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We present a representation of nitrogen and phosphorus cycling in the Functionally Assembled Terrestrial Ecosystem Simulator, a demographic vegetation model within the Energy Exascale Earth System land model. This representation is modular, and designed to allow testing of multiple hypothetical approaches for carbon-nutrient coupling in plants. Novel model hypotheses introduced in this work include, (a) the controls on plant acquisition of aqueous mineralized nutrients in the soil and (b) fairly straight forward methods of allocating nutrients to specific plant organs and their losses through live plant turnover as well as litter fluxes generated through plant mortality. This combines the new with pre-existing hypotheses (such as nitrogen fixation and soil decomposition) into a system that can accommodate plant-soil dynamics for a large number of size- and functional-type-resolved plant cohorts within a time-since-disturbance-resolved ecosystem. Root uptake of nutrients is governed by fine root biomass, and plants vary in their fine root biomass allocation in order to balance carbon and nutrient limitations to growth. We test the sensitivity of the model to a wide range of parameter variations and structural representations, and in the context of observations at Barro Colorado Island, Panama. A key model prediction is that plants in the high-light-availability canopy positions allocate more carbon to fine roots than plants in low-light understory environments, given the widely different carbon versus nutrient constraints of these two niches within a given ecosystem. This model provides a basis for exploring carbon-nutrient coupling with vegetation demography within Earth system models.

Summary: Nutrient limitation may constrain the ability of recovering and mature tropical forests to serve as a carbon sink. However, it is unclear to what extent trees can utilize nutrient acquisition strategies – especially root phosphatase enzymes and mycorrhizal symbioses – to overcome low nutrient availability across secondary succession.Using a large‐scale, full factorial nitrogen and phosphorus fertilization experiment of 76 plots along a secondary successional gradient in lowland wet tropical forests of Panama, we tested the extent to which root phosphatase enzyme activity and mycorrhizal colonization are flexible, and if investment shifts over succession, reflective of changing nutrient limitation. We also conducted a meta‐analysis to test how tropical trees adjust these strategies in response to nutrient additions and across succession.We find that tropical trees are dynamic, adjusting investment in strategies – particularly root phosphatase – in response to changing nutrient conditions through succession. These changes reflect a shift from strong nitrogen to weak phosphorus limitation over succession. Our meta‐analysis findings were consistent with our field study; we found more predictable responses of root phosphatase than mycorrhizal colonization to nutrient availability.Our findings suggest that nutrient acquisition strategies respond to nutrient availability and demand in tropical forests, likely critical for alleviating nutrient limitation. [ABSTRACT FROM AUTHOR]

Summary: Climate models predict that everwet western Amazonian forests will face warmer and wetter atmospheric conditions, and increased cloud cover. It remains unclear how these changes will impact plant reproductive performance, such as flowering, which plays a central role in sustaining food webs and forest regeneration. Warmer and wetter nights may cause reduced flower production, via increased dark respiration rates or alteration in the reliability of flowering cue‐based processes. Additionally, more persistent cloud cover should reduce the amounts of solar irradiance, which could limit flower production.We tested whether interannual variation in flower production has changed in response to fluctuations in irradiance, rainfall, temperature, and relative humidity over 18 yrs in an everwet forest in Ecuador.Analyses of 184 plant species showed that flower production declined as nighttime temperature and relative humidity increased, suggesting that warmer nights and greater atmospheric water saturation negatively impacted reproduction. Species varied in their flowering responses to climatic variables but this variation was not explained by life form or phylogeny.Our results shed light on how plant communities will respond to climatic changes in this everwet region, in which the impacts of these changes have been poorly studied compared with more seasonal Neotropical areas. [ABSTRACT FROM AUTHOR]

Introduction: Individuals with co-occurring mental and physical health issues have worse health outcomes in both domains. Integration improves outcomes and aligns with patient preference, but health services tend to be siloed. The Mental Health in Medicine Clinic (MHiM) supports patients receiving inpatient or outpatient medical or surgical care at a tertiary academic hospital in Toronto, Canada. The predominantly virtual clinic has an interdisciplinary team offering services via stepped care, matching patient need with service intensity. Measurement-based care (MBC), the systematic evaluation of patient reported outcomes, was not initially used routinely in the clinic, but its implementation may improve treatment decision-making and may be useful in allocating patients within a stepped care model. Objectives: 1) To describe the stepped care model, referral patterns, diagnoses, and level of care provided since implementation of stepped care. 2) To conduct a quality improvement initiative to implement MBC in the clinic, with a goal of 50% of patients completing at the time of first assessment and prior to discharge from the clinic. Methods: We reviewed the electronic medical record for referral source, diagnoses, and level of stepped care within the clinic. We conducted semi-structured interviews with stakeholders (clinicians, administrative staff, patients) to explore barriers to implementation of MBC. Interviews were analyzed for themes around barriers and facilitators to MBC. Plan, Do, Study, Act cycles were carried out around change concepts informed by stakeholder interviews and relevant literature. Results: The MHiM clinic began operations in August 2020. The clinic operated on a physician-only model until March 2022 and then shifted to a stepped care model with an interdisciplinary team. The most frequent referral sources were internal medicine, COVID19 clinics, consultation-liaison psychiatry, red blood cell disorders clinic and cardiology. Since the implementation of stepped care, 250 referrals were assessed. 58% of new referrals were assessed by the psychiatrist, 42% were managed by the NP, and 25% consulted with the social worker. Referrals consisted of trauma and stress-related disorders (32%), depression (21%) or anxiety disorders (20%). Personality, substance use, and psychotic disorders accounted for less than 10% of referrals combined. Some patients did not have any diagnosis (6%). Results from the quality improvement initiative to implement MBC will also be presented. Conclusions: The MHiM clinic provides an integrated care pathway addressing comorbid mental and physical health conditions. We describe a novel stepped care model and the implementation of MBC. Future directions include ongoing quality improvement of MBC and its integration within the clinic to assess and re-assess service intensity. Disclosure of Interest: None Declared [ABSTRACT FROM AUTHOR]

