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Abstract Background Firearm violence is a significant public health issue. However, it is unclear if there is an association between the Social Vulnerability Index (SVI) and the intent of both fatal and nonfatal firearm injuries, and if these associations are modified by community race and ethnic composition. This study examines the association between community-level social vulnerability and firearm injury incidence in North Carolina (NC) using 2021–2022 emergency medical services (EMS) data. Additionally, it investigates how these associations vary by the intent of injury (assault, self-inflicted, and unintentional), and whether they are modified by community racial/ethnic composition. Methods This cross-sectional study utilized NC EMS data, capturing firearm incidents from January 1, 2021, to December 31, 2022. The SVI from the Centers for Disease Control and Prevention (CDC) was used to assess community-level vulnerability. The SVI’s racial/ethnic minority status component was removed for stratification analysis. Firearm injury rates were calculated per 100,000 population, and negative binomial regression models were used to estimate Incidence Rate Ratios (IRRs) for different SVI levels and intents of firearm injuries. Results During the study period, we identified 7,250 EMS encounters at non-healthcare locations related to firearm injuries, encompassing 2,648 NC census tracts. Assault was the leading cause of firearm injuries (n = 3,799), followed by self-inflicted (n = 1,498), and unintentional injuries (n = 722). High-SVI communities had significantly higher rates of firearm injuries compared to low-SVI communities, particularly for assault-related injuries. When the minority status component was excluded from SVI, racial/ethnic minority status emerged as a significant modifier, with higher rates of firearm injuries being observed in communities with larger racial/ethnic minority populations. Conclusion Community-level social vulnerability is significantly associated with firearm injury incidence, with the effect being more pronounced in racial/ethnic minority communities. These findings underscore the need for targeted public health interventions that address underlying social determinants of health (e.g., access to education) to reduce firearm violence. Future research should further explore the intersection of social vulnerability and racial/ethnic composition to develop effective prevention strategies.

Abstract The muskox (Ovibos moschatus), an integral component and iconic symbol of arctic biocultural diversity, is under threat by rapid environmental disruptions from climate change. We report a chromosomal-level haploid genome assembly of a muskox from Banks Island in the Canadian Arctic Archipelago. The assembly has a contig N50 of 44.7 Mbp, a scaffold N50 of 112.3 Mbp, a complete representation (100%) of the BUSCO v5.2.2 set of 9225 mammalian marker genes and is anchored to the 24 chromosomes of the muskox. Tabulation of heterozygous single nucleotide variants in our specimen revealed a very low level of genetic diversity, which is consistent with recent reports of the muskox having the lowest genome-wide heterozygosity among the ungulates. While muskox populations are currently showing no overt signs of inbreeding depression, environmental disruptions are expected to strain the genomic resilience of the species. One notable impact of rapid climate change in the Arctic is the spread of emerging infectious and parasitic diseases in the muskox, as exemplified by the range expansion of muskox lungworms, and the recent fatal outbreaks of Erysipelothrix rhusiopathiae, a pathogen normally associated with domestic swine and poultry. As a genomics resource for conservation management of the muskox against existing and emerging disease modalities, we annotated the genes of the major histocompatibility complex on chromosome 2 and performed an initial assessment of the genetic diversity of this complex. This resource is further supported by the annotation of the principal genes of the innate immunity system, genes that are rapidly evolving and under positive selection in the muskox, genes associated with environmental adaptations, and the genes associated with socioeconomic benefits for Arctic communities such as wool (qiviut) attributes. These annotations will benefit muskox management and conservation.

Abstract Social isolation and loneliness (SIL) are public health challenges that disproportionally affect individuals who experience structural and socio-economic exclusion. The social and health outcomes of SIL for people with experiences of being unhoused have largely remained unexplored. Yet, there is limited synthesis of literature focused on SIL to appropriately inform policy and targeted social interventions for people with homelessness experience. The aim of this scoping review is to synthesize evidence on SIL among people with lived experience of homelessness and explore how it negatively impacts their wellbeing. We carried out a comprehensive literature search from Medline, Embase, Cochrane Library, PsycINFO, CINAHL, Sociological Abstracts, and Web of Science's Social Sciences Citation Index and Science Citation Index for peer-reviewed studies published between January 1st, 2000 to January 3rd, 2023. Studies went through title, abstract and full-text screening conducted independently by at least two reviewers. Included studies were then analyzed and synthesized to identify the conceptualizations of SIL, measurement tools and approaches, prevalence characterization, and relationship with social and health outcomes. The literature search yielded 5,294 papers after removing duplicate records. Following screening, we retained 27 qualitative studies, 23 quantitative studies and two mixed method studies. SIL was not the primary objective of most of the included articles. The prevalence of SIL among people with homelessness experience varied from 25 to 90% across studies. A range of measurement tools were used to measure SIL making it difficult to compare results across studies. Though the studies reported associations between SIL, health, wellbeing, and substance use, we found substantial gaps in the literature. Most of the quantitative studies were cross-sectional, and only one study used health administrative data to ascertain health outcomes. More studies are needed to better understand SIL among this population and to build evidence for actionable strategies and policies to address its social and health impacts.

