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Purpose: Developmental changes in sleep in youth with autism spectrum disorder (ASD) are understudied. In non-ASD youth, adolescents exhibit a "night owl chronotype" (i.e., later sleep/wake timing) and social jetlag (i.e., shifts in sleep timing across school nights and weekends), with corresponding sleep problems. The purpose of this study is to evaluate age trends in chronotype, social jetlag, and sleep problems in high-risk youth with ASD. Methods: Youth with ASD (N = 171), ages 5-21 years old, were enrolled at the time of admission to specialized psychiatric units. Caregivers reported children's demographic information, habitual sleep timing, and sleep problems. Multivariate analyses evaluated the effect of age on chronotype, social jetlag, and sleep problems and the effects of chronotype and social jetlag on sleep problems. Covariates and moderators included sex, race, verbal ability, autism symptom severity, supplemental melatonin, and pubertal status. Results: Older age was associated with later chronotype, more social jetlag, fewer sleep anxiety/co-sleeping problems, fewer night waking and parasomnia problems, and more daytime alertness problems. The effect of age on chronotype was stronger for youth with greater social affective symptom severity. Mediation analyses showed that later chronotype statistically mediated the association between age and daytime alertness problems. Conclusions: Youth with ASD may exhibit night owl chronotype behavior and social jetlag as they enter adolescence. Shifts toward a later chronotype may be exacerbated by autism severity and may contribute to alertness problems and sleepiness during the day. Chronotype is modifiable and may be leveraged to improve daytime functioning in youth with ASD.

Admission to selective colleges has grown more competitive, yielding student bodies that are unrepresentative of the U.S. population. Admission officers report using sorting (e.g., GPA, standardized tests) and concertedly cultivated (e.g., extracurricular activities) and ascriptive status (e.g., whether an applicant identifies as a member of a racially minoritized group) criteria to make decisions. Using latent class analysis, we identified three groupings of institutions based on the admission criteria they claim to value. Public institutions largely practiced a "coarse sieve" approach that relied on sorting criteria. Some private institutions practiced "fine sieve" admissions by emphasizing concertedly cultivated and ascriptive status criteria. A few privates employed the "double sieve" that combined sorting and concertedly cultivated criteria. Results illuminate the shape of the admissions sieve, identifying institutional contexts that inform the admissions practices selective colleges claim to use.

Three trends have characterized state policymaking for higher education in the 21st century: divestment, accountability, and race neutrality. These policy agendas are often justified as an attempt to optimize system efficiency and performance by making institutional actors (agents) responsive to the demands of state officials (principals). In this manuscript, we present quantitative evidence that these three policy initiatives have not achieved their stated purpose. We use contemporary social theory to explain why this is the case. Finally, we call for deeper re-engagement of states and their higher education systems in place of transactional and technocratic models.

Abstract Accurate knowledge of species distributions is foundational for effective conservation efforts. Bats are a diverse group of mammals, with important roles in ecosystem functioning. However, our understanding of bats and their ecological importance is hindered by poorly defined ranges, mostly as a result of under-recording. This issue is exacerbated in Africa by the ongoing rapid discovery of new species, both de novo and splits of existing species, and by inaccessibility to museum specimens that are mostly hosted outside of the continent. Here we present the African bat database – a curated set of 17,285 unique locality records of all 266 species of bats from sub-Saharan Africa, vouched for by specimens and/or genetic sequencing, and aligned with current taxonomy. Based on these records, we also present Maxent-based distribution models and calculate the IUCN Red List metrics for Extent of Occurrence and Area of Occupancy. This database and online visualization tool provide an important open-source resource and is expected to significantly advance studies in ecology, and aid in bat conservation.

Abstract Long-term datasets provide context and understanding of complex ecological processes, including temporal variations in species diversity and ecosystem dynamics. This dataset is comprised of body length measurements (mm) of more than 380,000 larval or juvenile fish of 30 species from five English river catchments collected almost monthly over two decades. Such information can be used to determine growth rates, future recruitment success, population structure and compliance with monitoring protocols and conservation objectives. The dataset provides a baseline for analysing the impacts of anthropogenic disturbances such as climate change, pollution and habitat degradation, and, given that many fish populations are size structured with a positive relationship between fish body length and various biological attributes such as swimming ability, survival and fecundity, it will be invaluable for investigating natural and human- induced disturbances.

Abstract The epigenetic landscape plays a critical role in cancer progression, yet its therapeutic potential remains underexplored. Glucocorticoids are essential components of treatments for lymphoid cancers, but resistance, driven in part by epigenetic changes at glucocorticoid-response elements, poses a major challenge to effective therapies. Here we show that glucocorticoid treatment induces distinct patterns of chromosomal organization in glucocorticoid-sensitive and resistant acute lymphoblastic leukemia xenograft models. These glucocorticoid-response elements are primed by the pioneer transcription factor PU.1, which interacts with the glucocorticoid receptor. Eviction of PU.1 promotes receptor binding, increasing the expression of genes involved in apoptosis and facilitating a stronger therapeutic response. Treatment with a PU.1 inhibitor enhances glucocorticoid sensitivity, demonstrating the clinical potential of targeting this pathway. This study uncovers a mechanism involving PU.1 and the glucocorticoid receptor, linking transcription factor activity with drug response, and suggesting potential therapeutic strategies for overcoming resistance.

