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Pituitary tumours are surrounded by critical neurovascular structures and identification of these intra-operatively can be challenging. We have previously developed an AI model capable of sellar anatomy segmentation. This study aims to apply this model, and explore the impact of AI-assistance on clinician anatomy recognition. Participants were tasked with labelling the sella on six images, initially without assistance, then augmented by AI. Mean DICE scores and the proportion of annotations encompassing the centroid of the sella were calculated. Six medical students, six junior trainees, six intermediate trainees and six experts were recruited. There was an overall improvement in sella recognition from a DICE of score 70.7% without AI assistance to 77.5% with AI assistance (+6.7; p < 0.001). Medical students used and benefitted from AI assistance the most, improving from a DICE score of 66.2% to 78.9% (+12.8; p = 0.02). This technology has the potential to augment surgical education and eventually be used as an intra-operative decision support tool. [ABSTRACT FROM AUTHOR]

The educational approach known as positive education emerged from positive psychology and frequently attributes its conception of flourishing to Aristotelian eudaimonia. This is a point of contention between scholars who see positive psychology's flourishing as an epithet of Aristotelian virtues and others who have identified critical divergences between the philosophical foundations of positive psychology and Aristotle's normative ethics. Few scholars have examined whether adolescent understandings of flourishing reflect Aristotelian eudaimonia, and whether this is different in positive education students. This paper explores notion of the good life through the writings of 226 adolescents, 93 of whom attend a school that has implemented positive education. These are analysed through an Aristotelian lens, finding more similarities than differences between the groups. Both groups discussed relationships, emotions, and accomplishments, but moral goodness and virtue were not prominent. Conclusions are drawn about the implications of this for 'positive' education and the role it plays in nurturing flourishing. [ABSTRACT FROM AUTHOR]

The choice of appropriate physical quantities to characterize the biological effects of ionizing radiation has evolved over time coupled with advances in scientific understanding. The basic hypothesis in radiation dosimetry is that the energy deposited by ionizing radiation initiates all the consequences of exposure in a biological sample (e.g., DNA damage, reproductive cell death). Physical quantities defined to characterize energy deposition have included dose, a measure of the mean energy imparted per unit mass of the target, and linear energy transfer (LET), a measure of the mean energy deposition per unit distance that charged particles traverse in a medium. The primary advantage of using the "dose and LET" physical system is its relative simplicity, especially for presenting and recording results. Inclusion of additional information such as the energy spectrum of charged particles renders this approach adequate to describe the biological effects of large dose levels from homogeneous sources. The primary disadvantage of this system is that it does not provide a unique description of the stochastic nature of radiation interactions. We and others have used dose-averaged LET (LETd) as a correlative physical quantity to the relative biological effectiveness (RBE) of proton beams. This approach is based on established experimental findings that proton RBE increases with LETd. However, this approach might not be applicable to intensity-modulated proton therapy or other applications in which the proton energy spectrum is highly heterogeneous. In the current study, we irradiated cancer cells with scanning proton beams with identical LETd (3.4 keV/µm) but arising from two different proton energy/LET spectra (a narrow spectrum in group 1 and a widespread heterogeneous spectrum in group 2). Clonogenic survival after irradiation revealed significant differences in RBE at any cell surviving fraction: e.g., at a surviving fraction of 0.1, the RBE was 0.97 ± 0.03 in group 1 and 1.16 ± 0.04 in group 2 (p≤0.01), validating our hypothesis that LETd alone may not adequately indicate proton RBE. Further analysis showed that microdosimetric spectrum (the probability density function of the stochastic physical quantity lineal energy y) was helpful for interpreting observed differences in biological effects. However, more accurate use of microdosimetric spectrum to quantify RBE requires a cell line–specific mechanistic model. [ABSTRACT FROM AUTHOR]

Despite a high response rate in chimeric antigen receptor (CAR) T cell therapy for acute lymphocytic leukaemia (ALL)1–3, approximately 50% of patients relapse within the first year4–6, representing an urgent question to address in the next stage of cellular immunotherapy. Here, to investigate the molecular determinants of ultralong CAR T cell persistence, we obtained a single-cell multi-omics atlas from 695,819 pre-infusion CAR T cells at the basal level or after CAR-specific stimulation from 82 paediatric patients with ALL enrolled in the first two CAR T ALL clinical trials and 6 healthy donors. We identified that elevated type 2 functionality in CAR T infusion products is significantly associated with patients maintaining a median B cell aplasia duration of 8.4 years. Analysis of ligand–receptor interactions revealed that type 2 cells regulate a dysfunctional subset to maintain whole-population homeostasis, and the addition of IL-4 during antigen-specific activation alleviates CAR T cell dysfunction while enhancing fitness at both transcriptomic and epigenomic levels. Serial proteomic profiling of sera after treatment revealed a higher level of circulating type 2 cytokines in 5-year or 8-year relapse-free responders. In a leukaemic mouse model, type 2high CAR T cell products demonstrated superior expansion and antitumour activity, particularly after leukaemia rechallenge. Restoring antitumour efficacy in type 2low CAR T cells was attainable by enhancing their type 2 functionality, either through incorporating IL-4 into the manufacturing process or by priming manufactured CAR T products with IL-4 before infusion. Our findings provide insights into the mediators of durable CAR T therapy response and suggest potential therapeutic strategies to sustain long-term remission by boosting type 2 functionality in CAR T cells.Elevated type 2 functionality in CAR T cell infusion products is significantly associated with maintenance of a median B cell aplasia duration of 8.4 years in paediatric patients with acute lymphocytic leukaemia. [ABSTRACT FROM AUTHOR]

Purpose: Mesenchymal neoplasms composed of vascular, smooth muscle, and adipocytic components are uncommon in the nasal cavity. While angioleiomyoma (AL) is a smooth muscle tumor in the Head & Neck WHO classification, it is considered of pericytic origin in the Skin as well as Soft Tissue and Bone classifications. For nasal AL with an adipocytic component, the terms AL with adipocytic differentiation and angiomyolipoma (AML) have been applied, among others. AML is a type of perivascular epithelioid cell tumor (PEComa), most often arising in the kidney, sometimes associated with the tuberous sclerosis complex (TSC). It is uncertain whether nasal cavity AML and AL are best considered hamartomas or neoplasms, as their genetics are largely unexplored. Methods: We performed a multi-institutional retrospective study of nasal cavity mesenchymal lesions. Patient demographics, clinical histories, and histologic and immunohistochemical findings were collected. DNA and RNA were extracted from formalin-fixed, paraffin-embedded tissue and analyzed by SNP-based chromosomal microarray, targeted RNA fusion sequencing, and whole-exome sequencing. Results: Fifteen lesions (3–42 mm) were identified, predominantly in male (87%) patients with a median age of 60. Patients typically presented with obstructive symptoms, and none had a history of TSC. One AL was a recurrence from six years prior; 11 cases showed no recurrence (median 4.7 years, range: 0.88–12.4). Morphologically, 11 AML contained 30–80% smooth muscle, 10–25% vasculature, and 2–60% adipose tissue, while four AL contained 70–80% smooth muscle and 20–30% vasculature. Other histologic observations included ulceration, thrombosis, inflammation, myxoid change, senescent nuclei, and extramedullary hematopoiesis; no well-developed epithelioid cell morphology was identified. Immunohistochemically, all cases were positive for smooth muscle markers (actin, desmin, and/or caldesmon) and negative for melanocytic markers. Molecular analysis revealed loss of 3p and 11q in a single AML. No other known pathogenic copy number or molecular alterations were seen, including in TSC1/2, TFE3, or NOTCH2. Conclusion: Nasal cavity AML lacks morphologic, immunophenotypic, and genetic features of PEComa family AML. The significant histologic overlap between nasal AML and AL without distinguishing molecular features in either entity suggests "sinonasal angioleiomyoma with adipocytic differentiation" may be the most appropriate terminology for hybrid vascular and smooth muscle lesions containing adipocytic components. [ABSTRACT FROM AUTHOR]