Abstract Background Evidence is limited about healthcare cost disparities associated with homelessness, particularly in recent years after major policy and resource changes affecting people experiencing homelessness occurred after the onset of the COVID-19 pandemic. We estimated 1-year healthcare expenditures, overall and by type of service, among a representative sample of people experiencing homelessness in Toronto, Canada, in 2021 and 2022, and compared these to costs among matched housed and low-income housed individuals. Methods Data from individuals experiencing homelessness participating in the Ku-gaa-gii pimitizi-win cohort study were linked with Ontario health administrative databases. Participants (n = 640) were matched 1:5 by age, sex-assigned-at-birth and index month to presumed housed individuals (n = 3,200) and to low-income presumed housed individuals (n = 3,200). Groups were followed over 1 year to ascertain healthcare expenditures, overall and by healthcare type. Generalized linear models were used to assess unadjusted and adjusted mean cost ratios between groups. Results Average 1-year costs were $12,209 (95% CI $9,762-$14,656) among participants experiencing homelessness compared to $1,769 ($1,453-$2,085) and $1,912 ($1,510-$2,314) among housed and low-income housed individuals. Participants experiencing homelessness had nearly seven times (6.90 [95% confidence interval [CI] 5.98–7.97]) the unadjusted mean ratio (MR) of costs as compared to housed persons. After adjustment for number of comorbidities and history of healthcare for mental health and substance use disorders, participants experiencing homelessness had nearly six times (adjusted MR 5.79 [95% CI 4.13–8.12]) the expected healthcare costs of housed individuals. The two housed groups had similar costs. Conclusions Homelessness is associated with substantial excess healthcare costs. Programs to quickly resolve and prevent cases of homelessness are likely to better meet the health and healthcare needs of this population while being a more efficient use of public resources.

Background: Muscular strength is an important component of physical fitness. We evaluated the relationship between baseline muscular strength and risk of stroke among adults who were aged ≥65 years during follow-up. Methods: We included 7627 healthy adults (mean age = 43.9 years, 86.0% male) underwent a baseline physical examination between 1980 and 1989. Muscular strength was determined by 1-repetition maximum measures for bench press and leg press and categorized into age- and sex-specific tertiles for each measure. Cardiorespiratory fitness (CRF) was assessed via a maximal treadmill exercise test. Those enrolled in fee-for-service Medicare from 1999 to 2019 were included in the analyses. Associations between baseline strength and stroke outcomes were estimated using a modified Cox proportional hazards model. In a secondary analysis, we examined stroke risk by categories of CRF where Quintile 1 = low, Quintiles 2–3 = moderate, and Quintiles 4–5 = high CRF based on age and sex. Results: After 70,072 person-years of Medicare follow-up, there were 1211 earliest indications of incident stroke. In multivariable analyses, the hazard ratio (95% confidence interval (95%CI)) for stroke across bench press categories were 1.0 (referent), 0.96 (0.83–1.11), and 0.89 (0.77–1.04), respectively (p trend = 0.14). The trend across categories of leg press was also non-significant (p trend = 0.79). Adjusted hazard ratio (95%CI) for stroke across ordered CRF categories were 1.0 (referent), 0.90 (0.71–1.13), and 0.72 (0.57–0.92) (p trend < 0.01). Conclusion: While meeting public health guidelines for muscular strengthening activities is likely to improve muscular strength as well as many health outcomes in older adults, performing such activities may not be helpful in preventing stroke. Conversely, meeting guidelines for aerobic activity is likely to improve CRF and lower stroke risk.