Telehealth presents both the potential to improve access to care and to widen the digital divide contributing to health care disparities and obliging health care systems to standardize approaches to measure and display telehealth disparities. Based on a literature review and the operational experience of clinicians, informaticists, and researchers in the Supporting Pediatric Research on Outcomes and Utilization of Telehealth (SPROUT)-Clinical and Translational Science Awards (CTSA) Network, we outline a strategic framework for health systems to develop and optimally use a telehealth equity dashboard through a 3-phased approach of (1) defining data sources and key equity-related metrics of interest; (2) designing a dynamic and user-friendly dashboard; and (3) deploying the dashboard to maximize engagement among clinical staff, investigators, and administrators., (©Michael J Luke, Sansanee Craig, Suzinne Pak-Gorstein, Marlíse Arellano, Jessica Zhang, S Margaret Wright, John Chuo, Philip V Scribano. Originally published in the Interactive Journal of Medical Research (https://www.i-jmr.org/), 04.09.2024.)

With the ever-growing reliance on polymeric materials for numerous applications, new avenues to induce, design and control degradation are clearly important. Here, we describe a previously unreported approach to controlling enzymatic hydrolysis of high molecular weight branched polymers formed from the new free-radical polymer synthesis strategy transfer-dominated branching radical telomerisation (TBRT). Modifying the chemical nature of TBRT polymers may be accomplished through telogen selection and multi-vinyl taxogen (MVT) design, and we show telogen-driven control of enzyme-catalysed hydrolysis and the impact of careful placement of hydrolytically susceptible groups within readily synthesised MVTs. Our results indicate that utilising conventional free-radical chemistries and unsaturated monomers as feedstocks for highly branched polymer architectures has considerable potential for the design of future materials that degrade into very low molecular weight byproducts at variable and controllable rates., (© 2024. The Author(s).)

Background: Deep grey matter pathology is a key driver of disability worsening in people with multiple sclerosis. Quantitative susceptibility mapping (QSM) is an advanced magnetic resonance imaging (MRI) technique which quantifies local magnetic susceptibility from variations in phase produced by changes in the local magnetic field. In the deep grey matter, susceptibility has previously been validated against tissue iron concentration. However, it currently remains unknown whether susceptibility is abnormal in older progressive MS cohorts, and whether it correlates with disability., Objectives: To investigate differences in mean regional susceptibility in deep grey matter between people with secondary progressive multiple sclerosis (SPMS) and healthy controls; to examine in patients the relationships between deep grey matter susceptibility and clinical and imaging measures of disease severity., Methods: Baseline data from a subgroup of the MS-STAT2 trial (simvastatin vs. placebo in SPMS, NCT03387670) were included. The subgroup underwent clinical assessments and an advanced MRI protocol at 3T. A cohort of age-matched healthy controls underwent the same MRI protocol. Susceptibility maps were reconstructed using a robust QSM pipeline from multi-echo 3D gradient-echo sequence. Regions of interest (ROIs) in the thalamus, globus pallidus and putamen were segmented from 3D T1-weighted images, and lesions segmented from 3D fluid-attenuated inversion recovery images. Linear regression was used to compare susceptibility from ROIs between patients and controls, adjusting for age and sex. Where significant differences were found, we further examined the associations between ROI susceptibility and clinical and imaging measures of MS severity., Results: 149 SPMS (77% female; mean age: 53 yrs; median Expanded Disability Status Scale (EDSS): 6.0 [interquartile range 4.5-6.0]) and 33 controls (52% female, mean age: 57) were included.Thalamic susceptibility was significantly lower in SPMS compared to controls: mean (SD) 28.6 (12.8) parts per billion (ppb) in SPMS vs. 39.2 (12.7) ppb in controls; regression coefficient: -12.0 [95% confidence interval: -17.0 to -7.1], p < 0.001. In contrast, globus pallidus and putamen susceptibility were similar between both groups.In SPMS, a 10 ppb lower thalamic susceptibility was associated with a +0.13 [+0.01 to +0.24] point higher EDSS (p < 0.05), a -2.4 [-3.8 to -1.0] point lower symbol digit modality test (SDMT, p = 0.001), and a -2.4 [-3.7 to -1.1] point lower Sloan low contrast acuity, 2.5% (p < 0.01).Lower thalamic susceptibility was also strongly associated with a higher T2 lesion volume (T2LV, p < 0.001) and lower normalised whole brain, deep grey matter and thalamic volumes (all p < 0.001)., Conclusions: The reduced thalamic susceptibility found in SPMS compared to controls suggests that thalamic iron concentrations are lower at this advanced stage of the disease. The observed relationships between lower thalamic susceptibility and more severe physical, cognitive and visual disability suggests that reductions in thalamic iron may correlate with important mechanisms of clinical disease progression. Such mechanisms appear to intimately link reductions in thalamic iron with higher T2LV and the development of thalamic atrophy, encouraging further research into QSM-derived thalamic susceptibility as a biomarker of disease severity in SPMS., Competing Interests: 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., (© 2024 The Authors.)