People with mental disorders can receive treatment in the community. Some, however, fall out of services and into the criminal justice system, running the risk of imprisonment and a deteriorating mental health cycle. This editorial describes Mental Health Treatment Requirements (MHTRs), that is court-imposed sentences that enable people in the UK to access treatment in the community and divert them from short custodial sentences. MHTRs have proven successful for people with primary care mental health needs. It remains difficult to secure these sentences for people with secondary care mental health needs. Three new ‘proof of concept’ sites for secondary care MHTRs may help understand barriers and find solutions.

Abstract A key player in energy metabolism is phosphofructokinase-1 (PFK1) whose activity and behavior strongly influence glycolysis and thus have implications in many areas. In this research, PFK1 assays were performed to convert F6P and ATP into F-1,6-P and ADP for varied pH and ATP concentrations. PFK1 activity was assessed by evaluating F-1,6-P generation velocity in two ways: (1) directly calculating the time slope from the first two or more datapoints of measured product concentration (the initial-velocity method), and (2) by fitting all the datapoints with a differential equation explicitly representing the effects of ATP and pH (the modeling method). Similar general trends of inhibition were shown by both methods, but the former gives only a qualitative picture while the modeling method yields the degree of inhibition because the model can separate the two simultaneous roles of ATP as both a substrate of reaction and an inhibitor of PFK1. Analysis based on the model suggests that the ATP affinity is much greater to the PFK1 catalytic site than to the inhibitory site, but the inhibited ATP-PFK1-ATP complex is much slower than the uninhibited PFK1-ATP complex in product generation, leading to reduced overall reaction velocity when ATP concentration increases. The initial-velocity method is simple and useful for general observation of enzyme activity while the modeling method has advantages in quantifying the inhibition effects and providing insights into the process.

Abstract Background The use of patient-reported outcome measures (PROMs) in clinical research increases and use of heterogeneous instruments reflects how well diverse traits are captured by a medical specialty. In order to reflect the heterogeneity of current PROM use in ophthalmology, we reviewed the available literature. Methods The medical literature database Web of Science was searched for the most cited articles in clinical ophthalmology. Titles, abstracts and full text articles were reviewed for the use of PROMs and a list of the 100 most cited articles using PROMs was obtained and stratified by year of publication. Results A total of 1,996 articles were screened. Seventy-seven out of the 100 articles identified included one PROM, and the average number of instruments was 1.5 ± 1.1. The most widely used PROMs were the National Eye Institute Visual Function Questionnaire (33%), the Ocular Surface Disease Index (14%) and the Medical Outcomes Study Short Form (13%). A simulation analysis suggested that the distribution of PROM use in ophthalmology study did not significantly differ from a power law distribution. Twenty-two percent and fifteen percent of articles did not reference and did not specify the PROM used, respectively. This rate decreased in the more recently published articles (p = 0.041). Conclusions Our data suggest that the heterogeneity of PROMs applied in ophthalmology studies is low. The selection of PROMs for clinical studies should be done carefully, depending on the research goal.

Adventure sports coaches must make sound judgements and effective decisions to ensure they can manage the significant risks present in an operating environment that is hyper-dynamic and has significant environmental complexity (Collins & Collins, 2013). High-level stakeholders in adventure sports require coaches demonstrate competency to fulfill their responsibilities to look after their clients. Most adventure sports qualifications identify the importance of decision making, however, by using competence-oriented syllabi they may not provide effective methods to evaluate a prospective adventure sport coach's decision making. This paper identifies the need for expertise-oriented evaluation of decision making and explores decision support tools and educational validity theories in the evaluation process. It also considers how Collins and Collins' (2021) Big 5 style approach represents an exemplar decision support tool and may provide educational assessment validity, so presenting a sound methodology for coach educators to evaluate the quality of an adventure sports coaches' decision making.

Context: Adoption can provide a lifetime of benefits for children. Some adoptions however, experience severe challenges resulting in disruption, with children leaving home prematurely. Method: This qualitative study in Northern Ireland used interviews with parents from thirteen families whose adoptions had disrupted, to explore their perspective on the experience. Findings: Key findings focused on issues relating to firstly, the adopted child; secondly, adoption services; and finally, the parents and other family members. The impact of early adverse experiences on the children (developmental trauma) played out through behaviours, often violent, that their parents found extremely challenging. These increased as the children aged and had serious effects on family life. The adoptive parents thought they could have been better prepared through the adoption process to face challenging behaviours and more appropriately supported to prevent disruption. When their adopted child was admitted to state care, the parents typically felt initial relief but also guilt and loss. After the child had left home, they generally wished for more involvement with him or her despite the difficulties experienced. Discussion: This study confirmed previous findings about the extent of trauma experienced by some adoptive children, and the challenges that this may present to the adoptive parents. It highlighted how the manifestation of the trauma experienced by the child may lead to adoptive parents themselves experiencing primary or secondary trauma or compassion fatigue (defined in the Discussion section below) or a combination of all three. The preparation of adoptive parents should include greater awareness of possible challenges, and how to cope with these. The development of trauma-informed approaches to practice and service delivery is required to support families with adopted children more effectively. Co-production models for service development may assist in addressing the types of issues identified in post-adoption support services.