Objective: To assess the feasibility and potential scalability of telemedicine-enabled ambulances for the prehospital evaluation of patients with suspected acute stroke symptoms. Patients and Methods: A pilot study of telemedicine-enabled ambulances for evaluating patients with suspected acute stroke symptoms en route at 2 tertiary academic comprehensive stroke centers from January 1, 2018, to February 5, 2024. Charts of included patients were reviewed for demographic data, vascular risk factors, final diagnosis, time from arrival to neuroimaging, door-to–needle and door-to-puncture times in patients eligible for acute treatment, and any reported technical challenges during audio-video consultations. Results: Forty-seven patients (mean age, 68.0 years; 62% men) were evaluated via telemedicine-enabled ambulances, of which 35 (74%) where for hospital-to-hospital transferred patients. Mean time from arrival to neuroimaging was 11.8 minutes. Twenty-nine patients (62%) were diagnosed with acute ischemic stroke, and the remainder were diagnosed with intracranial hemorrhage (n=13), seizure (n=2), brain mass (n=1), or other diagnoses (n=3). Four patients (9%) received intravenous thrombolysis with alteplase (mean door to needle, 30.3 minutes), and 15 patients (32%) underwent mechanical thrombectomy (mean door to puncture, 72 minutes). Technical challenges were reported in 15 of the 42 (36%) cases, of which 10 (67%) were related to poor internet connectivity. Conclusion: Telemedicine-enabled ambulances in emergency medical services systems are novel, feasible, and potentially scalable options for evaluating patients with suspected acute stroke in the prehospital setting. However, optimization of infrastructure, staffing models, and internet connectivity is necessary, and larger studies evaluating the clinical and cost effectiveness of this approach are needed before widespread implementation.

Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)-Cas nucleases and human induced pluripotent stem cell (iPSC) technology can reveal deep insight into the genetic and molecular bases of human biology and disease. Undesired editing outcomes, both on-target (at the edited locus) and off-target (at other genomic loci) hinder the application of CRISPR-Cas nucleases. We developed Off-flow, a Nextflow-coded bioinformatic workflow that takes a specific guide sequence and Cas protein input to call four separate off-target prediction programs (CHOPCHOP, Cas-Offinder, CRISPRitz, CRISPR-Offinder) to output a comprehensive list of predicted off-target sites. We applied it to whole genome sequencing (WGS) data to investigate the occurrence of unintended effects in human iPSCs that underwent repair or insertion of disease-related variants by homology-directed repair. Off-flow identified a 3-base-pair-substitution and a mono-allelic genomic deletion at the target loci, KCNQ2, in 2 clones. Unbiased WGS analysis further identified off-target missense variants and a mono-allelic genomic deletion at the targeted locus, GNAQ, in 10 clones. On-target substitution and deletions had escaped standard PCR and Sanger sequencing analysis, while missense variants at other genomic loci were not detected by Off-flow. We used these results to filter out iPSC clones for subsequent functional experiments. Off-flow, which we make publicly available, works for human and mouse genomes currently and can be adapted for other genomes. Off-flow and WGS analysis can improve the integrity of studies using CRISPR/Cas-edited cells and animal models.

Abstract The 2023 wildfire season in Canada was unprecedented in its scale and intensity, spanning from mid-April to late October and across much of the forested regions of Canada. Here, we summarize the main causes and impacts of this exceptional season. The record-breaking total area burned (~15 Mha) can be attributed to several environmental factors that converged early in the season: early snowmelt, multiannual drought conditions in western Canada, and the rapid transition to drought in eastern Canada. Anthropogenic climate change enabled sustained extreme fire weather conditions, as the mean May–October temperature over Canada in 2023 was 2.2 °C warmer than the 1991–2020 average. The impacts were profound with more than 200 communities evacuated, millions exposed to hazardous air quality from smoke, and unmatched demands on fire-fighting resources. The 2023 wildfire season in Canada not only set new records, but highlights the increasing challenges posed by wildfires in Canada.

Abstract Hole spins in Ge/SiGe heterostructures have emerged as an interesting qubit platform with favourable properties such as fast electrical control and noise-resilient operation at sweet spots. However, commonly observed gate-induced electrostatic disorder, drifts, and hysteresis hinder reproducible tune-up of SiGe-based quantum dot arrays. Here, we study Hall bar and quantum dot devices fabricated on Ge/SiGe heterostructures and present a consistent model for the origin of gate hysteresis and its impact on transport metrics and charge noise. As we push the accumulation voltages more negative, we observe non-monotonous changes in the low-density transport metrics, attributed to the induced gradual filling of a spatially varying density of charge traps at the SiGe-oxide interface. With each gate voltage push, we find local activation of a transient low-frequency charge noise component that completely vanishes again after 30 hours. Our results highlight the resilience of the SiGe material platform to interface-trap-induced disorder and noise and pave the way for reproducible tuning of larger multi-dot systems.