Tumor-associated macrophages (TAMs) have been implicated as a tumor microenvironment (TME) cell population, which may be playing a vital role in the inhibition of effective T cell responses in the prostate TME. In this manuscript, we leverage a novel microscale cell culture platform, known as Stacks, to investigate mono-, co-, and tri-culture TME models comprised of prostate tumor cell lines, primary macrophages, and autologous T cells from patients with prostate cancer. Through multiplexed analysis of these multi-cellular prostate tumor models, we capture a dynamic interaction between primary TAMs and activated T cells that resulted in reciprocal proinflammatory activation of both cell populations upon interaction. These findings suggest that activated T cells are capable of reprogramming immunosuppressive TAMs in the context of prostate tumor models and that TAM reprogramming may play a key supportive role in restoring proinflammatory T cell tumor responses in the prostate TME. [ABSTRACT FROM AUTHOR]

White parents in the United States are unlikely to engage their preschool children in proactive discussions about race, instead waiting to follow their children's lead in broaching these topics. This passive approach risks missing critical opportunities to build children's positive racial identities and interrupt bias formation. This study aimed to increase parent-child discussions of race in white families in the U.S. through the implementation of a race-conscious book-reading curriculum in preschool classrooms. We hypothesized that children's proactive exposure to race-conscious content in preschool would have a spillover effect on parent-child conversations about race at home, such that white preschoolers and their parents would have more race-conscious conversations following the implementation of a classroom book-reading curriculum. Participants consisted of 29 monoracial white parents of preschool children, most of whom were highly educated, high-income mothers. Each day during the study period, parents reported any race-related conversations they had with their child. Results demonstrated that race-conscious conversations between white parents and their preschoolers increased following the implementation of the book reading curriculum. Book reading in preschool prompted children's bids for conversation about race with their parents on the same day, and these child-initiated bids resulted in more race-conscious parent-child conversations than bids initiated by parents or other adults. Further, families with more child-initiated bids had more total conversations about race than families with fewer conversations started by children. These findings suggest that white preschool children are capable of engaging in discussions about race and school-based socialization may be a promising avenue for supporting these conversations. Highlights: A race-conscious reading curriculum in preschool was associated with increased conversations about race in white families. Children's bids for conversation resulted in more race-conscious conversations than those started by parents. Racial socialization in white children does not occur in isolation; socialization at school can influence socialization at home. Leveraging multiple contexts may be a potential avenue for supporting racial socialization practices in white families. [ABSTRACT FROM AUTHOR]

Infections are common in patients with diabetes. Moreover, increasing incidence of antibiotic resistance impedes the complete bacterial clearance and calls for alternative treatment strategies. Along with antibacterial resistance, compromised host conditions create a favorable condition for the disease progression. In particular, cell junction proteins are of major importance as they contribute to a tight cell barrier, protecting against invading pathogens. However, the impact of high glucose on cell junction proteins has received little attention in the urinary bladder but merits closer investigation. Here, we report that during diabetes the expression of cell junction protein, claudin 14 is compromised in the human urine exfoliated cells and in the urinary bladder of type 2 diabetic mouse. Further in vitro analysis confirmed a direct correlation of lower intracellular calcium levels with claudin 14 expression in high glucose-treated human uroepithelial cells. Moreover, external calcium supplementation in high glucose-treated cells significantly affected the cell migration and restored the claudin 14 expression through focal adhesion and β-1 integrins. Strengthening the epithelial barrier is essential, especially in individuals with diabetes where basal calcium levels could contribute. [ABSTRACT FROM AUTHOR]

Tudor Interacting Repair Regulator (TIRR) is an RNA-binding protein (RBP) that interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. We utilized iCLIP to identify RNAs that directly bind to TIRR within cells, identifying the long non-coding RNA NEAT1 as the primary RNA partner. The high affinity of TIRR for NEAT1 is due to prevalent G-rich motifs in the short isoform (NEAT1_1) region of NEAT1. This interaction destabilizes the TIRR/53BP1 complex, promoting 53BP1's function. NEAT1_1 is enriched during the G1 phase of the cell cycle, thereby ensuring that TIRR-dependent inhibition of 53BP1's function is cell cycle-dependent. TDP-43, an RBP that is implicated in neurodegenerative diseases, modulates the TIRR/53BP1 complex by promoting the production of the NEAT1 short isoform, NEAT1_1. Together, we infer that NEAT1_1, and factors regulating NEAT1_1, may impact 53BP1-dependent DNA repair processes, with implications for a spectrum of diseases. TIRR interacts directly with 53BP1, restricting its access to DNA double-strand breaks (DSBs) and its association with p53. Here, the authors show that the lncRNA NEAT1, regulated by TDP-43, destabilizes the TIRR/53BP1 complex in G1, promoting 53BP1's function in DSB repair and p53 transactivation. [ABSTRACT FROM AUTHOR]

Although improving both the ecological and social conditions of agriculture are central pillars of agroecology, emerging empirical research has focused largely on exploring its ecological contributions. Key among the less studied social aspects is gender (in)equity. Drawing data from northern Malawi, this paper investigates the relationship between agroecology and women's autonomy in smallholder farming households. Overall, our findings showed participatory agroecology with a gender transformative lens can promote women's autonomy. Although there was no observed significant difference in women's autonomy at the baseline, women in agroecology practicing households (β = 0.20, p < 0.05) had significantly higher autonomy than their counterparts in non-agroecology households at the endline. These findings suggests that the broader gender-transformative praxis of agroecology which emphasizes the engagement of both men and women in deliberative dialogue and community-led education on social inequalities can contribute to improving household gender relations. In the context of widespread gender inequality in sub-Saharan Africa, and the limits these inequalities have on agricultural development, our findings provide promising entry points for development policy and the emerging sub-field of feminist agroecology. [ABSTRACT FROM AUTHOR]

Chirality conferral is fundamental for understanding the origin of life, and it is of direct importance for synthesizing new pharmaceuticals in the face of growing antibiotic resistance. Human-made, self-assembling nanostructures replicate the biological chirality conferral processes utilizing covalent and non-covalent bonds. However, chirality conferral from one form of matter to another via electromagnetic fields is more subtle and less explored. Here we report chirality conferral between gold nanohelices and achiral molecules (crystal violet). This conferral enables the experimental observation of a physical effect predicted in 1979—hyper-Raman optical activity. To benefit from Fermi's golden rule, the chirality conferral system was designed as doubly resonant, with the nanohelices and molecules resonating at the fundamental frequency and at the second-harmonic, respectively. We provide a theoretical framework for our results that expands the original mathematical formalism to include surface-enhanced hyper-Raman scattering and the chirality conferral process. Our results demonstrate that field-driven chirality conferral mechanisms are opening up entire fields of research, as exemplified by the discovery of a physical phenomenon. Theoretically predicted in 1979, hyper-Raman optical activity is now experimentally observed through chirality conferral from the electromagnetic field of chiral plasmonic gold nanohelices to crystal violet molecules that are achiral, sparking new science at the organic–inorganic interface. [ABSTRACT FROM AUTHOR]