This study focuses on the fabrication and characterisation of single-walled carbon nanotube (SWCNT) buckypapers and polyethersulfone (PES) flat-sheet membranes using Cyrene, aiming toevaluate its efficacy as a green solvent for these applications. Pristine SWCNTs were dispersed inCyrene without surfactants and compared to N-Methyl-2-pyrrolidone (NMP) dispersions. Buckypapers were fabricated from these dispersions and characterised using Scanning ElectronMicroscopy (SEM), Atomic Force Microscopy (AFM), and infrared spectroscopy. Their performancewas tested in wastewater and oil-water emulsion filtrations and antimicrobial activity. PESmembranes incorporating SWCNTs were prepared using phase inversion and analysed via SEM,optical microscopy, and contact angle. Membrane properties and water permeability were assessed,and bacterial challenge tests evaluated antimicrobial activity. Cyrene enabled the dispersion ofSWCNTs at higher concentrations (0.038 mg mL⁻1) compared to NMP (0.013 mg mL⁻1). Transmission Electron Microscopy (TEM) analysis revealed that Cyrene effectively debundles SWCNTs, yielding better dispersion. Buckypapers fabricated with Cyrene demonstrated dense, uniform networks with enhanced surface smoothness and promising filtration performance for wastewater treatment and oil-water separation. PES membranes made with Cyrene exhibited well-organised finger-like structures, interconnected pores, superior porosity, and higher water permeability than NMP-based membranes. Incorporating SWCNTs further improved membrane performance. However, bacterial challenge tests indicated no significant antimicrobial activity. The findings highlight Cyrene’s potential as a sustainable alternative to traditional solvents, offering improved material properties and filtration performance. Despite these advantages, further studies are necessary to address solvent residuals and long-term safety considerations, ensuring its suitability for broader applications.

ABSTRACT If left unchecked, infections involving antibiotic-refractory bacteria are expected to cause millions of deaths per year in the coming decades. Beyond genetically resistant bacteria, persisters, which are genetically susceptible cells that survive antibiotic doses that kill the rest of the clonal population, can potentially contribute to treatment failure and infection relapse. Stationary-phase bacterial cultures are enriched with persisters, and it has been shown that stimulating these populations with exogenous nutrients can reduce persistence to different classes of antibiotics, including topoisomerase-targeting fluoroquinolones (FQs). In this study, we show that adding glucose and amino acids to nutrient-starved Staphylococcus aureus cultures enhanced their sensitivity to FQs, including delafloxacin (Dela)—a drug that was recently approved for treating staphylococcal infections. We found that while the added nutrients increased nucleic acid synthesis, this increase was not required to sensitize S. aureus to FQs. We further demonstrate that addition of these nutrients increases membrane potential and the ability to generate harmful reactive oxygen species (ROS) during FQ treatment. Chelating iron, scavenging hydroxyl radicals, and limiting oxygenation during FQ treatment and during recovery following FQ treatment rescued nutrient-stimulated S. aureus. In all, our data suggest that while nutrient stimulation increases the activity of FQ targets in stationary-phase S. aureus, the resulting generation of ROS, presumably made possible through metabolic upregulation, is the primary driver of increased sensitivity to these drugs.IMPORTANCEStaphylococcus aureus causes many chronic and relapsing infections because of its ability to endure host immunity and antibiotic therapy. While several studies have focused on the nutrient requirements for the formation and maintenance of staphylococcal infections, the effects of the nutrient environment on bacterial responses to antibiotic treatment remain understudied. Here, we show that adding nutrients to starved S. aureus activates biosynthetic processes, including DNA synthesis, but it is the generation of harmful reactive oxidants that sensitizes S. aureus to DNA topoisomerase-targeting FQs. Our results suggest that the development of approaches aimed at perturbing metabolism and increasing oxidative stress can potentiate the bactericidal activity of FQs against antibiotic-tolerant S. aureus.

Background: Research can inform policies on substance use/substance use disorders (SU/SUDs), yet there is limited experimental investigation into strategies for optimizing policymakers’ engagement with SU/SUD research. This study tested the use of narratives to boost policymakers’ research engagement. Methods: In five rapid-cycle randomized controlled trials, SU/SUD research fact sheets were emailed to US legislative policymakers. We tested the use of narratives on the number of email opens, fact sheet clicks, and replies, relative to control emails without narratives. Narratives described lived experience with SU/SUD or motivations to study SU/SUD. The sender was a person with lived experience who authored the narrative or an author of the fact sheet. Results: When the narrative was about the sender’s own lived experience (Trial 1), or when the narrative was about the sender's motivations to study SU/SUDs (Trial 2), the fact sheet was clicked more than the control (p=.049; p=.012; respectively). When the narrative was about someone else’s experience (Trials 3 and 4), the email was opened (p’s

