Search

Abstract Recently classified as a unique species by the IUCN, African forest elephants (Loxodonta cyclotis) are critically endangered due to severe poaching. With limited knowledge about their ecological role due to the dense tropical forests they inhabit in central Africa, it is unclear how the Afrotropics are influenced by elephants. Although their role as seed dispersers is well known, they may also drive large‐scale processes that determine forest structure through the creation of elephant trails and browsing the understory, allowing larger, carbon‐dense trees to succeed. Multiple scales of lidar were collected by NASA in Lopé National Park, Gabon from 2015 to 2022. Utilizing two airborne lidar datasets in an African forest elephant stronghold, detailed canopy structural information was used in conjunction with elephant trail data to determine how forest structure varies on and off trails. Forest along elephant trails displayed different structural characteristics than forested areas off trails, with lower canopy height, canopy cover, and different vertical distribution of plant density. Less plant area density was found on trails at 1 m in height, while more vegetation was found at 12 m, compared to off trail locations. Trails in forest areas with previous logging history had lower plant area in the top of the canopy. Forest elephants can be considered as “logging light” ecosystem engineers, affecting canopy structure through browsing and movement. Both airborne lidar scales were able to capture elephant impact along trails, with the high‐resolution discrete return lidar performing higher than waveform lidar.

Abstract Background Endothelial glycocalyx (EG) degradation occurs in septic humans and EG products can be used as biomarkers of endothelial injury. Information about EG biomarkers and their association with disease severity is lacking in hospitalized foals. Objectives Measure serum syndecan‐1 (SDC‐1), heparan sulfate (HS), angiopoietin‐2 (ANG‐2), aldosterone (ALD), and plasma atrial natriuretic peptide (ANP) concentrations and to determine their association with disease severity and death in hospitalized foals. Animals Ninety foals ≤3 days old. Methods Prospective, multicenter, longitudinal study. Foals were categorized into hospitalized (n = 74; 55 septic; 19 sick nonseptic) and 16 healthy foals. Serum ([SDC‐1], [HS], [ANG‐2], [ALD]) and plasma (ANP) were measured over 72 hours using immunoassays. Results Serum ([SDC‐1], [HS], [ANG‐2], [ALD]) and plasma (ANP) were significantly higher in hospitalized and septic than healthy foals (P 58.7 ng/mL had higher odds of nonsurvival (odds ratio [OR] = 6.1; 95% confidence interval [CI] = 1.02‐36.7). Plasma (ANP) >11.5 pg/mL was associated with the likelihood of nonsurvival in hospitalized foals (OR = 7.2; 95% CI = 1.4‐37.4; P 1018 pg/mL on admission had higher odds of nonsurvival (OR = 6.5; 95% CI =1.2‐36.6; P

Abstract Objectives To explore the potential impacts of incorporating prebiopsy magnetic resonance imaging into primary care as a triage test within the prostate cancer diagnostic pathway. Subjects and methods Decision analytic modelling with decision trees was utilised for this early economic evaluation. A conceptual model was developed reflecting the common primary care routes to diagnosis for prostate cancer: opportunistic, asymptomatic prostate‐specific antigen (PSA) screening or symptomatic presentation. The use of multiparametric MRI (mpMRI) or biparametric MRI (bpMRI) as a primary care triage test following an elevated PSA result was evaluated. A health system perspective was adopted with a time horizon of 12 months. Health effects were expressed in terms of utilities drawn from the literature. The primary outcome was prostate cancer diagnosis. Evidence used to inform the model was drawn from published primary studies, systematic reviews, and secondary analyses of primary and secondary care datasets. Results Base case analysis showed that the PSA pathway was dominated by both mpMRI‐ and bpMRI‐based pathways for patients undergoing opportunistic screening and symptomatic assessment. bpMRI pathways had greater improvement in cost and utility than mpMRI pathways in both clinical scenarios. Significantly more MRI scans would be performed using the modelled approach (66 626 scans vs. 37 456 scans per 100 000 patients per annum), with fewer subsequent urgent suspected cancer referrals for both mpMRI (38% reduction for screening and symptomatic patients) and bpMRI (72% reduction for screening; 71% for symptomatic) pathways, and a small increase in number of missed cancer diagnoses. Deterministic sensitivity analyses, varying each parameter to its upper and lower 95% confidence intervals, showed no significant change in the dominance of the MRI‐based prostate cancer diagnostic pathways. Conclusion Using prostate MRI as a second‐level triage test for suspected prostate cancer in primary care could reduce health service costs without a detrimental effect on patient utility.

Congenital enterovirus infection can be associated with a pro‐inflammatory state triggering haemophagocytic lymphohistiocytosis (HLH). Enteroviruses are also known to cause transient neutropenia in healthy children. Two infants presented with temperature instability, lethargy, thrombocytopaenia, hepatosplenomegaly and evidence of hyperinflammation in the setting of perinatal maternal rash and household contacts with gastrointestinal symptoms. Whilst HLH was successfully treated in both, protracted neutropenia persisted. Immune dysregulation with enterovirus in the neonatal period can provoke the generation of autoantibodies to hematologic cells giving rise to conditions such as autoimmune neutropenia. Sustained neutropaenia, after resolution of secondary infectious forms of HLH, requires investigation for underlying aetiologies.

Abstract Screening a transposon‐mutagenized soybean population led to the discovery of a recessively inherited chlorotic phenotype. This “y24” phenotype results in smaller stature, weaker stems, and a smaller root system. Genome sequencing identified 15 candidate genes with mutations likely to result in a loss of function. Amplicon sequencing of a segregating population was then used to narrow the list to a single candidate mutation, a single‐base change in Glyma.07G102300 that disrupts splicing of the second intron. Single cell transcriptomic profiling indicates that this gene is expressed primarily in mesophyll cells, and RNA sequencing data indicate that it is upregulated in germinating seedlings by cold stress. Previous studies have shown that mutations to Os05g34040, the rice ortholog of Glyma.07G102300, produced a chlorotic phenotype that was more pronounced in cool temperatures. Growing soybean y24 mutants at lower temperatures also resulted in a more severe phenotype. In addition, transgenic expression of wild‐type Glyma.07G102300 in the knockout mutant of the Arabidopsis ortholog At4930720 rescues the chlorotic phenotype, further supporting the hypothesis that the mutation in Glyma.07G102300 is causal of the y24 phenotype. The variant analysis strategy used to identify the genes underlying this phenotype provides a template for the study of other soybean mutants.

Abstract Understanding tree transpiration variability is vital for assessing ecosystem water‐use efficiency and forest health amid climate change, yet most landscape‐level measurements do not differentiate individual trees. Using canopy temperature data from thermal cameras, we estimated the transpiration rates of individual trees at Harvard Forest and Niwot Ridge. PT‐JPL model was used to derive latent heat flux from thermal images at the canopy‐level, showing strong agreement with tower measurements (R2 = 0.70–0.96 at Niwot, 0.59–0.78 at Harvard at half‐hourly to monthly scales) and daily RMSE of 33.5 W/m2 (Niwot) and 52.8 W/m2 (Harvard). Tree‐level analysis revealed species‐specific responses to drought, with lodgepole pine exhibiting greater tolerance than Engelmann spruce at Niwot and red oak showing heightened resistance than red maple at Harvard. These findings show how ecophysiological differences between species result in varying responses to drought and demonstrate that these responses can be characterized by deriving transpiration from crown temperature measurements.

ABSTRACT Background There is wide variation in premature mortality rates in adults with severe mental illness (SMI) across London, with Tower Hamlets (a highly deprived and ethnically diverse area) scoring the highest. Objective To identify examples of best practice and co‐design recommendations for improving physical health checks and follow‐up care amongst people with SMI in Tower Hamlets. Methods Data were collected through online questionnaires (using SMI physical health best practice checklists), one‐on‐one interviews (n = 7) and focus groups (n = 3) with general practices, secondary mental health services, commissioners and leads of community services and public health programmes, experts by experience and community, voluntary and social enterprise organisations in Tower Hamlets. Data were analysed using deductive and inductive thematic analysis. Results Twenty‐two participants representing 15 general practices (out of 32), secondary mental health services, commissioners and public health leads completed the online questionnaires. Twenty‐one participants took part in interviews and focus groups. Examples of best practice included cleaning and validating the SMI register regularly by general practices, knowing the number of patients who had been offered and/or received physical health checks, having clear pathways to community and specialist care services, using various communication methods and having a key performance indicator (KPI) for tailored smoking cessation services for people with SMI. Recommendations included adopting evidence‐informed frameworks for risk stratification and utilising the wider primary care workforce with specific training to follow up on results, offer interventions and support navigating pathways and taking up follow‐up care. Incentivising schemes were needed to deliver additional physical health check components such as oral health, cancer screening, Covid‐19 vaccination and sexual health checks. Including KPIs in other community services' specifications with reference to SMI people was warranted. Further engagement with experts by experience and staff training were needed. Conclusion The present initiative identified best practice examples and co‐designed recommendations for improving physical health checks and follow‐up care in deprived and ethnically diverse people with SMI. Patient or Public Contribution This initiative was supported by three experts with experience, and two community organisations, who were involved in data curation and interpretation, development of recommendations and/or dissemination activities including writing this manuscript.