We give a complete list of all homogeneous spaces M = G / H where G is a simple compact Lie group, H a connected, closed subgroup, and G/H is simply connected, for which the isotropy representation of H on T p M decomposes into exactly two irreducible summands. For each homogeneous space, we determine whether it admits a G-invariant Einstein metric. When there is an intermediate subgroup H < K < G , we classify all the G-invariant Einstein metrics. This is an extension of the classification of isotropy irreducible spaces, given independently by Manturov (Dokl Akad Nauk SSSR 141:792–795, 1961; Dokl Akad Nauk SSSR 141:1034–1037, 1961; Tensor Semin Vector Anal 13:68–145, 1966) and Wolf (Acta Math 120:59–148, 1968; Acta Math 152:141–142, 1984). [ABSTRACT FROM AUTHOR]

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Aims/hypothesis: Insulitis, a hallmark of inflammation preceding autoimmune type 1 diabetes, leads to the eventual loss of functional beta cells. However, functional beta cells can persist even in the face of continuous insulitis. Despite advances in immunosuppressive treatments, maintaining functional beta cells to prevent insulitis progression and hyperglycaemia remains a challenge. The cannabinoid type 1 receptor (CB1R), present in immune cells and beta cells, regulates inflammation and beta cell function. Here, we pioneer an ex vivo model mirroring human insulitis to investigate the role of CB1R in this process. Methods: CD4+ T lymphocytes were isolated from peripheral blood mononuclear cells (PBMCs) from male and female individuals at the onset of type 1 diabetes and from non-diabetic individuals, RNA was extracted and mRNA expression was analysed by real-time PCR. Single beta cell expression from donors with type 1 diabetes was obtained from data mining. Patient-derived human islets from male and female cadaveric donors were 3D-cultured in solubilised extracellular matrix gel in co-culture with the same donor PBMCs, and incubated with cytokines (IL-1β, TNF-α, IFN-γ) for 24–48 h in the presence of vehicle or increasing concentrations of the CB1R blocker JD-5037. Expression of CNR1 (encoding for CB1R) was ablated using CRISPR/Cas9 technology. Viability, intracellular stress and signalling were assayed by live-cell probing and real-time PCR. The islet function measured as glucose-stimulated insulin secretion was determined in a perifusion system. Infiltration of immune cells into the islets was monitored by microscopy. Non-obese diabetic mice aged 7 weeks were treated for 1 week with JD-5037, then euthanised. Profiling of immune cells infiltrated in the islets was performed by flow cytometry. Results: CNR1 expression was upregulated in circulating CD4+ T cells from individuals at type 1 diabetes onset (6.9-fold higher vs healthy individuals) and in sorted islet beta cells from donors with type 1 diabetes (3.6-fold higher vs healthy counterparts). The peripherally restricted CB1R inverse agonist JD-5037 arrested the initiation of insulitis in humans and mice. Mechanistically, CB1R blockade prevented islet NO production and ameliorated the ATF6 arm of the unfolded protein response. Consequently, cyto/chemokine expression decreased in human islets, leading to sustained islet cell viability and function. Conclusions/interpretation: These results suggest that CB1R could be an interesting target for type 1 diabetes while highlighting the regulatory mechanisms of insulitis. Moreover, these findings may apply to type 2 diabetes where islet inflammation is also a pathophysiological factor. Data availability: Transcriptomic analysis of sorted human beta cells are from Gene Expression Omnibus database, accession no. GSE121863, available at https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSM3448161. [ABSTRACT FROM AUTHOR]

Designing a new API for a large-scale project requires developers to make strategic design choices that will allow the codebase to evolve sustainably. To create well-structured API components, developers can learn from existing APIs. However, the lack of standardized methods for comparing API designs often makes this learning process inefficient and challenging. To bridge this gap, we introduce API-Miner, which, to our knowledge, is one of the first engines to recommend API-to-API specifications. API-Miner retrieves relevant components from OpenAPI specifications-a widely recognized standard for describing web APIs. The engine introduces several key innovations: (1) novel techniques for processing and extracting critical information from OpenAPI specifications, (2) specialized feature extraction methods tailored to the technical domain of API specifications, and (3) a log-linear probabilistic model that integrates multiple signals to retrieve relevant and high-quality OpenAPI components based on a query specification. Through both quantitative and qualitative evaluations, API-Miner achieves a recall@1 of 91.7% and an F1 score of 56.2%, outperforming baseline models by 15.4 percentage points (pp) in recall@1 and 3.2 pp in F1. API-Miner enables developers to access relevant OpenAPI components from public or internal databases early in the API development cycle, facilitating the learning of best practices and the identification of potential redundancies. This tool helps streamline the development process and supports the creation of maintainable, high-quality APIs. The code for API-Miner is available at https://github.com/jpmorganchase/api-miner. [ABSTRACT FROM AUTHOR]

The implementation of nature-based solutions (NbS), including living shorelines, to mitigate estuarine habitat loss is increasing at a pace exceeding the evaluation of their long-term success. Constructed oyster reefs (CORs) made of shell, concrete, stone, and other materials are one living shoreline tactic that is widely utilized, yet few studies have been conducted to understand the development of CORs within the context of both physical and ecological parameters over longer time scales (4 + years). A COR-based living shoreline project at the Gandy’s Beach Preserve (GBP) in Delaware Bay, NJ, USA, had dual goals of coastal protection and habitat provisioning, which prompted the development of a goal-driven monitoring framework to track project objectives. Methods were developed to quantify the following multi-disciplinary metrics over 7 years: elevations of CORs, waves (height, period, and direction), shoreline elevations, change in extent of vegetation patches, oyster density and size, nekton richness and community composition, and horseshoe crab impingement. The CORs met most of their habitat provisioning objectives as they were colonized by a multi-generational population of shellfish and created habitat for nekton, while posing negligible hazards to horseshoe crabs. However, none of the coastal protection objectives was fully achieved including material stability, wave attenuation, and sediment elevation increase. Results highlight the value of longer-term monitoring to understand performance and the need to match the scale and type of NbS tactic(s) with both the scale of the landscape and the site-specific hydrodynamic conditions to meet project goals. [ABSTRACT FROM AUTHOR]

Evidence suggests that youth progressively experience mental health needs and discover mental health symptoms for the first time in adolescence. Schools have come to the forefront of providing mental health services, as adolescents spend most of their day in the academic setting. The current study aimed to examine individual and school-level factors related to school-based mental health service use. This study employed data from the National Longitudinal Study of Adolescent to Adult Health, sampling students between 12 and 17 years old across 172 schools (N = 14,464). The dependent variable was use of school-based mental health services (SMHS) in the past year. Individual-level predictors included sociodemographic characteristics, enabling factors, and need. School-level factors were then included. We conducted a multilevel logistic regression model clustering at the school level. The study found that approximately 11% of variation in SMHS utilization is explained at the school-level. The odds of SMHS use was significantly associated with anxiety, depressive symptoms, and risk-taking behaviors. The odds of SMHS was higher for females, Black compared to White students, and public assistance recipients. SMHS use was negatively associated with school connectedness. The racial breakdown of student enrollment and location of services were significant factors that predicted service use. This study is among the first empirical studies providing important evidence regarding individual and school-level predictors of SMHS utilization. The study has implications for the continued need for school-based mental health professionals and school institutions' efforts to meet students' mental health needs and increase their access to services. [ABSTRACT FROM AUTHOR]