Abstract. Objectives:. To develop and validate a prediction model for a deep surgical site infection (SSI) after fixation of a tibial plateau or pilon fracture. Design:. Pooled data from 2 randomized trials (VANCO and OXYGEN). Setting:. Fifty-two US trauma centers. Patients:. In total, 1847 adult patients with operatively treated tibial plateau or pilon fractures who met criteria for a high risk of infection. Intervention:. We considered 13 baseline patient characteristics and developed and externally validated prediction models using 3 approaches (logistic regression, stepwise elimination, and machine learning). Main Outcomes and Measures:. The primary prediction model outcome was a deep SSI requiring operative debridement within 182 days of definitive fixation. Our primary prognostic performance metric for evaluating the models was area under the receiver operating characteristic curve (AUC) with clinical utility set at 0.7. Results:. Deep SSI occurred in 75 VANCO patients (8%) and in 56 OXYGEN patients (6%). The machine learning model for VANCO (AUC = 0.65) and stepwise elimination model for OXYGEN (AUC = 0.62) had the highest internal validation AUCs. However, none of the external validation AUCs exceeded 0.64 (range, 0.58 to 0.64). Conclusions:. The predictive models did not reach the prespecified clinical utility threshold. Our models' inability to distinguish high-risk from low-risk patients is likely due to strict eligibility criteria and, therefore, homogeneous patient populations.

Glycogen-autophagy (‘glycophagy’) is a selective autophagy process involved in delivering glycogen to the lysosome for bulk degradation. Glycophagy protein intermediaries include STBD1 as a glycogen tagging receptor, delivering the glycogen cargo into the forming phagosome by partnering with the Atg8 homolog, GABARAPL1. Glycophagy is emerging as a key process of energy metabolism and development of reliable tools for assessment of glycophagy activity is an important priority. Here we show that antibodies raised against the N-terminus of the GABARAPL1 protein (but not the full-length protein) detected a specific endogenous GABARAPL1 immunoblot band at 18kDa. A stable GFP-GABARAPL1 cardiac cell line was used to quantify GABARAPL1 lysosomal flux via measurement of GFP puncta in response to lysosomal inhibition with bafilomycin. Endogenous glycophagy flux was quantified in primary rat ventricular myocytes by the extent of glycogen accumulation with bafilomycin combined with chloroquine treatment (no effect observed with bafilomycin or chloroquine alone). In wild-type isolated mouse hearts, bafilomycin alone and bafilomycin combined with chloroquine (but not chloroquine alone) elicited a significant increase in glycogen content signifying basal glycophagy flux. Collectively, these methodologies provide a comprehensive toolbox for tracking cardiac glycophagy activity to advance research into the role of glycophagy in health and disease.

Although famous for language, representation, and humor, Tristram Shandy also provides a modern ecocritical goad to humanism by asking about the distinction between ecocriticism and animal studies. Sterne demonstrate what I call an ‘oiko-logic’ that emphasizes the relationships we find developing across the household environment. Sterne is particularly interested in questions of what we would now call ‘ferality’ and domestication, how animality makes us human, and how sympathy supports the conscience of our species. Sterne’s eco-question is not if we should change our relationship to the environment, but how to calculate the appropriate change in our actions based on ecological circumstances, and he asks that we remember to account for who is carrying the social burden: Yorick’s horse, Maria’s goat, and Toby’s famous fly all carry an ecologically-based social burden for the humanity they encounter. Sterne’s ecological sensibility suggests that our conscience develops as we relate to the natural world by updating the input-output analysis with adroit calculations in collaboration with nature. What I call ‘calculations across animals’ has much in common with the emerging field of ecological economics, and Sterne shows us how humanity allows itself a certain great deal of latitude when considering the fallout of our actions on animals—meaning we can calculate for good or ill. So, for Sterne, the question becomes: how do we decide what’s good? He might whip around and say, ‘God’, but he also strongly suggests that watching humanity interact with nature can show us what goodness really looks like.

Abstract The arginyl-transferase ATE1 is a tRNA-dependent enzyme that covalently attaches an arginine molecule to a protein substrate. Conserved from yeast to humans, ATE1 deficiency in mice correlates with defects in cardiovascular development and angiogenesis and results in embryonic lethality, while conditional knockouts exhibit reproductive, developmental, and neurological deficiencies. Despite the recent revelation of the tRNA binding mechanism and the catalytic cycle of yeast ATE1, the structure-function relationship of ATE1 in higher organisms is not well understood. In this study, we present the three-dimensional structure of human ATE1 in an apo-state and in complex with its tRNA cofactor and a peptide substrate. In contrast to its yeast counterpart, human ATE1 forms a symmetric homodimer, which dissociates upon binding of a substrate. Furthermore, human ATE1 includes a unique and extended loop that wraps around tRNAArg, creating extensive contacts with the T-arm of the tRNA cofactor. Substituting key residues identified in the substrate binding site of ATE1 abolishes enzymatic activity and results in the accumulation of ATE1 substrates in cells.