ABSTRACT Background This systematic review investigates barriers and enablers to dental care utilization by disabled children. Given the high global prevalence of disabilities in children, coupled with poor oral hygiene and a 45% rate of dental caries in this group, developing inclusive oral health strategies is critical. The review aims to synthesize literature on factors affecting oral healthcare improvement for disabled children, identifying barriers, facilitators and knowledge gaps. Methods The review was conducted following the Joanna Briggs Institute's methods and reported according to PRISMA guidelines. A comprehensive search spanned multiple databases, considering perspectives from carers, parents, dentists and health professionals. The focus was on studies involving children up to age 17 with disabilities, as defined by WHO, using dental care services. Exclusions included non‐qualitative studies, populations over 18 and nondisabled children. There were no restrictions on publication date or language. Thematic synthesis of the studies extracted themes related to barriers and enablers in oral healthcare for disabled children. Results Thematic synthesis identified five overarching themes: stigma, communication issues, professional development, oral health education and medical‐dental collaboration. Facilitators included enhancing accessibility and availability of dental care through a holistic approach, improving dental care facility environments and ensuring skilled dental care providers. Discussion The review underscores the importance of interprofessional collaboration, improved parent/caregiver education and specialized dental facilities to support children with disabilities. It identifies key barriers and facilitators in dental care, including challenging stereotypes, improving communication between providers and parents, enhancing holistic training and addressing gaps in oral health education and integrated healthcare systems. Conclusion Addressing the complex dynamics of dental care for disabled children is essential for developing inclusive and effective preventive and therapeutic strategies. This review highlights the need for tailored approaches and enhanced support systems to improve oral health outcomes in this vulnerable population. Patient and Public Contribution The members of the family support department, Middle East and North Africa (MENA) Organization for Rare Disease and Disability who provided the disability voice and contributed to providing input to the review protocol.

Abstract Ontogenetic changes in area use, habitat use, and trophic interactions play an important role in the ecology, demography, and ultimately population dynamics of many species. Assumed to be driven by shifting life‐history requirements, trophic niche shifts in white sharks (Carcharodon carcharias) are well documented, but the timing of the spatial niche shift that is hypothesized to occur with the trophic niche shift remains poorly understood. To document how fine‐scale area use varies as sharks age and the timing of the ontogenetic spatial shift of this top predator, we tracked individual white sharks tagged as young‐of‐the‐year or young juveniles over multiple years. Using data from juvenile white sharks detected over multiple years in a nursery habitat with a high‐density receiver array, we found no difference in area use with age. However, using a coast‐wide receiver array including nursery and adult habitat, we found the probability of detecting a juvenile white shark in nursery habitat decreased with age, with a concurrent increasing probability of detection in adult habitat. As the conservation and management of this species relies on understanding nursery habitat use and age‐related movements, data presented here address an important knowledge gap for the understudied juvenile to subadult life stages and the ontogenetic habitat shift of this species.

Abstract Objective The objectives of the study were to assess emergency medicine (EM) physician perceptions of the EM job market 2 years after “The Emergency Medicine Physician Workforce: Projections for 2030” was published in Annals of Emergency Medicine and to examine how the workforce report may have influenced perceptions about job prospects. Methods A cross‐sectional survey was conducted in 2022 of EM residents, fellows, and attendings at 21 practice sites. Main outcomes were perceptions of the likelihood of currently finding any job, currently finding a desirable job, and confidence in the future EM job market. Results Note that 831 of 1938 physicians (42.9%) responded. A total of 92.4% reported a high likelihood of finding any job currently, 49.8% reported a high likelihood of finding a desirable job currently, and 44.4% reported future confidence. Workforce report familiarity was associated with greater likelihood of finding a desirable job. Fellows were least confident in the future. Residents with desired Midwest location were twice as confident in the future job market; those with desired West location were less confident. Attendings 20 or more years post‐training were more than twice as likely to report a high likelihood of finding a desirable job and almost twice as likely to report future confidence. Attendings in leadership were nearly three times as likely to report high a likelihood of finding a desirable job and future confidence. Conclusion EM trainees and attendings have favorable perceptions of the current job market but are less confident in future prospects. As the projected surplus of EM physicians appears to have had an impact, updated projections are needed for more accurate assessments of the future of the specialty.

Abstract Corrosion processes are often discussed as stochastic events. Here, it is shown that some of these seemingly random processes are not driven by nanoscopic fluctuations but rather by the spatial distribution of micrometer‐scale heterogeneities that trigger fast reactions associated with corrosion. Using a novel excitable reaction‐diffusion model, corrosion waves traveling over the metal surface and the associated material loss are described. This resulting nonuniform corrosion penetration, seen as a height loss in modeling, exposes buried intermetallic particles, which depending on the local electrochemical state of the surface trigger or block new waves. Informed by quantitative experimental data for the Mg–Al–Zn alloy AZ31B, wave speeds, wave widths, and average material loss are accurately captured. Morphogenic mitigation based on wave‐breaking microparticles is also simulated. While AZ31B corrosion is identified as a process driven by rare‐wave events, this study predicts several other corrosion regimes that proceed via spots or patchy patterns, opening the door for new protection, design, and prediction strategies.

Abstract Canavan disease is a leukodystrophy caused by ASPA mutations that diminish oligodendroglial aspartoacylase activity, and is characterized by markedly elevated brain concentrations of the aspartoacylase substrate N‐acetyl‐l‐aspartate (NAA) and by astroglial and intramyelinic vacuolation. Astroglia express NaDC3 (encoded by SLC13A3), a sodium‐coupled transporter for NAA and other dicarboxylates. Astroglial conditional Slc13a3 deletion in aspartoacylase‐deficient Canavan disease model mice (“CD mice”) reversed brain NAA elevation and improved motor function. These results demonstrate that astroglial NaDC3 contributes to brain NAA elevation in CD mice, and suggest that suppressing astroglial NaDC3 activity would ameliorate human Canavan disease.

Abstract Background Traditional plaster‐cast fabrication of an ankle‐foot orthosis (AFO), although robust, is time‐consuming and cumbersome. 3D scanning is quickly gaining attention as an alternative to plaster casting the foot and ankle region for AFO fabrication. The aim of this study was to assess the accuracy and speed of two high‐performing 3D scanners compared with plaster casting in pediatric patients requiring an AFO. Methods Ten participants (mean age 10.0 ± 3.9 years) prescribed AFOs for a movement disorder were 3D scanned with the high‐cost Artec Eva (Eva) and low‐cost Structure Sensor II (SSII) using one‐person (1p) and two‐person (2p) protocols. Accuracy and speed for both 3D scanners were compared with corresponding plaster cast measures (≤5% acceptable difference). Bland and Altman plots were generated to show mean bias and limits of agreement. Results Overall, Eva and SSII were accurate for foot, ankle, and lower leg key clinical landmarks (Eva‐1p: 4.4 ± 7.3%; Eva‐2p: 3.2 ± 7.5%; SSII‐1p: 0.6 ± 7.4%; SSII‐2p: 0.7 ± 8.2%). Bland and Altman plots for the SSII demonstrated lower biases for 1p (bias 0.5 mm, LoA: −12.4–13.5 mm) and 2p (0.4 mm, LoA: −11.4–12.2 mm) protocols compared with Eva for 1p (bias 2.3 mm, LoA: −8.0–12.7 mm) and 2p (1.8 mm, LoA: −10.7–14.3 mm) protocols. The SSII 2p protocol was the fastest 3D scanning method (26.4 ± 11.1 s). Conclusions The high‐cost Eva and low‐cost SSII 3D scanners using the 1p and 2p protocols produced comparable accuracy and faster capture of key clinical landmarks compared with plaster cast measures for the fabrication of AFOs in pediatric patients.