Abstract Fast electrical signaling in dendrites is central to neural computations that support adaptive behaviors. Conventional techniques lack temporal and spatial resolution and the ability to track underlying membrane potential dynamics present across the complex three-dimensional dendritic arbor in vivo. Here, we perform fast two-photon imaging of dendritic and somatic membrane potential dynamics in single pyramidal cells in the CA1 region of the mouse hippocampus during awake behavior. We study the dynamics of subthreshold membrane potential and suprathreshold dendritic events throughout the dendritic arbor in vivo by combining voltage imaging with simultaneous local field potential recording, post hoc morphological reconstruction, and a spatial navigation task. We systematically quantify the modulation of local event rates by locomotion in distinct dendritic regions, report an advancing gradient of dendritic theta phase along the basal-tuft axis, and describe a predominant hyperpolarization of the dendritic arbor during sharp-wave ripples. Finally, we find that spatial tuning of dendritic representations dynamically reorganizes following place field formation. Our data reveal how the organization of electrical signaling in dendrites maps onto the anatomy of the dendritic tree across behavior, oscillatory network, and functional cell states.

Abstract Background A sizeable proportion of pathogenic genetic variants identified in young children tested for congenital differences are associated with neurodevelopmental psychiatric disorders (NPD). In this growing group, a genetic diagnosis often precedes the emergence of diagnosable developmental concerns. Here, we describe DAGSY (Developmental Assessment of Genetically Susceptible Youth), a novel interdisciplinary ‘genetic-diagnosis-first’ clinic integrating psychiatric, psychological and genetic expertise, and report our first observations and feedback from families and referring clinicians. Methods We retrieved data on referral sources and indications, genetic and NPD diagnoses and recommendations for children seen at DAGSY between 2018 and 2022. Through a survey, we obtained feedback from twenty families and eleven referring clinicians. Results 159 children (mean age 10.2 years, 57.2% males) completed an interdisciplinary (psychiatry, psychology, genetic counselling) DAGSY assessment during this period. Of these, 69.8% had a pathogenic microdeletion or microduplication, 21.5% a sequence-level variant, 4.4% a chromosomal disorder, and 4.4% a variant of unknown significance with emerging evidence of pathogenicity. One in four children did not have a prior NPD diagnosis, and referral to DAGSY was motivated by their genetic vulnerability alone. Following assessment, 76.7% received at least one new NPD diagnosis, most frequently intellectual disability (24.5%), anxiety (20.7%), autism spectrum (18.9%) and specific learning (16.4%) disorder. Both families and clinicians responding to our survey expressed satisfaction, but also highlighted some areas for potential improvement. Conclusions DAGSY addresses an unmet clinical need for children identified with genetic variants that confer increased vulnerability for NPD and provides a crucial platform for research in this area. DAGSY can serve as a model for interdisciplinary clinics integrating child psychiatry, psychology and genetics, addressing both clinical and research needs for this emerging population.

The application of extracellular vesicles, particularly exosomes (EXs), is rapidly expanding in the field of medicine, owing to their remarkable properties as natural carriers of biological cargo. This study investigates utilization of exosomes derived from stromal cells of tumor adjacent normal tissues (NAF-EXs) for personalized medicine, which can be derived at the time of diagnosis by endoscopic ultrasound. Herein, we show that exosomes (EXs) derived from NAFs demonstrate differential bio-physical characteristics, efficient cellular internalization, drug loading efficiency, pancreatic tumor targeting and delivery of payloads. NAF-derived EXs (NAF-EXs) were used for loading ormeloxifene (ORM), a potent anti-cancer and desmoplasia inhibitor as a model drug. We found that ORM maintains normal fibroblast cell phenotype and renders them incompatible to be triggered for a CAF-like phenotype, which may be due to regulation of Ca2+ influx in fibroblast cells. NAF-EXs-ORM effectively blocked oncogenic signaling pathways involved in desmoplasia and epithelial mesenchymal transition (EMT) and repressed tumor growth in xenograft mouse model. In conclusion, our data suggests preferential tropism of NAF-EXs for PDAC tumors, thus imply feasibility of developing a novel personalized medicine for PDAC patients using autologous NAF-EXs for improved therapeutic outcome of anti-cancer drugs. Additionally, it provides the opportunity of utilizing this biological scaffold for effective therapeutics in combination with standard therapeutic regimen.