Chemoprophylactic prevention of veterinary heartworm disease in companion animals, caused by the vector-borne nematode parasite Dirofilaria immitis, is a multi-billion-dollar global market. Experimental use of cats and dogs in preclinical heartworm drug testing is increasing due to evolving drug-resistance to frontline macrocyclic lactones and renewed investment in alternative preventative drug research. We and others recently published data demonstrating proof-of-concept of utilising lymphopenic severe-combined immunodeficient (SCID) or Recombination Activating Gene (RAG)2 deficient mice with additional knockout of the IL-2/7 receptor gamma chain (γc) as alternative preventative drug screening research models of dirofilariasis. Here we summarise the current knowledge of candidate immunodeficient mouse models tested, including a comparison of susceptibility using different background strains of mice, different D. immitis isolates, following use of anti-inflammatory treatments to further suppress residual innate immunity, and efficacies achieved against different reference anthelmintics. We supplement this precis with new data on treatment response to the veterinary anthelmintic, oxfendazole, and initial evaluation of D. immitis susceptibility in CB.17 SCID and C57BL/6 RAG2 -/-γc -/- mice. We conclude that in addition to NSG and NXG mice, RAG2 -/-γc -/- mice on either a BALB/c or C57BL/6 background offer an alternative screening model option, widening access to academic and commercial laboratories wishing to pursue initial rapid in vivo drug screening whilst avoiding potentially unnecessary cat or dog testing.

Background Implementation of the cardiovascular disease (CVD) prevention guidelines in the UK has been repeatedly evaluated under the auspices of the British Cardiovascular Society in three Action on Secondary and Primary Prevention by Intervention to Reduce Events (ASPIRE) surveys in 1994–1995, 2008–2010 and 2017–2019. The primary care arm of ASPIRE-2-PREVENT (A-3-P) was conducted to evaluate lifestyle and medical risk factor management in people at high risk of atherosclerotic CVD in everyday clinical practice.Methods A-3-P was a cross-sectional survey in 27 general practices and health centres across 5 English National Health Service regions. Patients with no history of atherosclerotic CVD started on blood pressure and/or lipid and/or glucose lowering treatments were identified retrospectively and interviewed at least 6 months after the initiation of medication.Results 557 patients attended the interview and examination (45.8% women; mean age 61.7±10.8 years). The risk factor control was poor: 9.3% of patients were smokers, 38.1% obese (body mass index≥30 kg/m2) and 53.5% centrally obese (waist circumference≥88 cm for women, ≥102 cm for men). Only 37.8% of patients on blood pressure-lowering therapies achieved the target of

Background Heart failure (HF) is not included in atrial fibrillation (AF) bleeding risk prediction scores, reflecting uncertainty regarding its importance as a risk factor for major haemorrhage. We aimed to report the relative risk of first major haemorrhage in people with HF and AF compared with people with AF without HF (‘AF only’).Methods English primary care cohort study of 2 178 162 people aged ≥45 years in the Clinical Practice Research Datalink from January 2000 to December 2018, linked to secondary care and mortality databases. We used traditional survival analysis and competing risks methods, accounting for all-cause mortality and anticoagulation.Results Over 7.56 years median follow-up, 60 270 people were diagnosed with HF and AF of whom 4996 (8.3%) had a major haemorrhage and 36 170 died (60.0%), compared with 8256 (6.4%) and 34 375 (27.2%), respectively, among 126 251 people with AF only. Less than half those with AF were prescribed an anticoagulant (45.6% from 2014 onwards), although 75.7% were prescribed an antiplatelet or anticoagulant. In a fully adjusted Cox model, the HR for major haemorrhage was higher among people with HF and AF (2.52, 95% CI 2.44 to 2.61) than AF only (1.87, 95% CI 1.82 to 1.92), even in a subgroup analysis of people prescribed anticoagulation. However, in a Fine and Gray competing risk model, the HR of major haemorrhage was similar for people with AF only (1.82, 95% CI 1.77 to 1.87) or HF and AF (1.71, 95% CI 1.66 to 1.78).Conclusions People with HF and AF are at increased risk of major haemorrhage compared with those with AF only and current prediction scores may underestimate the risk of haemorrhage in HF and AF. However, people with HF and AF are more likely to die than have a major haemorrhage and therefore an individual’s expected prognosis should be carefully considered when predicting future bleeding risk.

Neurophysiological signals, comprised of both periodic (e.g., oscillatory) and aperiodic (e.g., non-oscillatory) activity, undergo complex developmental changes between childhood and adulthood. With much of the existing literature primarily focused on the periodic features of brain function, our understanding of aperiodic signals is still in its infancy. Here, we are the first to examine age-related changes in periodic (peak frequency and power) and aperiodic (slope and offset) activity using optically pumped magnetometers (OPMs), a new, wearable magnetoencephalography (MEG) technology that is particularly well-suited for studying development. We examined age-related changes in these spectral features in a sample (N=65) of toddlers (1–3 years), children (4–5 years), young adults (20–26 years), and adults (27–38 years). Consistent with the extant literature, we found significant age-related decreases in the aperiodic slope and offset, and changes in peak frequency and power that were frequency-specific; we are the first to show that the effect sizes of these changes also varied across brain regions. This work not only adds to the growing body of work highlighting the advantages of using OPMs, especially for studying development, but also contributes novel information regarding the variation of neurophysiological changes with age across the brain.