Abstract After days of intense solar activity, active region AR3664 launched seven CMEs toward Earth producing an extreme G5 geomagnetic storm commencing at 17:05 UT on 10 May 2024. The storm impacted power grids, disrupted precision navigational systems used by farming equipment, and generated aurora seen around the globe. The storm produced remarkable effects on composition, temperature, and dynamics in the Earth's thermosphere that were observed by NASA's Global‐scale Observations of the Limb and Disk (GOLD) mission and are reported here for the first time. We use synoptic disk images of ΣO/N2 and neutral temperature (at ∼160 km) measured by GOLD to directly link dynamics resulting from the storm with dramatic changes in thermospheric composition and temperature. We observe a heretofore unseen spatial morphology simultaneously in ΣO/N2, neutral temperature, and total electron content. Equator‐to‐pole temperature differences reach 400 K with high latitude peak neutral temperatures near 160 km exceeding 1400 K.

Abstract Bird collisions with aircraft pose a serious threat to human safety. However, broad‐scale patterns in how bird strikes might vary through space and time have yet to be fully understood. Here, we conducted a biogeographical study of bird strikes to answer two questions: (1) Are bird strikes higher at certain times of the year in the Northern and Southern Hemispheres? and (2) Is seasonality in bird strikes more prominent in the Northern Hemisphere than in the Southern Hemisphere? To answer these questions, we collated data on monthly bird strikes from 122 airports across the globe and used circular statistics to test for hemispherical asymmetries in the circular mean and variance in bird strikes. Results showed that annual peaks in bird strikes occurred between late summer to autumn seasons, and as a result, they occurred at opposite times of year in the northern and southern hemispheres. Results also showed that bird strikes were more seasonal in the Northern Hemisphere than in the Southern Hemisphere, where strikes tended to occur more consistently throughout the year. Practical implication: Overall results indicate that avian collisions with aircraft show strong biogeographical patterning, concomitant with global patterns in bird breeding seasons and migration tendencies.

Abstract INTRODUCTION Sodium phenylbutyrate and taurursodiol (PB and TURSO) is hypothesized to mitigate endoplasmic reticulum stress and mitochondrial dysfunction, two of many mechanisms implicated in Alzheimer's disease (AD) pathophysiology. METHODS The first‐in‐indication phase 2a PEGASUS trial was designed to gain insight into PB and TURSO effects on mechanistic targets of engagement and disease biology in AD. The primary clinical efficacy outcome was a global statistical test combining three endpoints relevant to disease trajectory (cognition [Mild/Moderate Alzheimer's Disease Composite Score], function [Functional Activities Questionnaire], and total hippocampal volume on magnetic resonance imaging). Secondary clinical outcomes included various cognitive, functional, and neuropsychiatric assessments. Cerebrospinal fluid (CSF) biomarkers spanning multiple pathophysiological pathways in AD were evaluated in participants with both baseline and Week 24 samples (exploratory outcome). RESULTS PEGASUS enrolled 95 participants (intent‐to‐treat [ITT] cohort); cognitive assessments indicated significantly greater baseline cognitive impairment in the PB and TURSO (n = 51) versus placebo (n = 44) group. Clinical efficacy outcomes did not significantly differ between treatment groups in the ITT cohort. CSF interleukin‐15 increased from baseline to Week 24 within the placebo group (n = 34). In the PB and TURSO group (n = 33), reductions were observed in core AD biomarkers phosphorylated tau‐181 (p‐tau181) and total tau; synaptic and neuronal degeneration biomarkers neurogranin and fatty acid binding protein‐3 (FABP3); and gliosis biomarker chitinase 3‐like protein 1 (YKL‐40), while the oxidative stress marker 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG) increased. Between‐group differences were observed for the Aβ42/40 ratio, p‐tau181, total tau, neurogranin, FABP3, YKL‐40, interleukin‐15, and 8‐OHdG. Additional neurodegeneration, inflammation, and metabolic biomarkers showed no differences between groups. DISCUSSION While between‐group differences in clinical outcomes were not observed, most likely due to the small sample size and relatively short treatment duration, exploratory biomarker analyses suggested that PB and TURSO engages multiple pathophysiologic pathways in AD. Highlights Proteostasis and mitochondrial stress play key roles in Alzheimer's disease (AD). Sodium phenylbutyrate and taurursodiol (PB and TURSO) targets these mechanisms. The PEGASUS trial was designed to assess PB and TURSO effects on biologic AD targets. PB and TURSO reduced exploratory biomarkers of AD and neurodegeneration. Supports further clinical development of PB and TURSO in neurodegenerative diseases.

Abstract Background High‐risk soft tissue sarcomas of the extremities and trunk wall (eSTS), as defined by the Sarculator nomogram, are more likely to benefit from (neo)adjuvant anthracycline‐based therapy compared to low/intermediate‐risk patients. The biology underpinning these differential treatment outcomes remain unknown. Methods We analysed proteomic profiles and clinical outcomes of 123 eSTS patients. A Cox model for overall survival including the Sarculator was fitted to individual data to define four risk groups. A DNA replication protein signature‐Sarcoma Proteomic Module 6 (SPM6) was evaluated for association with clinicopathological factors and risk groups. SPM6 was added as a covariate together with Sarculator in a multivariable Cox model to assess improvement in prognostic risk stratification. Results DNA replication and cell cycle proteins were upregulated in high‐risk versus very low‐risk patients. Evaluation of the functional effects of CRISPR‐Cas9 gene knockdown of proteins enriched in high‐risk patients using the cancer cell line encyclopaedia database identified candidate drug targets. SPM6 was significantly associated with tumour malignancy grade (p = 1.6e‐06), histology (p = 1.4e‐05) and risk groups (p = 2.6e‐06). Cox model analysis showed that SPM6 substantially contributed to a better calibration of the Sarculator nomogram (Index of Prediction Accuracy = 0.109 for Sarculator alone versus 0.165 for Sarculator + SPM6). Conclusions Risk stratification of patient with STS is defined by distinct biological pathways across a range of cancer hallmarks. Incorporation of SPM6 protein signature improves prognostic risk stratification of the Sarculator nomogram. This study highlights the utility of integrating protein signatures for the development of next‐generation nomograms.

Abstract Background The neutrophil‐lymphocyte ratio (NLR) in human medicine is an objective biomarker that reflects prognosis. The NLR as an independent biomarker to help predict nonsurvival in hospitalized neonatal foals has not been thoroughly interrogated. Objectives/Hypothesis Retrospectively evaluate if the NLR at admission is associated with nonsurvival in sick hospitalized foals

Abstract Increasing attention has been drawn to the misuse of statistical methods over recent years, with particular concern about the prevalence of practices such as poor experimental design, cherry picking and inadequate reporting. These failures are largely unintentional and no more common in ecology than in other scientific disciplines, with many of them easily remedied given the right guidance. Originating from a discussion at the 2020 International Statistical Ecology Conference, we show how ecologists can build their research following four guiding principles for impactful statistical research practices: (1) define a focussed research question, then plan sampling and analysis to answer it; (2) develop a model that accounts for the distribution and dependence of your data; (3) emphasise effect sizes to replace statistical significance with ecological relevance; and (4) report your methods and findings in sufficient detail so that your research is valid and reproducible. These principles provide a framework for experimental design and reporting that guards against unsound practices. Starting with a well‐defined research question allows researchers to create an efficient study to answer it, and guards against poor research practices that lead to poor estimation of the direction, magnitude, and uncertainty of ecological relationships, and to poor replicability. Correct and appropriate statistical models give sound conclusions. Good reporting practices and a focus on ecological relevance make results impactful and replicable. Illustrated with two examples—an experiment to study the impact of disturbance on upland wetlands, and an observational study on blue tit colouring—this paper explains the rationale for the selection and use of effective statistical practices and provides practical guidance for ecologists seeking to improve their use of statistical methods.