Abstract Filaments made of residues 120-254 of transmembrane protein 106B (TMEM106B) form in an age-dependent manner and can be extracted from the brains of neurologically normal individuals and those of subjects with a variety of neurodegenerative diseases. TMEM106B filament formation requires cleavage at residue 120 of the 274 amino acid protein; at present, it is not known if residues 255-274 form the fuzzy coat of TMEM106B filaments. Here we show that a second cleavage appears likely, based on staining with an antibody raised against residues 263-274 of TMEM106B. We also show that besides the brain TMEM106B inclusions form in dorsal root ganglia and spinal cord, where they were mostly found in non-neuronal cells. We confirm that in the brain, inclusions were most abundant in astrocytes. No inclusions were detected in heart, liver, spleen or hilar lymph nodes. Based on their staining with luminescent conjugated oligothiophenes, we confirm that TMEM106B inclusions are amyloids. By in situ immunoelectron microscopy, TMEM106B assemblies were often found in structures resembling endosomes and lysosomes.

Abstract Childhood radioactive iodine exposure from the Chornobyl accident increased papillary thyroid carcinoma (PTC) risk. While cervical lymph node metastases (cLNM) are well-recognized in pediatric PTC, the PTC metastatic process and potential radiation association are poorly understood. Here, we analyze cLNM occurrence among 428 PTC with genomic landscape analyses and known drivers (131I-exposed = 349, unexposed = 79; mean age = 27.9 years). We show that cLNM are more frequent in PTC with fusion (55%) versus mutation (30%) drivers, although the proportion varies by specific driver gene (RET-fusion = 71%, BRAF-mutation = 38%, RAS-mutation = 5%). cLNM frequency is not associated with other characteristics, including radiation dose. cLNM molecular profiling (N = 47) demonstrates 100% driver concordance with matched primary PTCs and highly concordant mutational spectra. Transcriptome analysis reveals 17 differentially expressed genes, particularly in the HOXC cluster and BRINP3; the strongest differentially expressed microRNA also is near HOXC10. Our findings underscore the critical role of driver alterations and provide promising candidates for elucidating the biological underpinnings of PTC cLNM.

A generation ago thrombolytic therapy led to a paradigm shift in myocardial infarction (MI), from Q-wave/non-Q-wave to ST-segment elevation MI (STEMI) vs non-STEMI. Using STE on the electrocardiogram (ECG) as a surrogate marker for acute coronary occlusion (ACO) allowed for rapid diagnosis and treatment. But the vast research catalyzed by the STEMI paradigm has revealed increasing anomalies: 25% of “non-STEMI” have ACO with delayed reperfusion and higher mortality. Studying these limitations has given rise to the occlusion MI (OMI) paradigm, based on the presence or absence of ACO in the patient rather than STE on ECG. The OMI paradigm shift harnesses advanced ECG interpretation aided by artificial intelligence, complementary bedside echocardiography and advanced imaging, and clinical signs of refractory ischemia, and offers the next opportunity to transform emergency cardiology and improve patient care. This State-of-the-Art Review examines the paradigm shifts from Q wave to STEMI to OMI.

Background Previous work has demonstrated disparities in the management of cardiovascular disease among men and women. We sought to evaluate these disparities and their associations with clinical outcomes among patients admitted with acute coronary syndromes to the Veterans Affairs Healthcare System. Methods and Results We identified all patients that were discharged with acute coronary syndromes within the Veterans Affairs Healthcare System from October 1, 2015 to September 30, 2022. Medical and procedural management of patients was subsequently assessed, stratified by sex. In doing so, we identified 76 454 unique admissions (2327 women, 3.04%), which after propensity matching created an analytic cohort composed of 6765 men (74.5%) and 2295 women (25.3%). Women admitted with acute coronary syndromes were younger with fewer cardiovascular comorbidities and a lower prevalence of preexisting prescriptions for cardiovascular medications. Women also had less coronary anatomic complexity compared with men (5 versus 8, standardized mean difference [SMD]=0.40), as calculated by the Veterans Affairs SYNTAX score. After discharge, women were significantly less likely to receive cardiology follow‐up at 30 days (hazard ratio [HR], 0.858 [95% CI, 0.794–0.928]) or 1 year (HR, 0.891 [95% CI, 0.842–0.943]), or receive prescriptions for guideline‐indicated cardiovascular medications. Despite this, 1‐year mortality rates were lower for women compared with men (HR, 0.841 [95% CI, 0.747–0.948]). Conclusions Women are less likely to receive appropriate cardiovascular follow‐up and medication prescriptions after hospitalization for acute coronary syndromes. Despite these differences, the clinical outcomes for women remain comparable. These data suggest an opportunity to improve the posthospitalization management of cardiovascular disease regardless of sex.