Introduction: Understanding relationships between in vivo neurometabolic changes and Alzheimer's disease (AD) pathology in the hippocampus, a region vulnerable to early changes in AD, will support early diagnosis., Methods: Two studies using 1 H-MRS examined concentrations of myo-inositol (MI), total creatine (tCr) and total NAA (tNAA) in the hippocampus. The first study compared hippocampal metabolite concentrations in healthy young and older adults and the second study assessed relationships between hippocampal metabolites and cerebrospinal fluid (CSF) measurements of Aβ42, phosphotau 181 (pTau181), and total tau (t-Tau) while adjusting for demographic covariates and spectral characteristics (linewidth, signal- to-noise ratio) in a separate group of older adults ranging from cognitively normal (CN) to AD-dementia., Results: Hippocampal MI, but not tCr or tNAA, was increased in cognitively normal older versus young adults. Within the second older adult group, MI and tNAA, but not tCr, were linked to increases in CSF pTau181 and t-Tau, but not Aβ42., Discussion: Tau deposition in cognitively normal individuals is associated with biochemical changes related to glial reactivity and neural integrity in the hippocampus.

Ovine pulmonary adenocarcinoma (OPA) is an infectious, neoplastic lung disease of sheep that causes significant animal welfare and economic issues throughout the world. Understanding OPA pathogenesis is key to developing tools to control its impact. Central to this need is the availability of model systems that can monitor and track events after Jaagsiekte sheep retrovirus (JSRV) infection. Here, we report the development of an experimentally induced OPA model intended for this purpose. Using three different viral dose groups (low, intermediate and high), localised OPA tumour development was induced by bronchoscopic JSRV instillation into the segmental bronchus of the right cardiac lung lobe. Pre-clinical OPA diagnosis and tumour progression were monitored by monthly computed tomography (CT) imaging and trans-thoracic ultrasound scanning. Post mortem examination and immunohistochemistry confirmed OPA development in 89% of the JSRV-instilled animals. All three viral doses produced a range of OPA lesion types, including microscopic disease and gross tumours; however, larger lesions were more frequently identified in the low and intermediate viral groups. Overall, 31% of JSRV-infected sheep developed localised advanced lesions. Of the sheep that developed localised advanced lesions, tumour volume doubling times (calculated using thoracic CT 3D reconstructions) were 14.8 ± 2.1 days. The ability of ultrasound to track tumour development was compared against CT; the results indicated a strong significant association between paired CT and ultrasound measurements at each time point (R 2 = 0.799, p < 0.0001). We believe that the range of OPA lesion types induced by this model replicates aspects of naturally occurring disease and will improve OPA research by providing novel insights into JSRV infectivity and OPA disease progression.

Fluorescence polarization (Fpol) imaging of methylene blue (MB) is a promising quantitative approach to thyroid cancer detection. Clinical translation of MB Fpol technology requires reduction of the data analysis time that can be achieved via deep learning-based automated cell segmentation with a 2D U-Net convolutional neural network. The model was trained and tested using images of pathologically diverse human thyroid cells and evaluated by comparing the number of cells selected, segmented areas, and Fpol values obtained using automated (AU) and manual (MA) data processing methods. Overall, the model segmented 15.8% more cells than the human operator. Differences in AU and MA segmented cell areas varied between - 55.2 and + 31.0%, whereas differences in Fpol values varied from - 20.7 and + 10.7%. No statistically significant differences between AU and MA derived Fpol data were observed. The largest differences in Fpol values correlated with greatest discrepancies in AU versus MA segmented cell areas. Time required for auto-processing was reduced to 10 s versus one hour required for MA data processing. Implementation of the automated cell analysis makes quantitative fluorescence polarization-based diagnosis clinically feasible., (© 2024. The Author(s).)

Evidence suggests that engaging in physical activity improves the mental and physical health of transplant recipients. An opportunity to be more active could be participating in the national and international network of Transplant Games. Although the literature on motivations for and the experience of taking part in the Games is available, little is known about what role applied practitioners, specifically sport and exercise psychologists could play as transplant recipients prepare and compete. This paper offers perspectives on the provision of a sports performance well-being service delivered at the British Transplant Games. The paper consists of several sections. The first offers background and how the service came into being. The second provides details of the model and philosophy that underpinned the service delivery. The third includes the trainee and exercise practitioner's casework and the challenges therein. Informed by the team's reflections and post-games survey the final section proposes recommendations for future applied sport and exercise services at this unique event., 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., (© 2024 Duncan, Nateri, Lind, Leddington-Wright, Bloxham, Moffitt and Sykes.)

