interest or competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Spirometry is a point-of-care lung function test that helps support the diagnosis and monitoring of chronic lung disease. The quality and interpretation accuracy of spirometry is variable in primary care. This study aims to evaluate whether artificial intelligence (AI) decision support software improves the performance of primary care clinicians in the interpretation of spirometry, against reference standard (expert interpretation)., Methods and Analysis: A parallel, two-group, statistician-blinded, randomised controlled trial of primary care clinicians in the UK, who refer for, or interpret, spirometry. People with specialist training in respiratory medicine to consultant level were excluded. A minimum target of 228 primary care clinician participants will be randomised with a 1:1 allocation to assess fifty de-identified, real-world patient spirometry sessions through an online platform either with (intervention group) or without (control group) AI decision support software report. Outcomes will cover primary care clinicians' spirometry interpretation performance including measures of technical quality assessment, spirometry pattern recognition and diagnostic prediction, compared with reference standard. Clinicians' self-rated confidence in spirometry interpretation will also be evaluated. The primary outcome is the proportion of the 50 spirometry sessions where the participant's preferred diagnosis matches the reference diagnosis. Unpaired t-tests and analysis of covariance will be used to estimate the difference in primary outcome between intervention and control groups., Ethics and Dissemination: This study has been reviewed and given favourable opinion by Health Research Authority Wales (reference: 22/HRA/5023). Results will be submitted for publication in peer-reviewed journals, presented at relevant national and international conferences, disseminated through social media, patient and public routes and directly shared with stakeholders., Trial Registration Number: NCT05933694., Competing Interests: Competing interests: WM is Honorary President of the Association for Respiratory Technology and Physiology (ARTP). MT is CEO of ArtiQ—a company that produces artificial intelligence enabled lung function support software. JM and KO are employees of ArtiQ., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

This study examines the barriers to integrating portable Magnetic Resonance Imaging (MRI) systems into ambulance services to enable effective triaging of patients to the appropriate hospitals for timely stroke care and potentially reduce door-to-needle time for thrombolytic administration. The study employs a qualitative methodology using a digital twin of the patient handling process developed and demonstrated through semi-structured interviews with 18 participants, including 11 paramedics from an Emergency Medical Services system and seven neurologists from a tertiary stroke care centre. The interview transcripts were thematically analysed to determine the barriers based on the Systems Engineering Initiative for Patient Safety framework. Key barriers include the need for MRI operation skills, procedural complexities in patient handling, space constraints, and the need for training and policy development. Potential solutions are suggested to mitigate these barriers. The findings can facilitate implementing MRI systems in ambulances to expedite stroke treatment.

Background: Accurate outcome predictions for patients who had ischaemic stroke with successful reperfusion after endovascular thrombectomy (EVT) may improve patient treatment and care. Our study developed prediction models for key clinical outcomes in patients with successful reperfusion following EVT in an Australian population., Methods: The study included all patients who had ischaemic stroke with occlusion in the proximal anterior cerebral circulation and successful reperfusion post-EVT over a 7-year period. Multivariable logistic regression and Cox regression models, incorporating bootstrap and multiple imputation techniques, were used to identify predictors and develop models for key clinical outcomes: 3-month poor functional status; 30-day, 1-year and 3-year mortality; survival time., Results: A total of 978 patients were included in the analyses. Predictors associated with one or more poor outcomes include: older age (ORs for every 5-year increase: 1.22-1.40), higher premorbid functional modified Rankin Scale (ORs: 1.31-1.75), higher baseline National Institutes of Health Stroke Scale (ORs: 1.05-1.07) score, higher blood glucose (ORs: 1.08-1.19), larger core volume (ORs for every 10 mL increase: 1.10-1.22), pre-EVT thrombolytic therapy (ORs: 0.44-0.56), history of heart failure (outcome: 30-day mortality, OR=1.87), interhospital transfer (ORs: 1.42 to 1.53), non-rural/regional stroke onset (outcome: functional dependency, OR=0.64), longer onset-to-groin puncture time (outcome: 3-year mortality, OR=1.08) and atherosclerosis-caused stroke (outcome: functional dependency, OR=1.68). The models using these predictors demonstrated moderate predictive abilities (area under the receiver operating characteristic curve range: 0.752-0.796)., Conclusion: Our models using real-world predictors assessed at hospital admission showed satisfactory performance in predicting poor functional outcomes and short-term and long-term mortality for patients with successful reperfusion following EVT. These can be used to inform EVT treatment provision and consent., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patients with a large vessel occlusion require a transfer from a primary stroke centre to access thrombectomy, often over significant distances in regional areas. We sought to optimise stroke care access in the regional South Australian Tele-Strokeservice (SATS) to improve patient access to thrombectomy., Methods: We undertook a 24-month interventional historically controlled cohort study comparing acute stroke care metrics in the SATS. This consisted of a 12-month control period and a 12-month intervention monitoring period. The study intervention considered of an education package provided to the regional hospitals, a stroke neurologist roster to receive consultations and the intervention of a centralised tele-stroke system to provide treatment advice and organise patient transfers where needed. The SATS services 61 rural hospitals in South Australia, and Alice Springs in the Northern Territory. Suspected acute stroke patients presenting to the participating regional hospitals in SATS network where a telehealth consultation took place., Results: Over the study period, there were 919 patient referrals, with 449 consultations in the pre-intervention phase and 470 in the post-intervention phase. Demographic features in both epochs were similar. The post-intervention phase was associated with shorter door-to-scan time (35 min, IQR: 18,70; vs. 49 min, IQR:25,102, p  < 0.0001), faster door-to-thrombolysis time (58 min, IQR: 39,91, vs.83 min, IQR: 55,100, p  = 0.0324) and a higher portion of patients treated with thrombectomy (54, 11.5% vs. 26, 5.8%, p  = 0.002)., Conclusion: An optimised implementation of a streamlined telehealth platform with ongoing education and feedback to referring sites was associated with improved stroke workflow metrics and higher thrombectomy rates., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Kurunawai, Chen, Willcour, Tan, Mahadevan, Waters, Harvey, Van Eunen, Dixon, Piantedosi, Bivard, Parsons, Davis, Donnan, Jannes and Kleinig.)