Context: Landscape fragmentation, which has demonstrated links to habitat loss, increased isolation, a loss of connectivity, and decreased biodiversity, is difficult to quantify. Traditional pattern-based approaches to measuring fragmentation use landscape metrics to quantify aspects of the composition or configuration of landscapes. Objective: The objective of this study was to examine the relative improvements of an alternative activity-based approach using the cost of traversing a landscape as a proxy for fragmentation and compare it with the traditional approach. Methods: One thousand binary landscapes varying in composition and configuration were simulated, and least-cost path analysis provided the data to calculate the activity-based metrics, which were compared with computed traditional pattern-based metrics. Results: Activity-based fragmentation assessments were sensitive to levels of landscape fragmentation, but offered improvements over exiting pattern-based methods in that some metrics varied monotonically across the spectrum of landscape configurations and thus makes their interpretation more holistically meaningful. Conclusions: This study provides a modular conceptual framework for assessing fragmentation using activity-based metrics that offer functional improvements over existing pattern-based approaches. While we present a focused theoretical implementation, the process to be measured and the scale of observation can be altered to suit specific user requirements, ecosystems, or species of interest. [ABSTRACT FROM AUTHOR]

Inflammaging, the chronic, progressive proinflammatory state associated with aging, has been associated with multiple negative health outcomes in humans. The pathophysiology of inflammaging is complex; however, it is often characterized by high serum concentrations of inflammatory mediators such as tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, and C-reactive protein (CRP). Few studies have evaluated the effects of age on inflammatory cytokines in companion dogs, and most of these studies included dogs of a single breed. In this cross-sectional study, we measured multiple circulating inflammatory markers and hematological parameters in banked serum samples from 47 healthy companion dogs of various breeds enrolled in the Dog Aging Project. Using univariate linear models, we investigated the association of each of these markers with age, sex, body weight, and body condition score (BCS), a measure of obesity in the dog. Serum IL-6, IL-8, and TNF-α concentrations were all positively associated with age. Lymphocyte count was negatively associated with age. Platelet count had a negative association with body weight. IL-2, albumin, cholesterol, triglyceride, bilirubin, S100A12, and NMH concentrations were not associated with age, weight, BCS, or sex after adjustment for multiple comparisons. Our findings replicate previous findings in humans, including increases in IL-6 and TNF-α with age, giving more evidence to the strength of the companion dog as a model for human aging. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is the leading cause of death worldwide. To this end, human cardiac organoids (hCOs) have been developed for improved organotypic CVD modeling over conventional in vivo animal models. Utilizing human cells, hCOs hold great promise to bridge key gaps in CVD research pertaining to human-specific conditions. hCOs are multicellular 3D models which resemble heart structure and function. Varying hCOs fabrication techniques leads to functional and phenotypic differences. To investigate heterogeneity across hCO platforms, we performed a transcriptomic analysis utilizing bulk RNA-sequencing from four previously published unique hCO studies. We further compared selected hCOs to 2D and 3D hiPSC-derived cardiomyocytes (hiPSC-CMs), as well as fetal and adult human myocardium bulk RNA-sequencing samples. Upon investigation utilizing Principal Component Analysis, K-means clustering analysis of key genes, and further downstream analyses such as Gene Set Enrichment (GSEA), Gene Set Variation (GSVA), and GO term enrichment, we found that hCO fabrication method influences maturity and cellular heterogeneity across models. Thus, we propose that adjustment of fabrication method will result in an hCO with a defined maturity and transcriptomic profile to facilitate its specified applications, in turn maximizing its modeling potential. [ABSTRACT FROM AUTHOR]

The effective design of combinatorial libraries to balance fitness and diversity facilitates the engineering of useful enzyme functions, particularly those that are poorly characterized or unknown in biology. We introduce MODIFY, a machine learning (ML) algorithm that learns from natural protein sequences to infer evolutionarily plausible mutations and predict enzyme fitness. MODIFY co-optimizes predicted fitness and sequence diversity of starting libraries, prioritizing high-fitness variants while ensuring broad sequence coverage. In silico evaluation shows that MODIFY outperforms state-of-the-art unsupervised methods in zero-shot fitness prediction and enables ML-guided directed evolution with enhanced efficiency. Using MODIFY, we engineer generalist biocatalysts derived from a thermostable cytochrome c to achieve enantioselective C-B and C-Si bond formation via a new-to-nature carbene transfer mechanism, leading to biocatalysts six mutations away from previously developed enzymes while exhibiting superior or comparable activities. These results demonstrate MODIFY's potential in solving challenging enzyme engineering problems beyond the reach of classic directed evolution. The effective design of cold-start enzyme libraries to balance fitness and diversity enables access to enzyme variants that are readily evolvable and close to the optima in the fitness landscape. Here, the authors develop MODIFY (machine learning-optimized library design with improved fitness and diversity), a machine learning algorithm to co-optimize expected fitness and sequence diversity of starting libraries, enhancing the efficiency of directed evolution in enzyme engineering. [ABSTRACT FROM AUTHOR]

The ability to distinguish multiple forms of plutonium from one another, such as oxide and metal, is paramount in areas of nuclear nonproliferation and international safeguards. In its metal form, plutonium can be readily used in a nuclear weapon, while oxide forms are associated with nuclear reactor fuel. Oxide-based plutonium forms emit neutrons with an energy spectrum that is significantly different from the fission neutrons that are emitted from plutonium metal. Organic scintillation detectors output pulses that are proportional to the neutron energy deposited, and therefore present a means of distinguishing these plutonium forms based on their energy spectra. In this work, metal and oxide forms of plutonium were measured using a handheld detection system based on an organic glass scintillator. Monte Carlo modeling of these experiments was performed to provide insight into the origin of the features in the observed light output spectra. Through analysis of multiple regions of these spectra, in a matter of minutes we were able to unambiguously discriminate oxide and metal plutonium forms from one another and from a plutonium-beryllium neutron source, which was considered for comparison because these sources are commonly used in industrial applications. The ability to discriminate weapons-usable material from nuclear reactor fuel has applications in nuclear treaty verification and safeguards. [ABSTRACT FROM AUTHOR]

Objectives: Two key parental reflective capacities—mindful parenting (MP) and parental reflective functioning (PRF) — have been shown to promote healthy parent-child relationships through parents' increased sensitivity and responsiveness to their children's needs in spite of parenting stressors. Despite the theoretical overlap between these two constructs, researchers have continued to examine them independently. Therefore, the purpose of this scoping review was to review the overlapping and distinctive outcomes and correlates in the empirical MP and PRF literatures. Method: A comprehensive literature search across the MP and PRF literature for studies published from 2005 through early 2020 (pre-COVID-19 pandemic) was conducted. Results: A review of 301 articles (n = 180 MP and n = 121 PRF) revealed overlapping study outcomes and correlates, including improvement in parent and child well-being, parenting behaviors, and attachment. Both MP and PRF literatures suggest MP and PRF are amenable to intervention-induced changes, although mostly documented in White mothers, which results may not be generalizable to diverse populations. Conclusions: Researchers should consider the impact MP and PRF have on positive family relationships. Results suggest that scholars should consider investigating and intervening on MP and PRF simultaneously. Specifically, results identified MP and PRF convergent associations and perhaps synergistic impacts on positive parenting behaviors. Limitations and future directions are discussed. Preregistration: This review was not preregistered. [ABSTRACT FROM AUTHOR]