Abstract Objective Most families with heritable neuromuscular disorders do not receive a molecular diagnosis. Here we evaluate diagnostic utility of exome, genome, RNA sequencing, and protein studies and provide evidence‐based recommendations for their integration into practice. Methods In total, 247 families with suspected monogenic neuromuscular disorders who remained without a genetic diagnosis after standard diagnostic investigations underwent research‐led massively parallel sequencing: neuromuscular disorder gene panel, exome, genome, and/or RNA sequencing to identify causal variants. Protein and RNA studies were also deployed when required. Results Integration of exome sequencing and auxiliary genome, RNA and/or protein studies identified causal or likely causal variants in 62% (152 out of 247) of families. Exome sequencing alone informed 55% (83 out of 152) of diagnoses, with remaining diagnoses (45%; 69 out of 152) requiring genome sequencing, RNA and/or protein studies to identify variants and/or support pathogenicity. Arrestingly, novel disease genes accounted for

Mitochondrial metabolism and electron transport chain (ETC) function are essential for tumour proliferation and metastasis. However, the impact of ETC function on cancer immunogenicity is not well understood. In a recent study, Mangalhara et al. found that inhibition of complex II leads to enhanced tumour immunogenicity, T‐cell‐mediated cytotoxicity and inhibition of tumour growth. Surprisingly, this antitumour effect is mediated by succinate accumulation affecting histone methylation. Histone methylation promotes the transcriptional upregulation of major histocompatibility complex–antigen processing and presentation (MHC‐APP) genes in a manner independent of interferon signalling. Modulating mitochondrial electron flow to enhance tumour immunogenicity provides an exciting new therapeutic avenue and may be particularly attractive for tumours with reduced expression of MHC‐APP genes or dampened interferon signalling.

Introduction: Severe metabolic alkaloses are relatively rare but can carry a high mortality rate. Treatment involves supportive care and treatment of underlying causes. Case Report: A 55-year-old male dependent on a gastrojejunostomy tube presented to the emergency department for altered mental status. The patient had metabolic alkalosis, electrolyte abnormalities, and prolonged QT interval on electrocardiogram. Examination and history revealed that chronic drainage of gastric fluid via malfunctioning a gastrojejunostomy tube resulted in profound alkalosis. The patient recovered with supportive care, electrolyte repletion, and gastrojejunostomy tube replacement. Conclusion: This case highlights the importance of gastrointestinal acid-base pathophysiology.

Abstract The copper compound CuII(atsm) has progressed to phase 2/3 testing for treatment of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). CuII(atsm) is neuroprotective in mutant SOD1 mouse models of ALS where its activity is ascribed in part to improving availability of essential copper. However, SOD1 mutations cause only ~ 2% of ALS cases and therapeutic relevance of copper availability in sporadic ALS is unresolved. Herein we assessed spinal cord tissue from human cases of sporadic ALS for copper-related changes. We found that when compared to control cases the natural distribution of spinal cord copper was disrupted in sporadic ALS. A standout feature was decreased copper levels in the ventral grey matter, the primary anatomical site of neuronal loss in ALS. Altered expression of genes involved in copper handling indicated disrupted copper availability, and this was evident in decreased copper-dependent ferroxidase activity despite increased abundance of the ferroxidases ceruloplasmin and hephaestin. Mice expressing mutant SOD1 recapitulate salient features of ALS and the unsatiated requirement for copper in these mice is a biochemical target for CuII(atsm). Our results from human spinal cord indicate a therapeutic mechanism of action for CuII(atsm) involving copper availability may also be pertinent to sporadic cases of ALS.

ABSTRACT Background Bowel cancer screening using faecal immunochemical testing is provided in the United Kingdom with the aim of reducing mortality from colorectal cancer. However, there are low participant rates among ethnic minorities across the United Kingdom. Faith‐placed interventions have the potential to improve screening rates among such populations, but studies examining their effectiveness are scarce. Methods We delivered a presentation on bowel cancer screening to 204 Muslims in seven mosques in East London (intervention group). All participants completed a questionnaire regarding attitudes, perceptions and knowledge of bowel cancer screening before and after the presentation. Concurrently, we administered the questionnaire to 72 subjects attending a mosque that did not receive the presentation (comparison group). Results The intervention group showed a greater willingness to do the test (90% vs. 67%, p