Aims: Genetic testing can be used to improve the safety and effectiveness of commonly prescribed medicines-a concept known as pharmacogenetics. This study aimed to quantify members of the UK public's preferences for a pharmacogenetic service to be delivered in primary care in the National Health Service., Methods: Members of the UK population were surveyed via an online panel company. Respondents completed 1 of 2 survey versions, asking respondents to select their preferred pharmacogenetic testing service in the context of a presentation of low mood or pain. A conditional logit model was estimated, before the best functional form for the dataset was identified. Preference heterogeneity was identified via latent class analysis. Coefficients from the final selected models were used to estimate uptake in the context of different hypothetical pharmacogenetic services., Results: Responses from 1993 individuals were included in the analysis. There were no differences observed in preference between the 2 clinical scenarios. Conditional logit analysis, using maximum likelihood estimation, indicated that respondents preferred to have noninvasive tests and wanted their data to be shared between different healthcare organizations to guide future prescribing. There was a preference for regional over national data sharing initiatives, and respondents preferred to have access to their data. Predicted uptake varied considerably, ranging from 51% to >99%, depending on design of the service., Conclusion: This study identifies public preferences for a pharmacogenetic testing service and demonstrates how predicted uptake can be impacted by relatively minor adaptations. This highlights areas for prioritization during development of future pharmacogenetic services., (© 2024 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

Loss-of-function (LoF) variants in the lipid transporter ABCA7 significantly increase the risk of Alzheimer's disease (odds ratio ∼2), yet the pathogenic mechanisms and the neural cell types affected by these variants remain largely unknown. Here, we performed single-nuclear RNA sequencing of 36 human post-mortem samples from the prefrontal cortex of 12 ABCA7 LoF carriers and 24 matched non-carrier control individuals. ABCA7 LoF was associated with gene expression changes in all major cell types. Excitatory neurons, which expressed the highest levels of ABCA7, showed transcriptional changes related to lipid metabolism, mitochondrial function, cell cycle-related pathways, and synaptic signaling. ABCA7 LoF-associated transcriptional changes in neurons were similarly perturbed in carriers of the common AD missense variant ABCA7 p.Ala1527Gly (n = 240 controls, 135 carriers), indicating that findings from our study may extend to large portions of the at-risk population. Consistent with ABCA7's function as a lipid exporter, lipidomic analysis of isogenic iPSC-derived neurons (iNs) revealed profound intracellular triglyceride accumulation in ABCA7 LoF, which was accompanied by a relative decrease in phosphatidylcholine abundance. Metabolomic and biochemical analyses of iNs further indicated that ABCA7 LoF was associated with disrupted mitochondrial bioenergetics that suggested impaired lipid breakdown by uncoupled respiration. Treatment of ABCA7 LoF iNs with CDP-choline (a rate-limiting precursor of phosphatidylcholine synthesis) reduced triglyceride accumulation and restored mitochondrial function, indicating that ABCA7 LoF-induced phosphatidylcholine dyshomeostasis may directly disrupt mitochondrial metabolism of lipids. Treatment with CDP-choline also rescued intracellular amyloid β -42 levels in ABCA7 LoF iNs, further suggesting a link between ABCA7 LoF metabolic disruptions in neurons and AD pathology. This study provides a detailed transcriptomic atlas of ABCA7 LoF in the human brain and mechanistically links ABCA7 LoF-induced lipid perturbations to neuronal energy dyshomeostasis. In line with a growing body of evidence, our study highlights the central role of lipid metabolism in the etiology of Alzheimer's disease.

The movements and behaviour of mature European sea bass (Dicentrarchus labrax L.) in UK waters have not been studied extensively since a series of mark-recapture experiments during the 1970s, 80s and 90s. To better understand the timing and extent of seasonal migrations, 171 mature sea bass > 42 cm were internally tagged with floated electronic tags programmed to record temperature and depth, and released in the English Channel, in the southern North Sea and in the Irish Sea. Among the 48 tags returned to date, sea bass were at liberty for 370 ± 337 days and were recovered 172 ± 200 km from their respective release locations. Most tags were recovered from beaches (54%), or via the fishery (44%). A comparison of the reconstructed tracks from returned electronic tags with the recapture locations of 237 mark-recapture returns (6.5%) from 3615 sea bass released between 1970 and 2020 showed strong overlap. Seasonal movements between shallow areas (Q2-Q3) and deeper spawning areas (Q4-Q1) were accompanied by elevated vertical swimming speeds and average water temperatures of 8.5 °C in the English Channel and Irish Sea, but lower temperatures in the North Sea. Movements between the Celtic Sea/Irish Sea and the North Sea and vice versa demonstrate high levels of connectivity in UK waters. We demonstrate that a proportion of sea bass remained resident within the North Sea throughout the year, with a strong suggestion that spawning might be occurring. These data have significant implications for the future sustainable management of sea bass stocks in UK and surrounding waters., (© 2024. Crown.)