Purpose: Segmentation of surgical scenes may provide valuable information for real-time guidance and post-operative analysis. However, in some surgical video frames there is unavoidable ambiguity, leading to incorrect predictions of class or missed detections. In this work, we propose a novel method that alleviates this problem by introducing a hierarchy and associated hierarchical inference scheme that allows broad anatomical structures to be predicted when fine-grained structures cannot be reliably distinguished. Methods: First, we formulate a multi-label segmentation loss informed by a hierarchy of anatomical classes and then train a network using this. Subsequently, we use a novel leaf-to-root inference scheme ("Hiera-Mix") to determine the trade-off between label confidence and granularity. This method can be applied to any segmentation model. We evaluate our method using a large laparoscopic cholecystectomy dataset with 65,000 labelled frames. Results: We observed an increase in per-structure detection F1 score for the critical structures, when evaluated across their sub-hierarchies, compared to the baseline method: 6.0% for the cystic artery and 2.9% for the cystic duct, driven primarily by increases in precision of 11.3% and 4.7%, respectively. This corresponded to visibly improved segmentation outputs, with better characterisation of the undissected area containing the critical structures and fewer inter-class confusions. For other anatomical classes, which did not stand to benefit from the hierarchy, performance was unimpaired. Conclusion: Our proposed hierarchical approach improves surgical scene segmentation in frames with ambiguity, by more suitably reflecting the model's parsing of the scene. This may be beneficial in applications of surgical scene segmentation, including recent advancements towards computer-assisted intra-operative guidance. [ABSTRACT FROM AUTHOR]

Children in malaria-endemic regions can experience repeated Plasmodium infections over short periods of time. Effects of re-infection on multiple co-existing CD4+ T cell subsets remain unresolved. Here, we examine antigen-experienced CD4+ T cells during re-infection in mice, using scRNA-seq/TCR-seq and spatial transcriptomics. TCR transgenic TEM cells initiate rapid Th1/Tr1 recall responses prior to proliferating, while GC Tfh counterparts are refractory, with TCM/Tfh-like cells exhibiting modest non-proliferative responses. Th1-recall is a partial facsimile of primary Th1-responses, with no upregulated effector-associated genes being unique to recall. Polyclonal, TCR-diverse, CD4+ T cells exhibit similar recall dynamics, with individual clones giving rise to multiple effectors including highly proliferative Th1/Tr1 cells, as well as GC Tfh and Tfh-like cells lacking proliferative capacity. Thus, we show substantial diversity in recall responses mounted by multiple co-existing CD4+ T cell subsets in the spleen, and present graphical user interfaces for studying gene expression dynamics and clonal relationships during re-infection. CD4+ T cells are known to be important in Plasmodium infection. Here the authors use mouse models to track antigen-experienced TCR transgenic and polyclonal CD4+ T cells during Plasmodium re-infection, and show different T cell phenotypes and varied responses in different areas of the spleen. [ABSTRACT FROM AUTHOR]

Hypervariable region sequencing of the 16S ribosomal RNA (rRNA) gene plays a critical role in microbial ecology by offering insights into bacterial communities within specific niches. While providing valuable genus-level information, its reliance on data from targeted genetic regions limits its overall utility. Recent advances in sequencing technologies have enabled characterisation of the full-length 16S rRNA gene, enhancing species-level classification. Although current short-read platforms are cost-effective and precise, they lack full-length 16S rRNA amplicon sequencing capability. This study aimed to evaluate the feasibility of a modified 150 bp paired-end full-length 16S rRNA amplicon short-read sequencing technique on the Illumina iSeq 100 and 16S rRNA amplicon assembly workflow by utilising a standard mock microbial community and subsequently performing exploratory characterisation of captive (zoo) and free-ranging African elephant (Loxodonta africana) respiratory microbiota. Our findings demonstrate that, despite generating assembled amplicons averaging 869 bp in length, this sequencing technique provides taxonomic assignments consistent with the theoretical composition of the mock community and respiratory microbiota of other mammals. Tentative bacterial signatures, potentially representing distinct respiratory tract compartments (trunk and lower respiratory tract) were visually identified, necessitating further investigation to gain deeper insights into their implication for elephant physiology and health. [ABSTRACT FROM AUTHOR]

To understand how the human brain distinguishes itself from external stimulation, it was examined if motor predictions enable healthy adult volunteers to infer self-location and to distinguish their body from the environment (and other agents). By uniquely combining a VR-setup with full-body motion capture, a full-body illusion paradigm (FBI) was developed with different levels of motion control: (A) a standard, passive FBI in which they had no motion control; (B) an active FBI in which they made simple, voluntary movements; and (C) an immersive game in which they real-time controlled a human-sized avatar in third person. Systematic comparisons between measures revealed a causal relationship between (i) motion control (prospective agency), (ii) self-other identification, and (iii) the ability to locate oneself. Healthy adults could recognise their movements in a third-person avatar and psychologically align with it (action observation); but did not lose a sense of place (self-location), time (temporal binding), nor who they are (self/other). Instead, motor predictions enabled them to localise their body and to distinguish self from other. In the future, embodied games could target and strengthen the brain's control networks in psychosis and neurodegeneration; real-time motion simulations could help advance neurorehabilitation techniques by fine-tuning and personalising therapeutic settings. [ABSTRACT FROM AUTHOR]

The phenomenon of mixed/heterogenous treatment responses to cancer therapies within an individual patient presents a challenging clinical scenario. Furthermore, the molecular basis of mixed intra-patient tumor responses remains unclear. Here, we show that patients with metastatic lung adenocarcinoma harbouring co-mutations of EGFR and TP53, are more likely to have mixed intra-patient tumor responses to EGFR tyrosine kinase inhibition (TKI), compared to those with an EGFR mutation alone. The combined presence of whole genome doubling (WGD) and TP53 co-mutations leads to increased genome instability and genomic copy number aberrations in genes implicated in EGFR TKI resistance. Using mouse models and an in vitro isogenic p53-mutant model system, we provide evidence that WGD provides diverse routes to drug resistance by increasing the probability of acquiring copy-number gains or losses relative to non-WGD cells. These data provide a molecular basis for mixed tumor responses to targeted therapy, within an individual patient, with implications for therapeutic strategies. Mixed responses to targeted therapy within a patient are a clinical challenge. Here the authors show that TP53 loss-of-function cooperates with whole genome doubling which increases chromosomal instability. This leads to greater cellular diversity and multiple routes of resistance, which in turn promotes mixed responses to treatment. [ABSTRACT FROM AUTHOR]

The size and complexity of datasets resulting from comparative research experiments in the agricultural domain is constantly increasing. Often the number of variables measured in an experiment exceeds the number of experimental units composing the experiment. When there is a necessity to model the covariance relationships that exist between variables in these experiments, estimation difficulties can arise due to the resulting covariance structure being of reduced rank. A statistical method, based in a linear mixed model framework, is presented for the analysis of designed experiments where datasets are characterised by a greater number of variables than experimental units, and for which the modelling of complex covariance structures between variables is desired. Aided by a clustering algorithm, the method enables the estimation of covariance through the introduction of covariance clusters as random effects into the modelling framework, providing an extension of the traditional variance components model for building covariance structures. The method was applied to a multi-phase mass spectrometry-based proteomics experiment, with the aim of exploring changes in the proteome of barley grain over time during the malting process. The modelling approach provides a new linear mixed model-based method for the estimation of covariance structures between variables measured from designed experiments, when there are a small number of experimental units, or observations, informing covariance parameter estimates. [ABSTRACT FROM AUTHOR]