Abstract Background Research on genetic and environmental influences on speech and/or language difficulties (SaLD) is sparse, with inconsistent heritability estimates. We aimed to estimate the prevalence of parental reported SaLD and the relative contributions of genetic and environmental factors for the phenotype using a Swedish population‐based twin sample. We hypothesized that there would be a stronger genetic than environmental effect on SaLD. Methods Data were collected from The Child and Adolescent Twin Study in Sweden. The study sample included 16,774 twin pairs (16,946 males, 16,602 females), of which 5141 were monozygotic, 5861 dizygotic (DZ), and 5772 opposite‐sex DZ pairs. The language items in the Autism–Tics, Attention‐Deficit Hyperactivity Disorder, and other Comorbidities inventory were used to categorize individuals as having parental‐reported SaLD. A classical twin design was used to estimate the relative contribution of genetic and environmental factors to the liability of SaLD. Results The prevalence of SaLD was 7.85% (95% confidence interval (CI) [7.57%–8.15%]) and 7.27% (95% CI [6.99%–7.55%]) when excluding individuals with autism and intellectual disability (ID). We also found that SaLD were significantly more prevalent in males than females with a ratio of 2:1. The heritability was estimated to be 75% (95% CI [67%–83%]) for SaLD. Shared environment played a significant role with an estimated contribution of 22% (95% CI [14%–30%]). The heritability estimate was reduced to 70% but with overlapping CI when excluding individuals with autism and ID. Conclusions We provide evidence that SaLD is common in the population and under strong genetic influence. Future studies should focus on mapping the genetic architecture of SaLD and related disorders.

Background: This study explored the association between emotion word repertoire (EWR), attachment, reflective functioning and personality organization (PO) and suicidal behavior in borderline personality disorder (BPD) patients. Methods: The current study performed a secondary data analysis from a randomized control trial for BPD patients (all female; n = 87; age: m = 27; SD = 7.42). EWR was assessed via machine-scoring transcripts of Adult Attachment Interviews (AAI) for affective words using the VETA electronic scoring software for the Levels of Emotional Awareness Scale (LEAS). Generated scores were related to impairments in PO (Structured Interview for Personality Organization; STIPO), attachment organization (AAI) and mentalization (Reflective Functioning Scale), general symptom severity (Brief Symptom Inventory; BSI-53), self-harm and suicidal behavior. Independent effects of the investigated predictors were studied using Bayesian path analysis. Results: Corrected for education, findings in Bayesian path analysis suggest an independent negative association between EWR and suicide attempts (BE = −.32; 95 % CI [-.51, −.12]) and positive associations of deficits in PO with psychiatric symptoms (BE = .23; 95 % CI [.01, .44]) as well as suicide attempts (BE = .30; 95 % CI [.08, .49]). Discussion: The findings underscore the potential role of high EWR and PO as a protective factor for suicidal behavior in individuals with BPD.

Chemoprophylactic prevention of veterinary heartworm disease in companion animals, caused by the vector-borne nematode parasite Dirofilaria immitis, is a multi-billion-dollar global market. Experimental use of cats and dogs in preclinical heartworm drug testing is increasing due to evolving drug-resistance to frontline macrocyclic lactones and renewed investment in alternative preventative drug research. We and others recently published data demonstrating proof-of-concept of utilising lymphopenic severe-combined immunodeficient (SCID) or Recombination Activating Gene (RAG)2 deficient mice with additional knockout of the IL-2/7 receptor gamma chain (γc) as alternative preventative drug screening research models of dirofilariasis. Here we summarise the current knowledge of candidate immunodeficient mouse models tested, including a comparison of susceptibility using different background strains of mice, different D. immitis isolates, following use of anti-inflammatory treatments to further suppress residual innate immunity, and efficacies achieved against different reference anthelmintics. We supplement this precis with new data on treatment response to the veterinary anthelmintic, oxfendazole, and initial evaluation of D. immitis susceptibility in CB.17 SCID and C57BL/6 RAG2-/-γc-/- mice. We conclude that in addition to NSG and NXG mice, RAG2-/-γc-/- mice on either a BALB/c or C57BL/6 background offer an alternative screening model option, widening access to academic and commercial laboratories wishing to pursue initial rapid in vivo drug screening whilst avoiding potentially unnecessary cat or dog testing.