Abstract Background 5′‐adenosine monophosphate‐activated protein kinase (AMPK) agonists, particularly resveratrol (RES), have not been extensively evaluated for their effect on insulin dysregulation (ID) in horses. Objectives Evaluate the effects of treatment with RES (10 mg/kg PO q12h), metformin (MET; 30 mg/kg PO q12h), and aspirin (ASP; 20 mg/kg PO q24h) on experimentally induced ID. Animals Thirty‐three healthy, adult, light‐breed horses. Methods Unblinded, placebo‐controlled, experimental trial evaluating effects of AMPK agonists (RES, MET, and ASP) on experimentally induced ID. Horses were randomly assigned to a treatment group (RES, MET/ASP, RES/ASP, RES/MET/ASP, or placebo [CON]) after induction of ID with dexamethasone (0.08 mg/kg PO q24h for 7 days). Frequently sampled insulin‐modified IV glucose tolerance tests (FSIGTT) and oral sugar tests (OST) were performed at baseline, 7 days after ID, and ID plus 7 days of treatment. Minimal model and OST variables were compared between (1‐way ANOVA) and within (1‐way ANOVA for repeated measures) groups over time to determine effects of treatment on ID. Results Administration of dexamethasone for 14 days resulted in significantly altered insulin and glucose dynamics (SI, DI, basal [glucose], and [insulin]) and produced clinical signs of laminitis in 5 out of 33 (15%) of horses included in the study. Combination therapy with RES, MET, and ASP did not significantly improve insulin and glucose dynamics in horses with experimentally induced ID. Conclusions and Clinical Importance Metabolic testing before glucocorticoid administration should be considered in horses with clinical signs of metabolic syndrome.

Abstract Introduction Metastatic castration‐resistant prostate cancer (mCRPC) is a heterogeneous disease with prognoses varying from months to years at time of castration‐resistant diagnosis. Optimal first‐line therapy for those with different prognoses is unknown. Methods We conducted a retrospective cohort study of men in a national healthcare delivery system receiving first‐line therapy for mCRPC (abiraterone, enzalutamide, docetaxel, or ketoconazole) from 2010 to 2017, with follow‐up through 2019. Using commonly drawn prognostic labs at start of mCRPC therapy (hemoglobin, albumin, and alkaline phosphatase), we categorized men into favorable, intermediate, or poor prognostic groups depending on whether they had none, one to two, or all three laboratory values worse than designated laboratory cutoffs. We used Kaplan–Meier methods to examine prostate specific antigen (PSA) progression‐free and overall survival (OS) according to prognostic group and first‐line therapy, and multivariable cox regression to determine variables associated with survival outcomes. Results Among 4135 patients, median PSA progression‐free survival (PFS) was 6.9 months (95% confidence interval [CI] 6.6–7.3), and median OS 18.8 months (95% CI 18.0–19.6), ranging from 5.7 months (95% CI 4.8–7.0) in the poor prognosis group to 31.3 months (95% CI 29.7–32.9) in the favorable group. OS was similar regardless of initial treatment received for favorable and intermediate groups, but worse for those in the poor prognostic group who received ketoconazole (adjusted hazard ratio 2.07, 95% CI 1.2–3.6). PSA PFS was worse for those who received ketoconazole compared to abiraterone across all prognostic groups (favorable HR 1.76, 95% CI 1.34–2.31; intermediate HR 1.78, 95% CI 1.41–2.25; poor HR 8.01, 95% CI 2.93–21.9). Conclusion Commonly drawn labs at mCRPC treatment start may aid in predicting survival and response to therapies, potentially informing discussions with care teams. First‐line treatment selection impacts disease progression for all men with mCRPC regardless of prognostic group, but impacted OS only for men with poor prognosis at treatment start.

Abstract Brexucabtagene autoleucel (brexu‐cel) is an autologous CD19 CAR T‐cell product, approved for relapsed/refractory (r/r) mantle cell lymphoma (MCL). In ZUMA‐2, brexu‐cel demonstrated impressive responses in patients failing ≥2 lines, including a bruton's tyrosine kinase inhibitor, with an overall and complete response rate of 93% and 67%, respectively. Here, we report our real‐world intention‐to‐treat (ITT) outcomes for brexu‐cel in consecutive, prospectively approved patients, from 12 institutions in the United Kingdom between February 2021 and June 2023, with a focus on feasibility, efficacy, and tolerability. Of 119 approved, 104 underwent leukapheresis and 83 received a brexu‐cel infusion. Progressive disease (PD) and/or manufacturing (MF) were the most common reasons for failure to reach harvest and/or infusion. For infused patients, best overall and complete response rates were 87% and 81%, respectively. At a median follow‐up of 13.3 months, median progression‐free survival (PFS) for infused patients was 21 months (10.1–NA) with a 6‐ and 12‐month PFS of 82% (95% confidence interval [CI], 71–89) and 62% (95% CI, 49–73), respectively. ≥Grade 3 cytokine release syndrome and neurotoxicity occurred in 12% and 22%, respectively. On multivariate analysis, inferior PFS was associated with male sex, bulky disease, ECOG PS > 1 and previous MF. Cumulative incidence of non‐relapse mortality (NRM) was 6%, 15%, and 25% at 6, 12, and 24 months, respectively, and mostly attributable to infection. Outcomes for infused patients in the UK are comparable to ZUMA‐2 and other real‐world reports. However, ITT analysis highlights a significant dropout due to PD and/or MF. NRM events warrant further attention.

Abstract Objective We estimate annual hospital expenditures to achieve high emergency department (ED) pediatric readiness (HPR), that is, weighted Pediatric Readiness Score (wPRS) ≥ 88 (0–100 scale) across EDs with different pediatric volumes of children, overall and after accounting for current levels of readiness. Methods We calculated the annual hospital costs of HPR based on two components: (1) ED pediatric equipment and supplies and (2) labor costs required for a Pediatric Emergency Care Coordinator (PECC) to perform pediatric readiness tasks. Data sources to generate labor cost estimates included: 2021 national salary information from U.S. Bureau of Labor Statistics, detailed patient and readiness data from 983 EDs in 11 states, the 2021 National Pediatric Readiness Project assessment; a national PECC survey; and a regional PECC survey. Data sources for equipment and supply costs included: purchasing costs from seven healthcare organizations and equipment usage per ED pediatric volume. We excluded costs of day‐to‐day ED operations (ie, direct clinical care and routine ED supplies). Results The total annual hospital costs for HPR ranged from $77,712 (95% CI 54,719–100,694) for low volume EDs to $279,134 (95% CI 196,487–362,179) for very high volume EDs; equipment costs accounted for 0.9–5.0% of expenses. The total annual cost‐per‐patient ranged from $3/child (95% CI 2–4/child) to $222/child (95% CI 156–288/child). After accounting for current readiness levels, the cost to reach HPR ranged from $23,775 among low volume EDs to $145,521 among high volume EDs, with costs per patient of $4/child to $48/child. Conclusions Annual hospital costs for HPR are modest, particularly when considered per child.

Abstract The critical gelation conditions observed in dilute aqueous solutions of multiple nanoscale uranyl peroxide molecular clusters are reported, in the presence of multivalent cations. This gelation is dominantly driven by counterion‐mediated attraction. The gelation areas in the corresponding phase diagrams all appear in similar locations, with a characteristic triangle shape outlining three critical boundary conditions, corresponding to the critical cluster concentration, cation/cluster ratio, and the degree of counterion association with increasing cluster concentration. These interesting phrasal observations reveal general conditions for gelation driven by electrostatic interactions in hydrophilic macroionic solutions.

Abstract INTRODUCTION Recruitment of sufficient and diverse participants into clinical research for Alzheimer's disease and related dementias remains a formidable challenge. The primary goal of this manuscript is to provide an overview of an approach to diversifying research recruitment and to provide case examples of several methods for achieving greater diversity in clinical research enrollment. METHODS The University of Kansas Alzheimer's Disease Research Center (KU ADRC) developed MyAlliance for Brain Health (MyAlliance), a service‐oriented recruitment model. MyAlliance comprises a Primary Care Provider Network, a Patient and Family Network, and a Community Organization Network, each delivering tailored value to relevant parties while facilitating research referrals. RESULTS We review three methods for encouraging increased diversity in clinical research participation. Initial outcomes reveal an increase in underrepresented participants from 17% to 27% in a research registry. Enrollments into studies supported by the research registry experienced a 51% increase in proportion of participants from underrepresented communities. DISCUSSION MyAlliance shifts power, resources, and knowledge to community advocates, promoting brain health awareness and research participation, and demands substantial financial investment and administrative commitment. MyAlliance offers valuable lessons for building sustainable, community‐centered research recruitment infrastructure, emphasizing the importance of localized engagement and cultural understanding. Highlights MyAlliance led to a significant increase in the representation of underrepresented racial and ethnic groups and individuals from rural areas. The service‐oriented approach facilitated long‐term community engagement and trust‐building, extending partnerships between an academic medical center and community organizations. While effective, MyAlliance required substantial financial investment, with costs including infrastructure development, staff support, partner organization compensation, and promotional activities, underscoring the resource‐intensive nature of inclusive research recruitment efforts.