The movement ecology of European seabass, Dicentrarchus labrax, remains poorly understood, especially in the northern ranges of its distribution. To investigate migration patterns of seabass from the southern North Sea, we combined data from different projects from four countries using various tagging techniques. This resulted in 146 recaptures (out of 5598 externally marked seabass), 138 detected animals (out of 162 seabass fitted with an acoustic transmitter) and 76 archived depth and temperature series (out of 323 seabass with an archival tag). Using geolocation modelling, we distinguished different migration strategies, whereby individual fish migrated to the eastern English Channel (15.1%), the western English Channel (28.3%), the Celtic Sea and the norther part of the Bay of Biscay (17.0%), or stayed in the North Sea (39.6%). A high number of seabass exhibited fidelity to the North Sea (90.5% of recaptures, 55.3% for acoustic transmitters and 44.7% of archival tags). Although seabass are generally considered to migrate southwards in winter, a large number of individuals (n = 62) were observed in the southern North Sea, where spawning might potentially occur in a particular deep location along the coast of Norfolk in the UK. Our results highlight the need to consider fine-scaled population structuring in fisheries assessment, and indicate that current seasonal fisheries closures are not aligned with the ecology of seabass in the North Sea., (© 2024. The Author(s).)

Novel methods for sampling and characterizing biodiversity hold great promise for re-evaluating patterns of life across the planet. The sampling of airborne spores with a cyclone sampler, and the sequencing of their DNA, have been suggested as an efficient and well-calibrated tool for surveying fungal diversity across various environments. Here we present data originating from the Global Spore Sampling Project, comprising 2,768 samples collected during two years at 47 outdoor locations across the world. Each sample represents fungal DNA extracted from 24 m 3 of air. We applied a conservative bioinformatics pipeline that filtered out sequences that did not show strong evidence of representing a fungal species. The pipeline yielded 27,954 species-level operational taxonomic units (OTUs). Each OTU is accompanied by a probabilistic taxonomic classification, validated through comparison with expert evaluations. To examine the potential of the data for ecological analyses, we partitioned the variation in species distributions into spatial and seasonal components, showing a strong effect of the annual mean temperature on community composition., (© 2024. The Author(s).)

Introduction: Social drivers of health (SDH) strongly influence health outcomes and disparities. Although systemic level change is vital to address the disparities driven by SDH, it is also crucial that health care organizations develop the ability to care for patients in a manner that accounts for social factors and their influence on patient health. Although primary care is a natural fit for health-related social needs (HRSN) screening and intervention, significant barriers can impede primary care's effectiveness in this area., Methods: We conducted 3 focus groups with family medicine clinicians, clinical staff, and social care workers in an academic medical center using a semistructured discussion guide to explore current practices, perceived benefits, barriers, and potential opportunities and approaches for integrating routine HRSN screening in primary care., Results: 3 primary themes emerged from the focus groups. They included 1) the barriers to routine screening in primary care, including time, workload, emotional burden, patient factors, and team members' fear of inadequacy of resources or their own ability; 2) the importance and benefit of HRSN screening, including the opportunity to improve patient care through increased care team awareness of the patient's context, interventions to address HRSN, and improved relationships between the care team and the patient; and 3) recommendations for implementing routine screening in primary care, including opportunities to optimize workflow and technology, the importance of an electronic medical record (EMR)-integrated resource database, and the centrality of teamwork., Discussion: Family medicine health care teams embrace the importance of HRSN screening and the potential for positive impact. However, there are vital barriers and considerations to address for HRSN screening to be effectively integrated into primary care visits., Competing Interests: Conflict of interest: The authors have no conflicts of interest to disclose., (© Copyright 2024 by the American Board of Family Medicine.)