This article is inspired by the debate on curriculum innovation for graduate training, emerging out of linkages between universities and agribusiness development actors, targeting entrepreneurial action and employability of graduates. Experiences from implementation of a three-year joint project are enriched by a desk review, stakeholder feedback and interpretative analysis of process documents during the development of the regional graduate curriculum on Agri-Enterprise Development for Egerton and Gulu Universities in Kenya and Uganda, respectively. The graduate curriculum at the two universities in East Africa integrated the approaches of roundtable engagement and research as well as value chain cluster mapping and development through interactive sharing with agribusiness development facilitators. Simultaneously, the two implementing universities showcased the feasibility of integrating community engagement and entrepreneurial skills into a new curriculum. They achieved this by adopting two training approaches from their previous, more limited curriculum, which lacked student entrepreneurial experiential learning. The outcome from the first cohort of students in the innovative programs demonstrates significant institutional change in teaching and learning approaches. These changes prioritize a blend of action research and theoretical exposure. At the university-wide level, a student-centered teaching and learning approach has been established, facilitated by models like Student Farm Attachment, Student Enterprise Scheme, and Student Community Engagement. Additionally, university-based research teams have honed their skills in community action research, leading to the identification of relevant challenges and plausible solutions. Furthermore, students’ skills sets have increasingly enhanced employability. Strengthening linkages between universities and community development actors can enhance curriculum orientation toward problem-solving and entrepreneurial capacity building for young graduates. Purposeful engagement with communities by university faculty and students serves as a complementary extension approach and advisory service. Implementing an innovative curriculum has the potential to boost research uptake and foster innovation. This article demonstrates how university- industrial actors’ collaboration can be exploited for curriculum (re)design, review and up-dating for (a) enhanced relevance of universities to community needs and employability of graduates; and (b) improvements in the research uptake pathways that facilitate research-into-use for desired impacts at community level.

People experiencing homelessness have historically had high mortality rates compared to housed individuals in Canada, a trend believed to have become exacerbated during the COVID-19 pandemic. In this matched cohort study conducted in Toronto, Canada, we investigated all-cause mortality over a one-year period by following a random sample of people experiencing homelessness (n = 640) alongside matched housed (n = 6,400) and low-income housed (n = 6,400) individuals. Matching criteria included age, sex-assigned-at-birth, and Charlson comorbidity index. Data were sourced from the Ku-gaa-gii pimitizi-win cohort study and administrative databases from ICES. People experiencing homelessness had 2.7 deaths/100 person-years, compared to 0.7/100 person-years in both matched unexposed groups, representing an all-cause mortality unadjusted hazard ratio (uHR) of 3.7 (95% CI, 2.1–6.5). Younger homeless individuals had much higher uHRs than older groups (ages 25–44 years uHR 16.8 [95% CI 4.0–70.2]; ages 45–64 uHR 6.8 [95% CI 3.0–15.1]; ages 65+ uHR 0.35 [95% CI 0.1–2.6]). Homeless participants who died were, on average, 17 years younger than unexposed individuals. After adjusting for number of comorbidities and presence of mental health or substance use disorder, people experiencing homelessness still had more than twice the hazard of death (aHR 2.2 [95% CI 1.2–4.0]). Homelessness is an important risk factor for mortality; interventions to address this health disparity, such as increased focus on homelessness prevention, are urgently needed.

Digitized data is presented based on the 1966 and 1972 seminal papers by R. J. Bell and P. Dean, which in turn are based on a physical ball and stick model of vitreous silica. The original Bell and Dean paper supports the random network theory for glass structure proposed by Zachariasen in 1932. The data were collected and digitized by verifying the data set in the Appendix of the Bell and Dean paper. One error in location was corrected. The dataset provides a convenient method to determine specific information about bond locations and angles of silica and oxygen atoms if researchers want to test theories of glass structure or fracture in amorphous materials.

Tomographic three-dimensional ultrasound using handsfree electromagnetic tracking is an important adjunct to traditional two-dimensional duplex ultrasound examination. This technique allows vascular surgeons to better orientate and visualize the often complex anatomy along the entire length of the target vein. This paper reports a novel technique in preoperative and postoperative acquisition of superficial incompetent veins, thereby providing a comprehensive three-dimensional orientation of different pathological patterns of incompetence.