Abstract Background The term ‘care‐experienced’ refers to anyone who is currently in care or has been in care at any stage in their life. A complex interplay of factors leads to care‐experienced children and young people (CECYP) experiencing poorer oral health and access to dental care than their peers. A rapid review of the co‐production of health and social care research with vulnerable children and young people (CYP) was carried out to inform the development of a co‐produced research project exploring the oral health behaviours and access to dental services of CECYP. Here, ‘co‐production’ refers to the involvement of CYP in the planning or conduct of research with explicit roles in which they generate ideas, evidence and research outputs. Aim To learn how to meaningfully involve vulnerable CYP in the co‐production of health and social science research. Objectives To identify: Different approaches to facilitating the engagement of vulnerable CYP in co‐production of health and social science research; different activities carried out in such approaches, challenges to engaging vulnerable CYP in co‐production of health and social science research and ways to overcome them and areas of best practice in relation to research co‐production with vulnerable CYP. Search Strategy A rapid review of peer‐reviewed articles was conducted in six databases (MEDLINE, Embase, SocINDEX, CINAHL, PsycINFO and Web of Science) and grey literature to identify studies that engaged vulnerable CYP in co‐approaches to health and social research. Main Results Of 1394 documents identified in the search, 40 were included and analysed. A number of different approaches to co‐production were used in the studies. The CYP was involved in a range of activities, chiefly the development of data collection tools, data collection and dissemination. Individual challenges for CYP and researchers, practical and institutional factors and ethical considerations impacted the success of co‐production. Discussion and Conclusion Co‐production of health and social science with vulnerable CYP presents challenges to researchers and CYP calling for all to demonstrate reflexivity and awareness of biases, strengths and limitations. Used appropriately and well, co‐production offers benefits to researchers and CYP and can contribute to research that reflects the needs of vulnerable CYP. Adherence to the key principles of inclusion, safeguarding, respect and well‐being facilitates this approach. Patient and Public Contribution Members of our patient and public involvement and stakeholder groups contributed to the interpretation of the review findings. This manuscript was written together with a young care leaver, Skye Boswell, who is one of the authors. She contributed to the preparation of the manuscript, reviewing the findings and their interpretation.

Abstract Consensus guidelines recommend use of granulocyte colony stimulating factor in patients deemed at risk of chemotherapy‐induced neutropenia, however, these risk models are limited in the factors they consider and miss some cases of neutropenia. Clinical decision making could be supported using models that better tailor their predictions to the individual patient using the wealth of data available in electronic health records (EHRs). Here, we present a hybrid pharmacokinetic/pharmacodynamic (PKPD)/machine learning (ML) approach that uses predictions and individual Bayesian parameter estimates from a PKPD model to enrich an ML model built on her data. We demonstrate this approach using models developed on a large real‐world data set of 9121 patients treated for lymphoma, breast, or thoracic cancer. We also investigate the benefits of augmenting the training data using synthetic data simulated with the PKPD model. We find that PKPD‐enrichment of ML models improves prediction of grade 3–4 neutropenia, as measured by higher precision (61%) and recall (39%) compared to PKPD model predictions (47%, 33%) or base ML model predictions (51%, 31%). PKPD augmentation of ML models showed minor improvements in recall (44%) but not precision (56%), and data augmentation required careful tuning to control overfitting its predictions to the PKPD model. PKPD enrichment of ML shows promise for leveraging both the physiology‐informed predictions of PKPD and the ability of ML to learn predictor‐outcome relationships from large data sets to predict patient response to drugs in a clinical precision dosing context.

Abstract Background Abiraterone and enzalutamide are castration‐resistant prostate cancer (CRPC) therapies with potentially distinct associations with mental health symptoms given their differing antiandrogen targets. Methods We used national Veterans Health Administration data to identify patients with CRPC who received first‐line abiraterone or enzalutamide from 2010 to 2017. Using Poisson regression, we compared outpatient mental health encounters per 100 patient‐months on drug between the abiraterone and enzalutamide cohorts adjusting for patient factors (e.g., age). We compared mental health encounters in the year before versus after starting therapy using the McNemar test. Results We identified 2902 CRPC patients who received abiraterone (n = 1992) or enzalutamide (n = 910). We found no difference in outpatient mental health encounters between the two groups (adjusted incident rate ratio [aIRR] 1.04, 95% confidence interval [CI] 0.95–1.15). However, men with preexisting mental health diagnoses received 81.3% of the outpatient mental health encounters and had higher rates of these encounters with enzalutamide (aIRR 1.21, 95% CI 1.09–1.34). Among patients with ≥1 year of enrollment before and after starting abiraterone (n = 1139) or enzalutamide (n = 446), there was no difference in mental health care utilization before versus after starting treatment (17.0% of patients vs. 17.6%, p = 0.60, abiraterone; 16.4% vs. 18.4%, p = 0.26, enzalutamide). Conclusion We found no overall differences in mental health care utilization between CRPC patients who received first‐line abiraterone versus enzalutamide. However, men with preexisting mental health diagnoses received the majority of mental health care and had more mental health visits with enzalutamide.

Abstract Stage‐based demographic methods, such as matrix population models (MPMs), are powerful tools used to address a broad range of fundamental questions in ecology, evolutionary biology and conservation science. Accordingly, MPMs now exist for over 3000 species worldwide. These data are being digitised as an ongoing process and periodically released into two large open‐access online repositories: the COMPADRE Plant Matrix Database and the COMADRE Animal Matrix Database. During the last decade, data archiving and curation of COMPADRE and COMADRE, and subsequent comparative research, have revealed pronounced variation in how MPMs are parameterized and reported. Here, we summarise current issues related to the parameterisation and reporting of MPMs that arise most frequently and outline how they affect MPM construction, analysis, and interpretation. To quantify variation in how MPMs are reported, we present results from a survey identifying key aspects of MPMs that are frequently unreported in manuscripts. We then screen COMPADRE and COMADRE to quantify how often key pieces of information are omitted from manuscripts using MPMs. Over 80% of surveyed researchers (n = 60) state a clear benefit to adopting more standardised methodologies for reporting MPMs. Furthermore, over 85% of the 300 MPMs assessed from COMPADRE and COMADRE omitted one or more elements that are key to their accurate interpretation. Based on these insights, we identify fundamental issues that can arise from MPM construction and communication and provide suggestions to improve clarity, reproducibility and future research utilising MPMs and their required metadata. To fortify reproducibility and empower researchers to take full advantage of their demographic data, we introduce a standardised protocol to present MPMs in publications. This standard is linked to www.compadre‐db.org, so that authors wishing to archive their MPMs can do so prior to submission of publications, following examples from other open‐access repositories such as DRYAD, Figshare and Zenodo. Combining and standardising MPMs parameterized from populations around the globe and across the tree of life opens up powerful research opportunities in evolutionary biology, ecology and conservation research. However, this potential can only be fully realised by adopting standardised methods to ensure reproducibility.

Abstract Antiarrhythmic medications are fundamental in the acute and chronic management of pediatric arrhythmias. Particularly in the pediatric patient population, associated antiarrhythmic toxicities represent important potential adverse effects. Emergency medicine clinicians must be skilled in the detection, workup, and management of antiarrhythmic toxicity. This is a clinical review of the indications, pharmacology, adverse effects, and toxicologic treatment of antiarrhythmics commonly used in the pediatric patient population.

Abstract Introduction Creating safer care is a high priority across healthcare systems. Despite this, most systems tend to focus on mitigating past harm, not creating proactive solutions. Managers and staff identify safety threats often with little input from patients and their caregivers during their health encounters. Methods This is a qualitative descriptive study utilizing focus groups and one‐to‐one interviews with patients and caregivers who were currently using (or had previously used) services in health systems across Canada. Data were analysed via inductive thematic analysis to understand existing and desired strategies to promote safer and better quality care from the perspectives of patients and caregivers. Findings In our analysis, we identified three key themes (safety strategies) from patients' and caregivers' perspectives and experiences: Using Tools and Approaches for Engaging Patients and Caregivers in their Care; Having Accountability Processes and Mechanisms for Safe Care; and Enabling Patients and Caregivers Access to Information. Conclusions Safety is more than the absence of harm. Our findings outline a number of suggestions from patients and caregivers on how to make care safer, ranging from being valued on teams, participating as members of quality improvement tables, having access to health information, having access to an advocate to help make sense of information and having processes in place for disclosure and closure. Future work can further refine, implement and evaluate these strategies in practice. Patient or Public Contributions An advisory group guided the research and was co‐chaired by a patient partner. Members of the advisory group spanned patient and caregiver organizations and health sectors across Canada and included three patient partners and leaders who work closely with patients and caregivers in their day‐to‐day work. In the research itself, we engaged 28 patients and caregivers from across Canada to learn about their safety experiences and learn what safer care looks like from their perspectives.