Objectives: Accurate risk stratification of patients with stage II and III colorectal cancer (CRC) prior to treatment selection enables limited health resources to be efficiently allocated to patients who are likely to benefit from adjuvant chemotherapy. We aimed to investigate the cost-effectiveness of a recently developed deep learning-based prognostic method, Histotyping, from the perspective of the Norwegian healthcare system. Methods: Two partitioned survival models were developed to assess the cost-effectiveness of Histotyping for two treatment cohorts: patients with CRC stage II and III. For each of the two cohorts, Histotyping was used for risk stratification to assign adjuvant chemotherapy and was compared with the standard of care (SOC) (adjuvant chemotherapy to all patients). Health outcomes measured in the model were quality-adjusted life years (QALYs) and life years (LYs) gained. Deterministic and probabilistic sensitivity analyses were performed to determine the impact of uncertainty. Scenario analyses were performed to assess the impact of the parameters with the greatest uncertainty. Results: Risk-stratifying patients with CRC stage II and III using Histotyping was dominant (less costly and more effective) compared to SOC. In patients with CRC stage II, the net monetary benefit of Histotyping was 270,934 Norwegian kroners (NOK) (year of valuation is 2021), and the net health benefit of Histotyping was 0.99. In stage III, the net monetary benefit of Histotyping was 195,419 NOK, and the net health benefit of Histotyping was 0.71. Conclusions: Risk-stratifying patients with CRC using Histotyping prior to the administration of adjuvant chemotherapy is likely to be a cost-effective strategy in Norway. [ABSTRACT FROM AUTHOR]

Examining how heat affects people with Parkinson's disease is essential for informing clinical decision-making, safety, well-being, and healthcare planning. While there is evidence that the neuropathology associated with Parkinson's disease affects thermoregulatory mechanisms, little attention has been given to the association of heat sensitivity to worsening symptoms and restricted daily activities in people with this progressive disease. Using a cross-sectional study design, we examined the experiences of people diagnosed with Parkinson's disease in the heat. Two-hundred and forty-seven people completed an online survey (age: 66.0 ± 9.2 years; sex: male = 102 (41.3%), female = 145 (58.7%)), of which 195 (78.9%) reported becoming more sensitive to heat with Parkinson's disease. Motor and nonmotor symptoms worsened with heat in 182 (73.7%) and 203 (82.2%) respondents, respectively. The most commonly reported symptoms to worsen included walking difficulties, balance impairment, stiffness, tremor, fatigue, sleep disturbances, excess sweating, difficulty concentrating, and light-headedness when standing. Concerningly, over half indicated an inability to work effectively in the heat, and nearly half reported that heat impacted their ability to perform household tasks and social activities. Overall, heat sensitivity was common in people with Parkinson's disease and had a significant impact on symptomology, day-to-day activities and quality of life. [ABSTRACT FROM AUTHOR]

In recent years, dysphagia care has shifted toward a more patient-centered approach. This means that dysphagia clinicians are considering more factors in the treatment process including the goals of care, quality of life, and cultural values. The purpose of this scoping review was to examine relevant research and identify dysphagia interventions outside of those traditionally used by dysphagia clinicians that may improve swallowing function. A review of relevant studies was conducted using search terms related to swallowing and treatment. The search yielded 8439 unique studies. Of the 283 articles that underwent a full-text review, 37 articles were included in the final review. These articles highlighted three potential areas of non-traditional dysphagia intervention that may serve to provide holistic care, while also aiming to improve swallowing mechanisms: acupuncture and Eastern medicine interventions, vocal exercises, and physical function exercises. The results suggest that dysphagia clinicians should work collaboratively with other allied health professionals and consider non-traditional approaches to dysphagia care. Through the identification of potentially effective but non-traditional or non-Eurocentric interventions for dysphagia care, clinicians may promote a culturally relevant, patient-centered approach, in turn increasing patient acceptance of treatment plans and compliance. Future research should explore the efficacy and feasibility of these interventions in dysphagia rehabilitation, as well as their effectiveness compared to more traditional approaches. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies (mAbs) represent the largest class of therapeutic protein drug products. mAb glycosylation produces a heterogeneous, analytically challenging distribution of glycoforms that typically should be adequately characterized because glycosylation-based product quality attributes (PQAs) can impact product quality, immunogenicity, and efficacy. In this study, two products were compared using a panel of analytical methods. Two high-resolution mass spectrometry (HRMS) workflows were used to analyze N-glycans, while nuclear magnetic resonance (NMR) was used to generate monosaccharide fingerprints. These state-of-the-art techniques were compared to conventional analysis using hydrophilic interaction chromatography (HILIC) coupled with fluorescence detection (FLD). The advantages and disadvantages of each method are discussed along with a comparison of the identified glycan distributions. The results demonstrated agreement across all methods for major glycoforms, demonstrating how confidence in glycan characterization is increased by combining orthogonal analytical methodologies. The full panel of methods used represents a diverse toolbox that can be selected from based on the needs for a specific product or analysis. [ABSTRACT FROM AUTHOR]

Regulators, environmental advocates, and community groups in the United States (U.S.) are concerned about air pollution associated with the proliferating e-commerce and warehousing industries. Nationwide datasets of warehouse locations, traffic, and satellite observations of the traffic-related pollutant nitrogen dioxide (NO2) provide a unique capability to evaluate the air quality and environmental equity impacts of these geographically-dispersed emission sources. Here, we show that the nearly 150,000 warehouses in the U.S. worsen local traffic-related air pollution with an average near-warehouse NO2 enhancement of nearly 20% and are disproportionately located in marginalized and minoritized communities. Near-warehouse truck traffic and NO2 significantly increase as warehouse density and the number of warehouse loading docks and parking spaces increase. Increased satellite-observed NO2 near warehouses underscores the need for indirect source rules, incentives for replacing old trucks, and corporate commitments towards electrification. Future ground-based monitoring campaigns may help track impacts of individual or small clusters of facilities.Using satellite observations, communities in the U.S. containing warehouses experience more truck traffic and increased health-harming pollution with a disproportionate number of racial and ethnic minorities living in these communities. [ABSTRACT FROM AUTHOR]

The Werner syndrome RecQ helicase WRN was identified as a synthetic lethal target in cancer cells with microsatellite instability (MSI) by several genetic screens1–6. Despite advances in treatment with immune checkpoint inhibitors7–10, there is an unmet need in the treatment of MSI cancers11–14. Here we report the structural, biochemical, cellular and pharmacological characterization of the clinical-stage WRN helicase inhibitor HRO761, which was identified through an innovative hit-finding and lead-optimization strategy. HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. Pharmacological inhibition by HRO761 recapitulated the phenotype observed by WRN genetic suppression, leading to DNA damage and inhibition of tumour cell growth selectively in MSI cells in a p53-independent manner. Moreover, HRO761 led to WRN degradation in MSI cells but not in microsatellite-stable cells. Oral treatment with HRO761 resulted in dose-dependent in vivo DNA damage induction and tumour growth inhibition in MSI cell- and patient-derived xenograft models. These findings represent preclinical pharmacological validation of WRN as a therapeutic target in MSI cancers. A clinical trial with HRO761 (NCT05838768) is ongoing to assess the safety, tolerability and preliminary anti-tumour activity in patients with MSI colorectal cancer and other MSI solid tumours.HRO761 is a potent, selective, allosteric WRN inhibitor that binds at the interface of the D1 and D2 helicase domains, locking WRN in an inactive conformation. [ABSTRACT FROM AUTHOR]