IntroductionSleep disturbances, fear of sleep, and nightmares are among the most reported symptoms for military service members and veterans (henceforth “veterans”) with posttraumatic stress disorder (PTSD), potentially contributing to treatment resistance and heightened suicidality. Despite available evidence-based interventions, many veterans still report difficulties. The complementary intervention of a psychiatric service dog may contribute to improvements in sleep quality for veterans with PTSD.MethodsThis preregistered, non-randomized clinical trial evaluated the association between service dog partnership and sleep at 3 month follow-up. Participants were N = 155 veterans with PTSD (81 in the service dog group and 74 waitlisted controls). Measures included self-report surveys measuring PTSD severity (PTSD Checklist for DSM-5, PCL-5) sleep quality (Pittsburgh Sleep Quality Index, PSQI), sleep disturbance (PROMIS Sleep Disturbance), and fear of sleep (Fear of Sleep Inventory-Short Form, FoSI-SF); morning sleep diaries measuring nightmares; and wrist-worn actigraphy. Regression models and mediation analyses were performed.ResultsService dog partnership was significantly associated with better subjective sleep [PSQI: mean difference −2.2, 95% CI (−3.4, −1.1), p < 0.001; PROMIS Sleep Disturbance: −3.6, 95% CI (−6.3, −0.9), p = 0.004; FoSI-SF: −6.6, 95% CI (−9.7, −3.5), p < 0.001] and odds of nightmares [OR = 0.45, 95% CI (0.26, 0.76), p = 0.003]. Service dog partnership was not associated with a change in actigraphy-based measures of sleep [sleep onset: −4.5, 95% CI (−12.2, 3.2); sleep duration: −4.7, 95% CI (−25.9, 16.6); wake after sleep onset: 6.0, 95% CI (−2.1,14.1); sleep efficiency: −0.4, 95% CI (−3.4, 2.5)]. The estimated proportion of the effect of service dogs on PTSD severity mediated by fear of sleep was 0.26 [95% CI (0.10, 0.48)].DiscussionCompared to the control group, veterans with service dogs for PTSD reported better sleep quality, less sleep disturbance, and less fear of sleep after 3 months. However, service dog partnership was not associated with differences in actigraphy-measured sleep. These findings demonstrate the impact of psychiatric service dog partnerships on sleep quality for veterans with PTSD.

Value added lignin rich waste sludges from biorefinery processes are, as yet untapped valuable feedstocks that can be reformed into clean, high quality solid fuels. By water washing sludges produced from base hydrolyzed waste, a material stripped of water-soluble alkali and alkaline earth metals (ash) can be obtained. This work shows how leached bagasse, barley and wheat straw sludges can be valorised into clean, low ash solid biofuels that can be used to supplement global energy demands. Repurposed lignin rich sludges of 1.00–2.00 mm particle size feedstocks were found to exhibit calorific values +17.3 %, +16.8 % and +11.7 % for bagasse, wheat, and barley straw sludges, respectively higher than their untreated waste counterparts. Additionally, by employing densification in the absence of a binder,

IntroductionTransplantation of kidneys from expanded criteria donors (ECD), including after circulatory death (DCD), is associated with a higher risk of adverse events compared to kidneys from standard criteria donors. In previous studies, improvements in renal transplant outcomes have been seen when kidneys were perfused with gaseous oxygen during preservation (persufflation, PSF). In the present study, we assessed ex-vivo renal function from a Diffusion Contrast Enhanced (DCE)-MRI estimation of glomerular filtration rate (eGFR); and metabolic sufficiency from whole-organ oxygen consumption (WOOCR) and lactate production rates.MethodsUsing a porcine model of DCD, we assigned one kidney to antegrade PSF, and the contralateral kidney to static cold storage (SCS), both maintained for 24 h at 4°C. Post-preservation organ quality assessments, including eGFR, WOOCR and lactate production, were measured under cold perfusion conditions, and biopsies were subsequently taken for histopathological analysis.ResultsA significantly higher eGFR (36.6 ± 12.1 vs. 11.8 ± 4.3 ml/min, p

This study investigated the effect of freezing and subsequent aging on beef quality, particularly focusing on the extent of postmortem proteolysis and tenderization. The longissimus lumborum muscle was collected from 8 steers 24 h postmortem, sliced into 8 2.5-cm-thick steaks, and randomly allocated into 4 groups. Treatment groups consisted of 1) aging at 4°C for 24 h; 2) aging for 168 h; 3) freezing at −20°C for 24 h followed by thawing/aging for 24 h; and 4) freezing for 24 h followed by thawing/aging for 168 h. In general, freezing decreased the color intensity of the steaks, whereas aging increased it (P < 0.05). Freezing also increased water loss, evidenced by greater drip loss and purge loss (P < 0.05). On the other hand, both freezing and aging improved beef proteolysis and tenderness (P < 0.05). This was associated with enhanced protease activity, indicated by greater calpain-1 autolysis and cathepsin B activity (P < 0.05). Additionally, freezing may have accelerated the activation of caspase-3, but our sampling timing did not permit verifying this possibility. This increase in the activity of proteases is likely caused by ice crystals disrupting cellular organelles, releasing factors that trigger their activation. In support of this, frozen steaks displayed an elevated level of free calcium and mitochondrial dysfunction (P < 0.05). Collectively, these findings suggest that freezing enhances postmortem proteolysis and tenderness in beef, likely by compromising key cellular organelles and subsequently accentuating the activity of several endogenous protease systems during aging.