Abstract Iron deficiency (ID) and ID with anaemia (IDA) are serious global health problems that disproportionately affect women aged 15–49 years. Although food fortification is one of the most effective and sustainable ways to combat nutritional deficiencies, iron remains one of the most difficult micronutrients to fortify, given its tendency to react strongly with food constituents. Therefore, it is important to assess the sensory properties of foods fortified with iron to determine the acceptability and palatability in target populations. We aimed to determine the palatability and acceptability of a novel iron and zinc‐enriched powder fortified in tap water by conducting sensory evaluations in 35 women of reproductive age using a 9‐point hedonic scale, where participants rated the sensory properties of six samples containing different amounts of the active or placebo powder. We found significant differences between samples reconstituted at 1, 2, and 3 g/L for sensory properties, including overall taste. Participants were found to be more willing to drink the mineral‐enriched powder when prepared at the lowest concentration (1 g/L) compared to higher concentrations. Our results provide important insight into the sensory qualities of a novel formulation of an iron and zinc‐enriched powder for at‐home fortification and indicate consumer acceptability in reproductive‐aged women, a key group at risk for ID/IDA. If found to improve iron status, novel treatments like this product will contribute to global efforts to develop safe, acceptable and sustainable interventions for ID and IDA.

Abstract SH2B3 is a negative regulator of multiple cytokine receptor signalling pathways in haematopoietic tissue. To date, a single kindred has been described with germline biallelic loss‐of‐function SH2B3 variants characterized by early onset developmental delay, hepatosplenomegaly and autoimmune thyroiditis/hepatitis. Herein, we described two further unrelated kindreds with germline biallelic loss‐of‐function SH2B3 variants that show striking phenotypic similarity to each other as well as to the previous kindred of myeloproliferation and multi‐organ autoimmunity. One proband also suffered severe thrombotic complications. CRISPR‐Cas9 gene editing of zebrafish sh2b3 created assorted deleterious variants in F0 crispants, which manifest significantly increased number of macrophages and thrombocytes, partially replicating the human phenotype. Treatment of the sh2b3 crispant fish with ruxolitinib intercepted this myeloproliferative phenotype. Skin‐derived fibroblasts from one patient demonstrated increased phosphorylation of JAK2 and STAT5 after stimulation with IL‐3, GH, GM‐CSF and EPO compared to healthy controls. In conclusion, these additional probands and functional data in combination with the previous kindred provide sufficient evidence for biallelic homozygous deleterious variants in SH2B3 to be considered a valid gene‐disease association for a clinical syndrome of bone marrow myeloproliferation and multi‐organ autoimmune manifestations.

Background Excessive daytime sleepiness (EDS), experienced in 10% to 20% of the population, has been associated with cardiovascular disease and death. However, the condition is heterogeneous and is prevalent in individuals having short and long sleep duration. We sought to clarify the relationship between sleep duration subtypes of EDS with cardiovascular outcomes, accounting for these subtypes. Methods and Results We defined 3 sleep duration subtypes of excessive daytime sleepiness: normal (6–9 hours), short (9 hours), and compared these with a nonsleepy, normal‐sleep‐duration reference group. We analyzed their associations with incident myocardial infarction (MI) and stroke using medical records of 355 901 UK Biobank participants and performed 2‐sample Mendelian randomization for each outcome. Compared with healthy sleep, long‐sleep EDS was associated with an 83% increased rate of MI (hazard ratio, 1.83 [95% CI, 1.21–2.77]) during 8.2‐year median follow‐up, adjusting for multiple health and sociodemographic factors. Mendelian randomization analysis provided supporting evidence of a causal role for a genetic long‐sleep EDS subtype in MI (inverse‐variance weighted β=1.995, P=0.001). In contrast, we did not find evidence that other subtypes of EDS were associated with incident MI or any associations with stroke (P>0.05). Conclusions Our study suggests the previous evidence linking EDS with increased cardiovascular disease risk may be primarily driven by the effect of its long‐sleep subtype on higher risk of MI. Underlying mechanisms remain to be investigated but may involve sleep irregularity and circadian disruption, suggesting a need for novel interventions in this population.

Introduction Transradial access (TRA) has become increasingly utilized among neurointerventionalists. There is evidence of reduced complications and higher patient satisfaction compared to transfemoral access (TFA), but more data directly comparing the safety and efficacy of the two approaches is needed. To assess the proportion of technical success and complications with TRA versus TFA in patients who underwent neuroendovascular diagnostic and therapeutic procedures. Methods PRISMA guidelines were used to conduct a systematic review of the literature with PubMed/Medline, Scopus, Embase, and Cochrane databases up to February 2023. Randomized clinical trials (RCT) and observational studies that compared TRA and TFA were included. Studies reporting results of patients who underwent diagnostic angiograms, endovascular management of acute stroke, aneurysm repair, and carotid or vertebral stenting were included. Our primary outcome was technical success, defined as successful arterial access and completion of the intended procedure without crossover. Secondary safety outcomes were rate of complications including access site and non‐access site related, and other efficacy measures such as procedure duration, fluoroscopy time, and radiation exposure. Random effects model was used to perform a meta‐analysis. The Mantel‐Haenszel method was used to calculate risk ratio (RR) and 95% confidence intervals (CI) for each outcome. Heterogeneity was evaluated using I2 and considered high if over 70%. Results Twenty‐nine studies comprising 14,523 patients met inclusion criteria. TRA was attempted in 5,865 (40.38%) patients and TFA in 8,658 (59.62%). Baseline characteristics were similar between groups. The rate of technical success was 95.46% (95% CI: 93.59 – 96.81; p < 0.01) in the TRA group compared with 98.43% (95% CI: 97.60 – 98.97; p = 0.02) in the TFA group. Patients who underwent a diagnostic or therapeutic angiogram via TRA had a slightly lower chance of achieving technical success (RR = 0.98; 95% CI: 0.96 – 0.99; p < 0.01) compared to TFA, with substantial heterogeneity (I2 = 68%). Major access site complications were non‐significantly lower in the TRA group (RR = 0.64; 95% CI: 0.29 – 1.41; p = 0.81) with null heterogenicity (I2 = 0%) between groups. Minor access site complications were significantly lower in the TRA group (RR = 0.43; 95% CI 0.28 – 0.67; p < 0.01), with moderate heterogeneity (I2 = 57%). Non‐access site related complications (including mortality) were lower in the TRA group (RR = 0.69; 95% CI 0.51 – 0.94; p = 0.14) with low heterogeneity (I2 = 26%) between groups; for this outcome, the TRA approach shows a protective but not statistically significant result. Conclusion Our study suggests TRA is feasible and safe for diagnostic and therapeutic neuroendovascular procedures with low certainty of evidence. Minor complications were lower in the TRA group. RCTs directly comparing TRA vs TFA for these procedures are needed to confirm these results.

Abstract Background We expanded the Multidimensional Assessment Profiles (MAPS) Scales developmental specification model to characterize the normal:abnormal spectrum of internalizing (anxious and depressive) behaviors in early childhood via the MAPS‐Internalizing (MAPS‐INT) scale. Methods The MAPS‐INT item pool was generated based on clinical expertise and prior research. Analyses were conducted on a sub‐sample of families (n = 183) from the diverse When to Worry early childhood sample. Results Normal:abnormal descriptive patterns for both anxious and depressive behaviors were consistent with prior work: (1) extremes of normative variation are abnormal when very frequent; and (2) pathognomonic indicators that most children do not engage in and are abnormal, even if infrequent. Factor analysis revealed a two‐factor MAPS‐INT Anxious Behaviors structure (Fearful‐Worried and Separation Distress) and a unidimensional MAPS‐INT Depressive Behaviors factor with good fit and good‐to‐excellent test‐retest reliability and validity. Conclusions We characterized the normal:abnormal spectrum of internalizing behaviors in early childhood via the MAPS‐INT. Future research in larger representative samples can replicate and extend findings, including clinical thresholds and predictive utility. The MAPS‐INT helps lay the groundwork for dimensional characterization of the internalizing spectrum to advance neurodevelopmental approaches to emergent psychopathology and its earlier identification.