Background/objective: To explore the anti-tumour activity of combining AKT inhibition and docetaxel in PTEN protein null and WT prostate tumours. Methods: Mechanisms associated with docetaxel capivasertib treatment activity in prostate cancer were examined using a panel of in vivo tumour models and cell lines. Results: Combining docetaxel and capivasertib had increased activity in PTEN null and WT prostate tumour models in vivo. In vitro short-term docetaxel treatment caused cell cycle arrest in the majority of cells. However, a sub-population of docetaxel-persister cells did not undergo G2/M arrest but upregulated phosphorylation of PI3K/AKT pathway effectors GSK3β, p70S6K, 4E-BP1, but to a lesser extent AKT. In vivo acute docetaxel treatment induced p70S6K and 4E-BP1 phosphorylation. Treating PTEN null and WT docetaxel-persister cells with capivasertib reduced PI3K/AKT pathway activation and cell cycle progression. In vitro and in vivo it reduced proliferation and increased apoptosis or DNA damage though effects were more marked in PTEN null cells. Docetaxel-persister cells were partly reliant on GSK3β as a GSK3β inhibitor AZD2858 reversed capivasertib-induced apoptosis and DNA damage. Conclusion: Capivasertib can enhance anti-tumour effects of docetaxel by targeting residual docetaxel-persister cells, independent of PTEN status, to induce apoptosis and DNA damage in part through GSK3β. [ABSTRACT FROM AUTHOR]

Medical students' feedback orientation (their attitudes about and preferences for feedback from preceptors) may change over the course of the third year of medical school and is likely influenced by identity-related factors. This study proposed that both how students view themselves personally (i.e., impostor syndrome) and how they view themselves in relation to the group (i.e., identification with the profession) are identity factors related to related to feedback orientation during clinical rotations. 177 third-year medical students enrolled in a four-phase longitudinal survey study beginning at the start of clinical rotations and continuing every twelve weeks of the academic year thereafter. Feedback orientation was conceptualized and measured as comprising aspects of utility (i.e., feedback is valuable and useful), sensitivity (i.e., feeling intimidated or threatened by corrective feedback), confidentiality (i.e., public/private context of feedback), and retention (i.e., feedback remembered). Results indicated that these aspects of feedback orientation did not significantly change during the third year. Instead, impostor syndrome was at least marginally, significantly associated with all aspects of feedback orientation across phases. Group identity was associated with feedback utility and retention, and female-identifying students reported significantly greater feedback confidentiality and feedback retention. Interventions may be needed to improve medical students' attitudes about feedback, particularly for those who experience impostor syndrome. Fostering group cohesion among medical students may influence how well students remember feedback and find it useful. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The proinflammatory cytokines IFN-α, IFN-γ, IL-1β and TNF-α may contribute to innate and adaptive immune responses during insulitis in type 1 diabetes and therefore represent attractive therapeutic targets to protect beta cells. However, the specific role of each of these cytokines individually on pancreatic beta cells remains unknown. Methods: We used deep RNA-seq analysis, followed by extensive confirmation experiments based on reverse transcription-quantitative PCR (RT-qPCR), western blot, histology and use of siRNAs, to characterise the response of human pancreatic beta cells to each cytokine individually and compared the signatures obtained with those present in islets of individuals affected by type 1 diabetes. Results: IFN-α and IFN-γ had a greater impact on the beta cell transcriptome when compared with IL-1β and TNF-α. The IFN-induced gene signatures have a strong correlation with those observed in beta cells from individuals with type 1 diabetes, and the level of expression of specific IFN-stimulated genes is positively correlated with proteins present in islets of these individuals, regulating beta cell responses to 'danger signals' such as viral infections. Zinc finger NFX1-type containing 1 (ZNFX1), a double-stranded RNA sensor, was identified as highly induced by IFNs and shown to play a key role in the antiviral response in beta cells. Conclusions/interpretation: These data suggest that IFN-α and IFN-γ are key cytokines at the islet level in human type 1 diabetes, contributing to the triggering and amplification of autoimmunity. [ABSTRACT FROM AUTHOR]

Socioeconomic factors are important correlates of drug use behaviors and health-related outcomes in people who use drugs (PWUD) residing in urban areas. However, less is known about the complex overlapping nature of socioeconomic conditions and their association with a range of individual, drug use, and health-related factors in men and women who use drugs. Data were obtained from two community-recruited prospective cohorts of PWUD. Using a gender-stratified approach, we conducted repeated measures latent class analyses (RMLCA) to identify discrete latent socioeconomic subgroups. Multivariable generalized estimating equations were then used to identify correlates of class membership. Between June 2014 and December 2018, RMLCA of 9844 observations from 1654 participants revealed five distinct patterns of socioeconomic status for both men and women. These patterns were primarily distinguished by variations in income, material and housing security, income generation activity, exposure to violence, criminal justice involvement, and police contact. Across gender, progressive increases in exposure to multiple dimensions of socioeconomic disadvantage were found to be associated with frequent use of opioids and stimulants, accessing social services, and being hepatitis C virus antibody-positive. Similar but less congruent trends across gender were observed for age, binge drug use, engagement with opioid agonist therapy, and living with HIV. Gendered patterns of multiple and overlapping dimensions of socioeconomic adversity aligned with patterns of frequent drug use and health-related concerns, highlighting priority areas for gender-inclusive, multilevel responses to mitigate health disparities and meet the diverse socioeconomic needs of urban-dwelling men and women who use drugs. [ABSTRACT FROM AUTHOR]

In response to an increase in overdose deaths, there was a rapid scale-up of supervised consumption services (SCS), including federally sanctioned SCS and low-barrier SCS known as overdose prevention sites (OPS), in Vancouver, Canada, beginning in December 2016. However, little is known about the use of such services among adolescents and young adults (AYA) in this context. We therefore sought to characterize factors associated with the use of federally sanctioned SCS and OPS among street-involved AYA who inject drugs in Vancouver during an overdose crisis. From December 2016 to March 2020, data were collected from a prospective cohort of street-involved AYA aged 14 to 26 at baseline. Using multivariable generalized estimating equation analyses, we identified factors associated with recent use of federally sanctioned SCS and OPS, respectively. Among 298 AYA who inject drugs, 172 (57.8%) and 149 (50.0%) reported using federally sanctioned SCS and OPS during the study period, respectively. In multivariable analyses, public injecting, negative police interactions, and residing or spending time ≥ weekly in the Downtown Eastside neighborhood were all positively associated with the use of federally sanctioned SCS and OPS, respectively. Additionally, ≥ daily unregulated opioid use and residential eviction were positively associated with federally sanctioned SCS use, while requiring help injecting was inversely associated. Self-identified female or non-binary gender was also positively associated with OPS use (all p < 0.05). Both federally sanctioned SCS and OPS successfully engaged AYA at heightened risk of adverse health outcomes. However, the lack of accommodation of AYA who require manual assistance with injecting at federally sanctioned SCS may be inhibiting service engagement. [ABSTRACT FROM AUTHOR]

We use recent results about linking the number of zeros on algebraic varieties over ℂ, defined by polynomials with integer coefficients, and on their reductions modulo sufficiently large primes to study congruences with products and reciprocals of linear forms. This allows us to make some progress towards a question of B. Murphy, G. Petridis, O. Roche-Newton, M. Rudnev and I. D. Shkredov (2019) on an extreme case of the Erdős–Szemerédi conjecture in finite fields. [ABSTRACT FROM AUTHOR]