Modern analytical tools, from microfocus X-ray diffraction (XRD) to electron microscopy-based microtexture measurements, offer exciting possibilities of diffraction-based multiscale residual strain measurements. The different techniques differ in scale and resolution, but may also yield significantly different strain values. This study, for example, clearly established that high-resolution electron backscattered diffraction (HR-EBSD) and high-resolution transmission Kikuchi diffraction (HR-TKD) [sensitive to changes in interplanar angle (Δθθ)], provide quantitatively higher residual strains than micro-Laue XRD and transmission electron microscope (TEM) based precession electron diffraction (PED) [sensitive to changes in interplanar spacing (Δdd)]. Even after correcting key known factors affecting the accuracy of HR-EBSD strain measurements, a scaling factor of ∼1.57 (between HR-EBSD and micro-Laue) emerged. We have then conducted "virtual" experiments by systematically deforming an ideal lattice by either changing an interplanar angle (α) or a lattice parameter (a). The patterns were kinematically and dynamically simulated, and corresponding strains were measured by HR-EBSD. These strains showed consistently higher values for lattice(s) distorted by α, than those altered by a. The differences in strain measurements were further emphasized by mapping identical location with HR-TKD and TEM-PED. These measurements exhibited different spatial resolution, but when scaled (with ∼1.57) provided similar lattice distortions numerically., Competing Interests: Conflict of 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Microscopy Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Trace amine-associated receptor 1 (TAAR1) agonism shows promise for treating psychosis, prompting us to synthesise data from human and non-human studies., Methods: We co-produced a living systematic review of controlled studies examining TAAR1 agonists in individuals (with or without psychosis/schizophrenia) and relevant animal models. Two independent reviewers identified studies in multiple electronic databases (until 17.11.2023), extracted data, and assessed risk of bias. Primary outcomes were standardised mean differences (SMD) for overall symptoms in human studies and hyperlocomotion in animal models. We also examined adverse events and neurotransmitter signalling. We synthesised data with random-effects meta-analyses., Results: Nine randomised trials provided data for two TAAR1 agonists (ulotaront and ralmitaront), and 15 animal studies for 10 TAAR1 agonists. Ulotaront and ralmitaront demonstrated few differences compared to placebo in improving overall symptoms in adults with acute schizophrenia (N=4 studies, n=1291 participants; SMD=0.15, 95%CI: -0.05, 0.34), and ralmitaront was less efficacious than risperidone (N=1, n=156, SMD=-0.53, 95%CI: -0.86, -0.20). Large placebo response was observed in ulotaront phase-III trials. Limited evidence suggested a relatively benign side-effect profile for TAAR1 agonists, although nausea and sedation were common after a single dose of ulotaront. In animal studies, TAAR1 agonists improved hyperlocomotion compared to control (N=13 studies, k=41 experiments, SMD=1.01, 95%CI: 0.74, 1.27), but seemed less efficacious compared to dopamine D 2 receptor antagonists (N=4, k=7, SMD=-0.62, 95%CI: -1.32, 0.08). Limited human and animal data indicated that TAAR1 agonists may regulate presynaptic dopaminergic signalling., Conclusions: TAAR1 agonists may be less efficacious than dopamine D 2 receptor antagonists already licensed for schizophrenia. The results are preliminary due to the limited number of drugs examined, lack of longer-term data, publication bias, and assay sensitivity concerns in trials associated with large placebo response. Considering their unique mechanism of action, relatively benign side-effect profile and ongoing drug development, further research is warranted., Registration: PROSPERO-ID: CRD42023451628., Competing Interests: Competing interests: Andrea Cipriani received research, educational and consultancy fees from the Italian Network for Paediatric Trials, CARIPLO Foundation, Lundbeck, and Angelini Pharma. Toshi A. Furukawa reports personal fees from Boehringer-Ingelheim, Daiichi Sankyo, DT Axis, Kyoto University Original, Shionogi, and SONY, and a grant from Shionogi outside the submitted work; in addition, TAF has patents 2020-548587 and 2022-082495 pending, and intellectual properties for Kokoro-app licensed to Mitsubishi-Tanabe. Oliver D. Howes has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organised by Angellini, Autifony, Biogen, Boehringer-Ingelheim, Eli Lilly, Elysium, Heptares, Global Medical Education, Invicro, Jansenn, Karuna, Lundbeck, Merck, Neurocrine, Ontrack/ Pangea, Otsuka, Sunovion, Recordati, Roche, Rovi and Viatris/ Mylan. He was previously a part-time employee of Lundbeck A/v. Dr Howes has a patent for the use of dopaminergic imaging. In the last three years Stefan Leucht has received honoraria for advising/consulting and/or for lectures and/or for educational material from Angelini, Boehringer Ingelheim, Eisai, Ekademia, GedeonRichter, Janssen, Karuna, Kynexis, Lundbeck, Medichem, Medscape, Mitsubishi, Otsuka, NovoNordisk, Recordati, Rovi, Teva. Robert A. McCutcheon has received speaker/consultancy fees from Karuna, Janssen, Boehringer Ingelheim, and Otsuka, and is a director of a company that hosts psychotropic prescribing decision tools. Carmen Moreno received honoraria as a consultant and/or advisor and/or for lectures from Angelini, Compass, Esteve, Exeltis Janssen, Lundbeck, Neuraxpharm, Nuvelution, Otsuka, Pfizer, Servier and Sunovion outside the submitted work. Nobuyuki Nomura has received speaker fees from Eisai, Meiji Seika Pharma, Otsuka, and Sumitomo Pharma; and manuscript fees from Sumitomo Pharma. Edoardo G. Ostinelli has received research and consultancy fees from Angelini Pharma. No other competing interests were disclosed., (Copyright: © 2024 Siafis S et al.)

Harmful use of illicit drugs and/or alcohol is linked to life-limiting illness and complex health and social care needs, but people who use substances and have complex needs do not receive timely palliative care and fail to achieve quality standards for a good death. They and their families often require support from multiple health and social care services which are shown to be poorly integrated and fail to deliver interdisciplinary care. This study aimed to identify the existing barriers and facilitators within and between services in providing this population with a good death. Using a mixed methods approach of survey, focus groups and semi-structured interviews, we explored the perspectives of practitioner and management staff across a range of health and social disciplines and organisations in one combined authority in a large city in the north west of England. Our findings indicate that practitioners want to provide better care for this client group, but face structural, organisational and professional boundary barriers to delivering integrated and shared care. Differences in philosophy of care, piecemeal commissioning and funding of services, and regulatory frameworks for different services, lead to poor and inequitable access to health and social care services. Ways forward for improving care are suggested as bespoke hostel-based accommodation for palliative care for this client group, and specialist link workers who can transcend professional and organisational boundaries to support co-ordination of services and support. We conclude that it is no longer adequate to call for more training, better communication and improved joint working. Complex care at the end of life requires creative and cohesive systemic responses that enable multi-disciplinary practitioners to provide the care they wish to give and enables individuals using substances to get the respect and quality service they deserve., (© 2024. The Author(s).)