For an avian migrant, refueling capacity attainable during stopovers governs the entire migration schedule and, ultimately, its fitness. Specifically, timely replenishing energy stores is critical when migration involves crossing ecological barriers, within which refueling may be limited. Here, we tested the hypothesis that fuel deposition rates (FDRs) of migratory passerines within barrier‐edge stopover sites are constrained by the density of potential competitors, irrespective of migration season, phenology, and local environmental conditions. We also evaluated diverse intra‐ and inter‐specific competition scenarios and explored a potential mediation of density‐dependence by environmental factors. The analyzed data, collected by us over 13 consecutive years (2009–2022), contain information on seven species of long‐distance migratory insectivorous passerines measured within eight desert‐edge habitats throughout autumn and spring migrations. As predicted, our analyses revealed negative density‐dependence regulation of FDRs, consistent across species and migration seasons. Notably, bird density exerted its effect above and beyond the other factors known to influence FDR, such as relative ambient temperature, phenology, temporal progress of stopover, and body mass next to landfall. As expected, FDR increased at higher relative ambient temperatures and with the stopover's progress. In spring, FDR also rose as the season advanced. These findings signify the substantial impact of competition on the refueling performance of migratory passerines during their stopover on an ecological barrier's edge, acting over and above the other environmental factors. The detected importance of competition and its interrelation with other predictors provides an insight into stopover's functioning; environmentally imposed and inescapable interspecific interference is thus a significant limiting factor of FDR, a deleterious relationship potentially remediable by informed habitat restoration and planning.

Abstract INTRODUCTION The risk reduction for Alzheimer's disease (rrAD) trial was a multisite clinical trial to assess exercise and intensive vascular pharmacological treatment on cognitive function in community‐dwelling older adults at increased risk for Alzheimer's disease. METHODS Eligibility, consent, and randomization rates across different referral sources were compared. Informal interviews conducted with each site's project team were conducted upon study completion. RESULTS Initially, 3290 individuals were screened, of whom 28% were eligible to consent, 805 consented to participate (87.2% of those eligible), and 513 (36.3% of those consented) were randomized. Emails sent from study site listservs/databases yielded the highest amount (20.9%) of screened individuals. Professional referrals from physicians yielded the greatest percentage of consented individuals (57.1%). Referrals from non‐professional contacts (ie, friends, family; 75%) and mail/phone contact from a site (73.8%) had the highest yield of randomization. DISCUSSION Professional referrals or email from listservs/registries were most effective for enrolling participants. The greatest yield of eligible/randomized participants came from non‐professional and mail/phone contacts. Future trials should consider special efforts targeting these recruitment approaches. Highlights Clinical trial recruitment is commonly cited as a significant barrier to advancing our understanding of cognitive health interventions. The most cited referral source was email, followed by interviews/editorials on the radio, television, local newspapers, newsletters, or magazine articles. The referral method that brought in the largest number of contacts was email but did not result in the greatest yield of consents or eligible participants. The sources that yielded the greatest likelihood of consent were professional referrals (ie, physician), social media, and mail/phone contact from study site. The greatest yield of eligible/randomized participants came from non‐professional contacts and mail/phone contact from a site. Findings suggest that sites may need to focus on more selective referral sources, such as using contact mailing and phone lists, rather than more widely viewed recruitment sources, such as social media or TV/radio advertisements.

Abstract Regulatory T (Treg) cells are inevitable to prevent deleterious immune responses to self and commensal microorganisms. Treg function requires continuous expression of the transcription factor (TF) FOXP3 and is divided into two major subsets: resting (rTregs) and activated (aTregs). Continuous T cell receptor (TCR) signaling plays a vital role in the differentiation of aTregs from their resting state, and in their immune homeostasis. The process by which Tregs differentiate, adapt tissue specificity, and maintain stable phenotypic expression at the transcriptional level is still inconclusivei. In this work, the role of BATF is investigated, which is induced in response to TCR stimulation in naïve T cells and during aTreg differentiation. Mice lacking BATF in Tregs developed multiorgan autoimmune pathology. As a transcriptional regulator, BATF is required for Treg differentiation, homeostasis, and stabilization of FOXP3 expression in different lymphoid and non‐lymphoid tissues. Epigenetically, BATF showed direct regulation of Treg‐specific genes involved in differentiation, maturation, and tissue accumulation. Most importantly, FOXP3 expression and Treg stability require continuous BATF expression in Tregs, as it regulates demethylation and accessibility of the CNS2 region of the Foxp3 locus. Considering its role in Treg stability, BATF should be considered an important therapeutic target in autoimmune disease.

Abstract Some women who breastfeed will experience complex ongoing difficulties, such as breastfeeding aversion response (BAR). This recently named breastfeeding challenge is defined as feelings of aversion while breastfeeding for the entire time that the child is latched. This study provides the first prevalence data for the experience of BAR in Australian breastfeeding women. A national online survey investigated the breastfeeding experience of Australian women including data on (1) participant demographics, (2) breastfeeding experience with up to four children, (3) breastfeeding challenges and prevalence of BAR, and (4) the value of available breastfeeding support. This study found that of the Australian breastfeeding women who participated (n = 5511), just over one in five self‐identified as having experienced a BAR (n = 1227, 22.6%). Most reported experiencing some breastfeeding challenges, with only 4.5% (n = 247) having had no breastfeeding complications. Importantly, despite these difficulties, 86.9% of the total women in this study rated their overall breastfeeding experience as good (n = 2052, 37.6%), or very good (n = 2690, 49.3%), and 82.5% of those who experience BAR as good (n = 471, 38.7%) or very good (n = 533, 43.8%). BAR reporting was decreased in higher education and income groups. Women who are breastfeeding for the first time are more likely to encounter difficulties with breastfeeding such as BAR. Complications with breastfeeding are pervasive, but women who can overcome breastfeeding issues often report a positive overall breastfeeding experience.

Abstract Background Over the past decade, abiraterone and enzalutamide have largely replaced ketoconazole as oral treatments for castration‐resistant prostate cancer (CRPC). We investigated the differential adoption of abiraterone and enzalutamide across facilities in a national healthcare system to understand the impact a facility has on the receipt of these novel therapies. Methods Using data from the VA Corporate Data Warehouse, we identified a cohort of men with CRPC who received the most common first‐line therapies: abiraterone, enzalutamide, docetaxel, or ketoconazole between 2010 and 2017. We described variability in the adoption of abiraterone and enzalutamide across facilities by time period (2010–2013 or 2014–2017). We categorized facilities depending on the timing of adoption of abiraterone and enzalutamide relative to other facilities and described facility characteristics associated with early and late adoption. Results We identified 4998 men treated with ketoconazole, docetaxel, abiraterone, or enzalutamide as first‐line CRPC therapy between 2010 and 2017 at 125 national facilities. When limiting the cohort to oral therapies, most patients treated earlier in the study period (2010–2013) received ketoconazole. A dramatic shift was seen by the second half of the study period (2014–2017) with most men treated with first‐line abiraterone (61%). Despite this shift and a new standard of care, some facilities persisted in the widespread use of ketoconazole in the later period, so‐called late adopting facilities. After multivariable adjustment, patients who received treatment at a late adopting facility were more likely receiving care at a lower complexity, rural facility, with less urology and hematology/oncology workforce (all p