Riparian tetragnathid spiders are used as biosentinels of aquatic contamination because they are specialized feeders of aquatic emergent insects and are also prey items for terrestrial predators (e.g., birds). Analysis of both trophic position (e.g., stable nitrogen isotopes) and contaminant concentrations are needed to utilize tetragnathids as biosentinels, which can present challenges when collecting enough biomass to reach analytical detection limits, due to their relatively small size. The purpose of this study was to investigate the impacts of a controlled diet source on spider biomass, egg laying and stable isotope values ( 13C and 15N). Diet significantly influenced the biomass and egg laying of tetragnathids, with some spiders losing up to 50% of their biomass in a single egg-laying event. 13C had a faster turnover rate in the whole-body of spiders compared to legs, which is important, as spider legs are presently used as surrogates for whole-body 13C values. [ABSTRACT FROM AUTHOR]

There has been a great deal written about ChatGPT since its launch in late 2022. Many news stories specifically address the impact of ChatGPT on education. However, there has been little research showing what K-12 teachers are thinking about and doing with ChatGPT. This research article helps to fill that gap. A survey of Missouri teachers was conducted to hear from them about their experiences with and ideas for ChatGPT. Results indicate that teachers are concerned about the potential impact of ChatGPT on education, but many are looking for ways to effectively incorporate it into their classes. Finally, many educators are looking for support and professional development about how best to navigate this new technological landscape. [ABSTRACT FROM AUTHOR]

Purpose: Financial toxicity is a source of significant distress for patients with urologic cancers, yet few studies have addressed financial burden in this patient population. Methods: We developed a financial toxicity screening program using a lay health worker (LHW) and social worker (SW) to assess and mitigate financial toxicity in a single academic medical clinic. As part of a quality improvement project, the LHW screened all newly diagnosed patients with advanced stages of prostate, kidney, or urothelial cancer for financial burden using three COST tool questions and referred patients who had significant financial burden to an SW who provided personalized recommendations. The primary outcome was feasibility defined as 80% of patients with financial burden completing the SW consult. Secondary outcomes were patient satisfaction, change in COST Tool responses, and qualitative assessment of financial resources utilized. Results: The LHW screened a total of 185 patients for financial toxicity; 82% (n = 152) were male, 65% (n = 120) White, and 75% (n = 139) reported annual household income >$100,000 US Dollars; 60% (n = 114) had prostate cancer. A total of 18 (9.7%) participants screened positive for significant financial burden and were referred to the SW for consultation. All participants (100%) completed and reported satisfaction with the SW consultation and had 0.83 mean lower scores on the COST Tool post-intervention assessment compared to pre-intervention (95% confidence interval [0.26, 1.41]). Conclusion: This multidisciplinary financial toxicity intervention using an LHW and SW was feasible, acceptable, and associated with reduced financial burden among patients with advanced stages of urologic cancers. Future work should evaluate the effect of this intervention among cancer patients in diverse settings. [ABSTRACT FROM AUTHOR]

Background: To retrospectively review lateral wall orbital decompression for thyroid eye disease (TED) and to evaluate pre-operative CT scans to analyse the variation in proptosis reduction. Methods: Consecutive lateral wall orbital decompressions performed by a single surgeon were retrospectively reviewed. Pre-operative CT scan features and post-operative proptosis reduction were analysed. The sphenoid trigone cross-sectional areas were summed and multiplied by the slice thickness to yield bone volume. Cumulative extraocular muscle thickness was calculated by combining the maximum thickness of the four recti. "Trigone volume" and "cumulative muscle thickness" were correlated with proptosis reduction at 3 months post-surgery. Results: Out of 73 consecutive lateral wall orbital decompressions, 17 orbits had prior endonasal medial wall orbital decompression. In the remaining 56 orbits, the mean pre-operative and post-operative proptosis were 24.3 ± 1.6 mm and 20.9 ± 2.3 mm respectively. The proptosis reduction ranged from 1 to 7 mm (mean of 3.5 mm ± 1.3 (p < 0.001)). Mean sphenoid trigone volume was 895 ± 434.4 mm3. The mean cumulative muscle thickness was 20.4 ± 5 mm. The correlation coefficient between muscle thickness and proptosis reduction was − 0.3 and was statistically significant (p = 0.043). The correlation coefficient between sphenoidal trigone volume and proptosis reduction was 0.2 (p = 0.068). With a multivariate analysis, the coefficient of efficient of regression for muscle thickness was − 0.007 (p = 0.42) and the coefficient of regression for trigone volume was 0.0 (p = 0.046). Conclusion: Proptosis reduction following lateral wall orbital decompression can be variable. Extraocular muscle thickness had a significant correlation with the outcome, with greater proptosis reduction in orbits with thin muscles. The sphenoidal trigone size had a weak correlation with decompression outcome. [ABSTRACT FROM AUTHOR]

Interest in the psychology of misinformation has exploded in recent years. Despite ample research, to date there is no validated framework to measure misinformation susceptibility. Therefore, we introduce Verificationdone, a nuanced interpretation schema and assessment tool that simultaneously considers Veracity discernment, and its distinct, measurable abilities (real/fake news detection), and biases (distrust/naïvité—negative/positive judgment bias). We then conduct three studies with seven independent samples (Ntotal = 8504) to show how to develop, validate, and apply the Misinformation Susceptibility Test (MIST). In Study 1 (N = 409) we use a neural network language model to generate items, and use three psychometric methods—factor analysis, item response theory, and exploratory graph analysis—to create the MIST-20 (20 items; completion time < 2 minutes), the MIST-16 (16 items; < 2 minutes), and the MIST-8 (8 items; < 1 minute). In Study 2 (N = 7674) we confirm the internal and predictive validity of the MIST in five national quota samples (US, UK), across 2 years, from three different sampling platforms—Respondi, CloudResearch, and Prolific. We also explore the MIST's nomological net and generate age-, region-, and country-specific norm tables. In Study 3 (N = 421) we demonstrate how the MIST—in conjunction with Verificationdone—can provide novel insights on existing psychological interventions, thereby advancing theory development. Finally, we outline the versatile implementations of the MIST as a screening tool, covariate, and intervention evaluation framework. As all methods are transparently reported and detailed, this work will allow other researchers to create similar scales or adapt them for any population of interest. [ABSTRACT FROM AUTHOR]

The ability of Mycobacterium tuberculosis (Mtb) to persist in the host complicates and prolongs tuberculosis (TB) patient chemotherapy. Here we demonstrate that a neglected two-component system (TCS) of Mtb, TcrXY, is an autoregulated acid-sensing TCS that controls a functionally diverse 70-gene regulon required for bacterial persistence. Characterisation of two representatives of this regulon, Rv3706c and Rv3705A, implicate these genes as key determinants for the survival of Mtb in vivo by serving as important effectors to mitigate redox stress at acidic pH. We show that genetic silencing of the response regulator tcrX using CRISPR interference attenuates the persistence of Mtb during chronic mouse infection and improves treatment with the two front-line anti-TB drugs, rifampicin and isoniazid. We propose that targeting TcrXY signal transduction blocks the ability of Mtb to sense and respond to acid stress, resulting in a disordered program of persistence to render the organism vulnerable to existing TB chemotherapy.Stupar et al. describe a new role for the Mycobacterium tuberculosis two-component system, TcrXY, in the modulation of up to 70 genes, including two effectors, TarA and TarB which mitigate intracellular redox stress. [ABSTRACT FROM AUTHOR]