The periderm is a vital protective tissue found in the roots, stems, and woody elements of diverse plant species. It plays an important function in these plants by assuming the role of the epidermis as the outermost layer. Despite its critical role for protecting plants from environmental stresses and pathogens, research on root periderm development has been limited due to its late formation during root development, its presence only in mature root regions, and its impermeability. One of the most straightforward measurements for comparing periderm formation between different genotypes and treatments is periderm (phellem) length. We have developed PAT (Periderm Assessment Toolkit), a high-throughput user-friendly pipeline that integrates an efficient staining protocol, automated imaging, and a deep-learning-based image analysis approach to accurately detect and measure periderm length in the roots of Arabidopsis thaliana . The reliability and reproducibility of our method was evaluated using a diverse set of 20 Arabidopsis natural accessions. Our automated measurements exhibited a strong correlation with human-expert-generated measurements, achieving a 94% efficiency in periderm length quantification. This robust PAT pipeline streamlines large-scale periderm measurements, thereby being able to facilitate comprehensive genetic studies and screens. Although PAT proves highly effective with automated digital microscopes in Arabidopsis roots, its application may pose challenges with nonautomated microscopy. Although the workflow and principles could be adapted for other plant species, additional optimization would be necessary. While we show that periderm length can be used to distinguish a mutant impaired in periderm development from wild type, we also find it is a plastic trait. Therefore, care must be taken to include sufficient repeats and controls, to minimize variation, and to ensure comparability of periderm length measurements between different genotypes and growth conditions., Competing Interests: Competing interests: W.B. is a cofounder of Cquesta, a company that works on crop root growth and carbon sequestration., (Copyright © 2024 Gonzalo Villarino et al.)

Background: Clinical practice guidelines and guidance documents routinely offer prescribing clinicians' recommendations and instruction on the use of psychotropic drugs for mental illness. We sought to characterise parameters relevant to prescribing and deprescribing of benzodiazepine (BZD) and benzodiazepine receptor agonist (BZRA), in clinical practice guidelines and guidance documents internationally, for adult patients with unipolar depression, anxiety disorders and insomnia to understand similarities and discrepancies between evidence-based expert opinion., Methods: A Scoping Review was conducted to characterize documents that offered evidence-based and/or consensus pharmacologic guidance on the management of unipolar depression, anxiety disorders, obsessive-compulsive disorders, post-traumatic stress disorders and insomnia. A systematic search was conducted of PubMed, SCOPUS, PsycINFO and CINAHL from inception to October 13, 2023 and supplemented by a gray literature search. Documents were screened in Covidence for eligibility. Subsequent data-charting on eligible documents collected information on aspects of both prescribing and deprescribing., Findings: 113 documents offering guidance on BZD/BZRA use were data-charted. Overall, documents gathered were from Asia (n = 11), Europe (n = 34), North America (n = 37), Oceania (n = 7), and South America (n = 4) with the remainder being "International" (n = 20) and not representative to any particular region or country. By condition the documents reviewed covered unipolar depressive disorders (n = 28), anxiety disorders, obsessive-compulsive disorder and post-traumatic stress disorder (n = 42) and Insomnia (n = 25). Few documents (n = 18) were sufficiently specific and complete to consider as de-prescribing focused documents., Interpretation: Documents were in concordance in terms of BZD and BZRA not being used routinely as first-line pharmacologic agents. When used, it is advisable to restrict their duration to "short-term" use with the most commonly recommended duration being less than four weeks. Documents were less consistent in terms of prescriptive recommendations for specific drug, dosing and administration pattern (i.e regular or 'as needed') selection for each condition. Deprescribing documents were unanimously in favor of gradual dose reduction and patient shared decision-making. However, approaches towards dose-tapering differed substantially. Finally, there were inconsistencies and/or insufficiency of detail, among deprescribing documents, in terms of switching to a long-acting BZD, use of adjunctive pharmacotherapies and micro-tapering., Funding: The authors received no funding for this work., Competing Interests: Brandt, Bressi, Cadogan, Witt-Doerring (M & J) and Wright have all served as either advisors or directors to the Alliance for Benzodiazepine Best Practices; a not-for-profit organization with the mission to inform evidence-based improvements in the use of benzodiazepines and Z-drugs. Wright has received personal payment (unrelated to this project) for his past service as medical director of the Alliance for Benzodiazepine Best Practices., (© 2024 The Author(s).)

The taxonomic characterization of ancient microbiomes is a key step in the rapidly growing field of paleomicrobiology. While PCR amplification of the 16S ribosomal RNA (rRNA) gene is a widely used technique in modern microbiota studies, this method has systematic biases when applied to ancient microbial DNA. Shotgun metagenomic sequencing has proven to be the most effective method in reconstructing taxonomic profiles of ancient dental calculus samples. Nevertheless, shotgun sequencing approaches come with inherent limitations that could be addressed through hybridization enrichment capture. When employed together, shotgun sequencing and hybridization capture have the potential to enhance the characterization of ancient microbial communities. Here, we develop, test, and apply a hybridization enrichment capture technique to selectively target 16S rRNA gene fragments from the libraries of ancient dental calculus samples generated with shotgun techniques. We simulated data sets generated from hybridization enrichment capture, indicating that taxonomic identification of fragmented and damaged 16S rRNA gene sequences was feasible. Applying this enrichment approach to 15 previously published ancient calculus samples, we observed a 334-fold increase of ancient 16S rRNA gene fragments in the enriched samples when compared to unenriched libraries. Our results suggest that 16S hybridization capture is less prone to the effects of background contamination than 16S rRNA amplification, yielding a higher percentage of on-target recovery. While our enrichment technique detected low abundant and rare taxa within a given sample, these assignments may not achieve the same level of specificity as those achieved by unenriched methods., Competing Interests: The authors declare that they have no competing interests., (© 2024 Eisenhofer et al.)