Abstract Background Supporting limb laminitis (SLL) is a complication of severe orthopedic disease in horses and is often life‐limiting, yet the pathophysiology remains obscure. Hypothesis/Objectives To investigate the role of digital lamellar inflammatory signaling in the pathophysiology of SLL using a model of unilateral weight bearing, hypothesizing that there would be evidence of lamellar inflammation in limbs subjected to the model. Animals Thirteen healthy adult Standardbred horses were used for this study (11 geldings, 2 mares; mean age 6.5 ± 2.5 years; mean body weight 458.3 ± 32.8 kg). Methods Randomized controlled experimental study. A steel shoe with a custom insert was applied to a randomly selected front foot of 7 horses; 6 horses were unshod and served as controls. After 92 hours, all horses were humanely euthanized, and digital lamellar samples were collected. Lamellar protein and mRNA were isolated and used to perform western blot and PCR. Results Lamellar concentrations of IL‐6 mRNA were higher in SL tissue than IL HIND tissue (median [25%‐75%] normalized copy number 191 [111‐3060] and 48 [25‐74], respectively; P=.003), and lamellar concentrations of COX‐2 mRNA were higher in SL tissue than CON tissue (normalized copy number 400 [168‐634] and 125 [74‐178], respectively; P=.007). Lamellar concentrations of IL‐1B, IL‐10, and COX‐1 mRNA were not significantly different between groups. The concentrations of phosphorylated (activated) STAT1 and STAT3 proteins were higher in SL (0.5 [0.35‐0.87] and 1.35 [1.1‐1.7], respectively) compared to CON (0.24 [0.09‐0.37] and 0.31 [0.16‐037]) and UL HIND (0.27 [0.19‐0.37] and 0.38 [0.24‐0.5]); P=0.01 and P

Abstract Background Peroxisome proliferator‐activated receptor agonists such as fibrates restore oxidative metabolism in cytotoxic T‐lymphocytes, thereby enhancing response to immune checkpoint inhibitors (ICI) in preclinical models. However, there is no evidence in humans on the clinical impact of fibrates as an adjunct to ICI. Methods In this cohort study of Veterans with non‐small cell lung cancer (NSCLC) receiving ICI, fibrate exposure was defined as a prescription filled within 90 days of an ICI infusion. Overall survival (OS), measured from the start of ICI, was compared between exposed and unexposed Veterans. Cox multivariable analysis (MVA) was used to identify factors associated with OS. A sensitivity analysis of Veterans with stage IV NSCLC who received docetaxel without ICI was similarly performed. Results The ICI cohort included 3593 Veterans, of whom 301 (8.5%) coincidentally received a fibrate. Veterans receiving fibrates were more likely to be older, white, male, and married, and to have greater comorbidity burden, but less likely to receive chemotherapy. Coincidental fibrates were associated with improved OS both on MVA (HR 0.86, 95%CI 0.75–0.99) and in a matched subset (HR 0.75, 95%CI 0.63–0.90). In contrast, among the cohort of 968 Veterans treated with chemotherapy, fibrates did not have a significant impact on OS by MVA (HR 0.99, 95%CI 0.79–1.25) or in a matched subset (HR 1.02, 95%CI CI 0.75–1.39). Conclusions Concomitant fibrates are associated with improved OS among NSCLC patients receiving ICI but not among those receiving chemotherapy. This hypothesis‐generating observation supports a potential role for fibrates as an adjunct to immunotherapy.

Abstract Introduction Patients discharged following hospitalization for COVID‐19 require clear discharge protocols, information resources and communications to adequately prepare them to safely and successfully transition from hospital to home. Our study focuses on the patients' transition to recovering at home including their hospital discharge preparation and hospital experiences. Methods A qualitative descriptive study design involved interviewing patients who had been hospitalized for COVID‐19 in one urban Alberta, Canada centre. Purposive sampling was used to select patients from a centralized COVID‐19 hospital patient database stratified by month between March 2020 and February 2021. Other inclusion criteria (e.g., sex and age) were also considered. Semi‐structured interviews with patients were recorded, transcribed and analysed using thematic analysis. Data sufficiency and saturation were determined. Results Twelve patients shared their lived experiences and recovery journey from COVID‐19. Themes were reported under three main areas as framed by the study aim—the current status of patients recovering at home, including the supports they used to manage; their discharge process and preparation to go home; and their various hospital‐related experiences. Suggestions for improving aspects of the patient journey were also captured. Conclusion Findings provided details of the needs, information gaps and what matters most to patients when they are recovering from COVID‐19 at home, including their preparation to safely and successfully transition from hospital to home (i.e., feeling well prepared to go home, including being adequately assessed and having clear discharge protocols and communication). Key learnings were applied to improve or develop patient discharge and transition resources. Patient or Public Contribution A patient/family advisor and patient experience partners were involved throughout the study, codeveloping all aspects, from the study design to the reporting and application of the findings. Leading into the study, patient experiences and feedback regarding the home from hospital recovery journey informed multiple aspects, including the codevelopment of the interview guide.

Abstract Chlorthalidone (CTD) may be superior to hydrochlorothiazide (HCTZ) in the reduction of adverse cardiovascular events in hypertensive patients. The mechanism of the potential benefit of CTD could be related to antiplatelet effects. The objective of this study was to determine if CTD or HCTZ have antiplatelet effects. This study was a prospective, double‐blind, randomized, three‐way crossover comparison evaluating the antiplatelet effects of CTD, HCTZ, and aspirin (ASA) in healthy volunteers. The effects of these treatments on platelet activation and aggregation were assessed using a well‐established method with five standard platelet agonists. Thirty‐four patients completed the three‐way crossover comparing pre‐ and post‐treatment changes in platelet activation and aggregation studies. There were statistically significant antiplatelet effects with ASA but not with CTD or HCTZ. Hypokalemia occurred in 0 (0%), 10 (30%), and 6 (18%) of the ASA, CTD, and HCTZ patients, respectively. The results of our study suggest that the benefits of CTD and HCTZ in reducing adverse cardiovascular events in patients with hypertension is not a result of an antiplatelet effect. In our study, hypokalemia with CTD was more prevalent than that reported in a large outcome trial in patients with hypertension. The clinical relevance of this finding is uncertain.

Background Chromosomal microarray analysis (CMA) provides an opportunity to understand genetic causes of congenital heart disease (CHD). The methods for describing cardiac phenotypes in patients with CMA abnormalities have been inconsistent, which may complicate clinical interpretation of abnormal testing results and hinder a more complete understanding of genotype–phenotype relationships. Methods and Results Patients with CHD and abnormal clinical CMA were accrued from 9 pediatric cardiac centers. Highly detailed cardiac phenotypes were systematically classified and analyzed for their association with CMA abnormality. Hierarchical classification of each patient into 1 CHD category facilitated broad analyses. Inclusive classification allowing multiple CHD types per patient provided sensitive descriptions. In 1363 registry patients, 28% had genomic disorders with well‐recognized CHD association, 67% had clinically reported copy number variants (CNVs) with rare or no prior CHD association, and 5% had regions of homozygosity without CNV. Hierarchical classification identified expected CHD categories in genomic disorders, as well as uncharacteristic CHDs. Inclusive phenotyping provided sensitive descriptions of patients with multiple CHD types, which occurred commonly. Among CNVs with rare or no prior CHD association, submicroscopic CNVs were enriched for more complex types of CHD compared with large CNVs. The submicroscopic CNVs that contained a curated CHD gene were enriched for left ventricular obstruction or septal defects, whereas CNVs containing a single gene were enriched for conotruncal defects. Neuronal‐related pathways were over‐represented in single‐gene CNVs, including top candidate causative genes NRXN3, ADCY2, and HCN1. Conclusions Intensive cardiac phenotyping in multisite registry data identifies genotype–phenotype associations in CHD patients with abnormal CMA.

Abstract Breastfeeding initiation rates in Australia are high but duration rates fall well below the World Health Organization targets. Return to work is a known factor impacting 6 months exclusive breastfeeding and continuation into the infants second year of life. Work related factors can influence a woman's confidence in maintaining breastmilk supply after return to employment and determine whether she meets her personal breastfeeding goals. This cross‐sectional online survey is the first Australian study to explore women's experience of maintaining breastfeeding after return to work, in all work sectors. Results revealed variations across work sectors reflected in worker autonomy and confidence in speaking up about breastfeeding rights. Women who had autonomy or flexibility in planning their workday were more likely to be confident in maintaining breastmilk supply. The main predictors for milk supply confidence and meeting personal breastfeeding goals included having: a suitable place to express milk; confidence in speaking out about rights; a formal return‐to‐work plan; a supportive workplace; and returning to work after the period of exclusive breastfeeding. This study reveals that supportive workplace environments can lead to increased confidence in maintaining milk supply, extending durations of breastfeeding. Women who are confident in their rights to express breastmilk, or breastfeed at work, are more likely to meet their own breastfeeding goals. Education, and awareness raising, on the rights of breastfeeding women in the workplace, is a gender equity imperative that can improve experiences for breastfeeding women, and, increase manager and co‐worker knowledge for creating enabling workplace environments for breastfeeding employees.