Total femur replacement is a well-recognized salvage procedure and an alternative to hip disarticulation in patients with massive femoral bone loss. Compared to conventional total femur replacement, intramedullary total femur (IMTF) requires less soft tissue dissection and preserves femoral bone stock and soft-tissue attachments. Despite these advantages, patients can still anticipate compromised functional outcomes and high complication rates following IMTF. Prior studies describe IMTF with the patient positioned laterally and utilizing posterior or anterolateral approaches to the hip. We describe our IMTF technique performed via the direct anterior approach in the supine position. In our experience, this is an effective method, with potential benefits including intraoperative limb length and rotational assessment, use of fluoroscopy, more convenient exposure of the knee, and potential lower rates of hip instability.

To manage Earth in the Anthropocene, new tools, new institutions, and new forms of international cooperation will be required. Earth Virtualization Engines is proposed as an international federation of centers of excellence to empower all people to respond to the immense and urgent challenges posed by climate change.

Abstract The cerebellum, through its connectivity with the cerebral cortex, plays an integral role in regulating cognitive and affective processes, and its dysregulation can result in neurodevelopmental disorder (NDD)-related behavioural deficits. Identifying cerebellar-cerebral functional connectivity (FC) profiles in children with NDDs can provide insight into common connectivity profiles and their correlation to NDD-related behaviours. 479 participants from the Province of Ontario Neurodevelopmental Disorders (POND) network (typically developing = 93, Autism Spectrum Disorder = 172, Attention Deficit/Hyperactivity Disorder = 161, Obsessive-Compulsive Disorder = 53, mean age = 12.2) underwent resting-state functional magnetic resonance imaging and behaviour testing (Social Communication Questionnaire, Toronto Obsessive-Compulsive Scale, and Child Behaviour Checklist – Attentional Problems Subscale). FC components maximally correlated to behaviour were identified using canonical correlation analysis. Results were then validated by repeating the investigation in 556 participants from an independent NDD cohort provided from a separate consortium (Healthy Brain Network (HBN)). Replication of canonical components was quantified by correlating the feature vectors between the two cohorts. The two cerebellar-cerebral FC components that replicated to the greatest extent were correlated to, respectively, obsessive-compulsive behaviour (behaviour feature vectors, r POND-HBN = −0.97; FC feature vectors, r POND-HBN = −0.68) and social communication deficit contrasted against attention deficit behaviour (behaviour feature vectors, r POND-HBN = −0.99; FC feature vectors, r POND-HBN = −0.78). The statistically stable (|z| > 1.96) features of the FC feature vectors, measured via bootstrap re-sampling, predominantly comprised of correlations between cerebellar attentional and control network regions and cerebral attentional, default mode, and control network regions. In both cohorts, spectral clustering on FC loading values resulted in subject clusters mixed across diagnostic categories, but no cluster was significantly enriched for any given diagnosis as measured via chi-squared test (p > 0.05). Overall, two behaviour-correlated components of cerebellar-cerebral functional connectivity were observed in two independent cohorts. This suggests the existence of generalizable cerebellar network differences that span across NDD diagnostic boundaries.

Abstract Optically pumped magnetometers (OPMs) offer a new wearable means to measure magnetoencephalography (MEG) signals, with many advantages compared to conventional systems. However, OPMs are an emerging technology, thus characterizing and replicating MEG recordings is essential. Using OPM-MEG and SQUID-MEG, this study investigated evoked responses, oscillatory power, and functional connectivity during emotion processing in 20 adults, to establish replicability across the two technologies. Five participants with dental fixtures were included to assess the validity of OPM-MEG recordings in those with irremovable metal. Replicable task-related evoked responses were observed in both modalities. Similar patterns of oscillatory power to faces were observed in both systems. Increased connectivity was found in SQUID-versus OPM-MEG in an occipital and parietal anchored network. Notably, high quality OPM-MEG data were retained in participants with metallic fixtures, from whom no useable data were collected using conventional MEG.

Abstract Recent biological surveys of ancient inselbergs in southern Malawi and northern Mozambique have led to the discovery and description of many species new to science, and overlapping centres of endemism across multiple taxa. Combining these endemic taxa with data on geology and climate, we propose the ‘South East Africa Montane Archipelago’ (SEAMA) as a distinct ecoregion of global biological importance. The ecoregion encompasses 30 granitic inselbergs reaching > 1000 m above sea level, hosting the largest (Mt Mabu) and smallest (Mt Lico) mid-elevation rainforests in southern Africa, as well as biologically unique montane grasslands. Endemic taxa include 127 plants, 45 vertebrates (amphibians, reptiles, birds, mammals) and 45 invertebrate species (butterflies, freshwater crabs), and two endemic genera of plants and reptiles. Existing dated phylogenies of endemic animal lineages suggests this endemism arose from divergence events coinciding with repeated isolation of these mountains from the pan-African forests, together with the mountains’ great age and relative climatic stability. Since 2000, the SEAMA has lost 18% of its primary humid forest cover (up to 43% in some sites)—one of the highest deforestation rates in Africa. Urgently rectifying this situation, while addressing the resource needs of local communities, is a global priority for biodiversity conservation.