Background: The oncogenic protein HOXA9 plays a critical role in leukemia transformation and maintenance, and its aberrant expression is a hallmark of most aggressive acute leukemia. Although inhibiting the upstream regulators of HOXA9 has been proven as a significant therapeutic intervention, the comprehensive regulation network controlling HOXA9 expression in leukemia has not been systematically investigated., Results: Here, we perform genome-wide CRISPR/Cas9 screening in the HOXA9-driven reporter acute leukemia cells. We identify a poorly characterized RNA-binding protein, RBM5, as the top candidate gene required to maintain leukemia cell fitness. RBM5 is highly overexpressed in acute myeloid leukemia (AML) patients compared to healthy individuals. RBM5 loss triggered by CRISPR knockout and shRNA knockdown significantly impairs leukemia maintenance in vitro and in vivo. Through domain CRISPR screening, we reveal that RBM5 functions through a noncanonical transcriptional regulation circuitry rather than RNA splicing, such an effect depending on DNA-binding domains. By integrative analysis and functional assays, we identify HOXA9 as the downstream target of RBM5. Ectopic expression of HOXA9 rescues impaired leukemia cell proliferation upon RBM5 loss. Importantly, acute protein degradation of RBM5 through auxin-inducible degron system immediately reduces HOXA9 transcription., Conclusions: We identify RBM5 as a new upstream regulator of HOXA9 and reveal its essential role in controlling the survival of AML. These functional and molecular mechanisms further support RBM5 as a promising therapeutic target for myeloid leukemia treatment., (© 2023. The Author(s).)

Introduction: Consideration of the cost of care and value in healthcare is now a recognized element of physician training. Despite the urgency to educate trainees in high-value care (HVC), educational curricula and evaluation of these training paths remain limited, especially with respect to emergency medicine (EM) residents. We aimed to complete a needs assessment and evaluate curricular preferences for instruction on HVC among EM residents., Methods: This was a qualitative, exploratory study using content analysis of two focus groups including a total of eight EM residents from a single Midwestern EM residency training program. Participants also completed a survey questionnaire., Results: There were two themes. Within the overall theme of resident experience with and perception of HVC, we found five sub-themes: 1) understanding of HVC focuses on diagnosis and decision-making; 2) concern about patient costs, including the effects on patients' lives and their ability to engage with recommended outpatient care; 3) conflict between internal beliefs and external expectations, including patients' perceptions of value; 4) approach to HVC changes with increasing clinical experience; and 5) slow-moving, political discussion around HVC. Within the overall theme of desired education and curricular design, we identified four sub-themes: 1) limited prior education on HVC and health economics; 2) motivation to receive training on HVC and health economics; 3) desire for discussion-based format for HVC curriculum; and 4) curriculum targeted to level of training. Respondents indicated greatest acceptability of interactive, discussion-based formats., Discussion: We conducted a targeted needs assessment for HVC among EM residents. We identified broad interest in the topic and limited self-reported baseline knowledge. Curricular content may benefit from incorporating resident concerns about patient costs and conflict between external expectations and internal beliefs about HVC. Curricular design may benefit from a focus on interactive, discussion-based modalities and tailoring to the learner's level of training., Competing Interests: Conflicts of Interest: By the WestJEM article submission agreement, all authors are required to disclose all affiliations, funding sources and financial or management relationships that could be perceived as potential sources of bias. This work was supported by internal departmental funding from a designated Resident Research Fund. No author reports any related conflicts of interest. Bennett H. Lane reports receiving research grant support from the Society for Academic Emergency Medicine Foundation for investigator-initiated work on interhospital transfers by air. Bennett H. Lane also reports an equity interest and consulting fees from TriAxia Health for unrelated work.

Humans are exposed to micro-and-nano plastics (MNPs) through various routes, but the adverse health effects of MNPs on different organ systems are not yet fully understood. This review aims to provide an overview of the potential impacts of MNPs on various organ systems and identify knowledge gaps in current research. The summarized results suggest that exposure to MNPs can lead to health effects through oxidative stress, inflammation, immune dysfunction, altered biochemical and energy metabolism, impaired cell proliferation, disrupted microbial metabolic pathways, abnormal organ development, and carcinogenicity. There is limited human data on the health effects of MNPs, despite evidence from animal and cellular studies. Most of the published research has focused on specific types of MNPs to assess their toxicity, while other types of plastic particles commonly found in the environment remain unstudied. Future studies should investigate MNPs exposure by considering realistic concentrations, dose-dependent effects, individual susceptibility, and confounding factors., Competing Interests: Declaration of interests The authors have no conflict of interest to declare., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)