Resumo Embora o modelo existente de classificação do infarto agudo do miocárdio (IAM) em IAMCSST e IAMSSST tenha sido benéfico, considera-se hoje que ele falha em abordar a complexidade das síndromes coronarianas agudas. O estudo tem como objetivo examinar o atual paradigma IAMCSST-IAMSSST e defender um modelo mais detalhado, chamado de oclusão coronariana aguda (OCA) e Ausência de Oclusão Coronária Aguda (NOCA), para um diagnóstico e um manejo do IAM mais precisos. Realizou-se uma análise abrangente da literatura médica existente, com foco nas limitações do modelo IAMCSST-IAMSSST. O estudo também descreve uma nova abordagem diagnóstica para pacientes apresentando do torácica nos departamentos de emergência. O modelo IAMCSST-IAMSSST tradicional falha em prover um diagnóstico preciso e um tratamento efetivo, principalmente na identificação de oclusões da artéria coronária. O modelo OCA-NOCA é mais preciso em termos anatômicos e fisiológicos, e apoiado por pesquisa clínica extensa e opiniões de especialistas. Ele destaca a necessidade de rápida realização de eletrocardiogramas (ECGs) e terapias de reperfusão para casos suspeitos de OCA, visando melhorar os desfechos dos pacientes. O modelo OCA-NOCA abre um novo caminho para pesquisas e aplicações clínicas futuras. Ele defende um entendimento mais abrangente dos mecanismos subjacentes das síndromes coronarianas agudas, levando a planos individualizados de tratamentos. Espera-se que essa nova abordagem incite novos debates e pesquisas acadêmicas, principalmente na área de cardiologia no Brasil, com o objetivo de aumentar a precisão diagnóstica e a eficácia do tratamento de pacientes com IAM.

IntroductionPatients with major mental illness (MMI) and substance use disorders (SUD) face barriers in accessing healthcare. In this population-based retrospective cohort study, we investigated the uptake of COVID-19 vaccination in Ontario, Canada among community-dwelling individuals receiving healthcare for major mental illness (MMI) and/or substance use disorders (SUD), comparing them to matched general population controls.MethodsUsing linked health administrative data, we identified 337,290 individuals receiving healthcare for MMI and/or SUD as of 14 December 2020, matched by age, sex, and residential geography to controls without such healthcare. Follow-up extended until 31 December 2022 to document vaccination events.ResultsOverall, individuals receiving healthcare for MMI and/or SUD (N = 337,290) had a slightly lower uptake of first (cumulative incidence 82.45% vs. 86.44%; hazard ratio [HR] 0.83 [95% CI 0.82–0.83]) and second dose (78.82% vs. 84.93%; HR 0.77 [95% CI 0.77–0.78]) compared to matched controls. Individuals receiving healthcare for MMI only (n = 146,399) had a similar uptake of first (87.96% vs. 87.59%; HR 0.97 [95% CI 0.96–0.98]) and second dose (86.09% vs. 86.05%, HR 0.94 [95% CI 0.93–0.95]). By contrast, individuals receiving healthcare for SUD only (n = 156,785) or MMI and SUD (n = 34,106) had significantly lower uptake of the first (SUD 78.14% vs. 85.74%; HR 0.73 [95% CI 0.72–0.73]; MMI & SUD 78.43% vs. 84.74%; HR 0.76 [95% CI 0.75–0.77]) and second doses (SUD 73.12% vs. 84.17%; HR 0.66 [95% CI 0.65–0.66]; MMI & SUD 73.48% vs. 82.93%; HR 0.68 [95% CI 0.67–0.69]).DiscussionThese findings suggest that effective strategies to increase vaccination uptake for future COVID-19 and other emerging infectious diseases among community-dwelling people with SUD are needed.

Summary: Background: Lower socioeconomic status, as measured by the Index of Multiple Deprivation (IMD), is associated with higher rates of smoking-related disease mortality, and with poor uptake of cancer screening. Here we explore whether socioeconomic status impacts the effectiveness of a single round of low-dose-CT screening, or impacts other causes of death, in the UKLS LDCT screening trial. Methods: IMD quintiles were defined according to UK-wide data, with the deprived group defined as the lower two quintiles (Q1-2) and the less deprived as Q3-5. Follow-up data was obtained for lung cancer diagnosis (median follow-up 9.1 years) and cause of death (median follow-up 9.9 years). Outcomes were compared based on IMD group and trial arm (CT or control). Findings: More deprived quintiles were less likely to respond to the questionnaire, but this population was more likely to be selected for screening by the LLP risk model. Lower IMD quintiles benefitted from low-dose-CT screening in terms of lung cancer survival (HR 1.89, 95% CI 1.16–3.08) to the same extent as upper quintiles (HR 1.87, 95% CI 1.07–3.26). However, there was a bigger impact on deaths due to COPD and emphysema in more deprived quintiles. Interpretation: Whilst LDCT screening benefit for lung cancer was similar, significant impact on the rates of death from other smoking-related diseases, notably COPD and emphysema, was seen primarily in lower socioeconomic groups. Future research is required to confirm how lung cancer screening benefits other disease outcomes. Funding: NIHR Health Technology Assessment Programme; NIHR Policy Research programme; Roy Castle Lung Cancer Foundation.

The COVID-19 pandemic generated large amounts of data on the disease pathogenesis leading to a need for organizing the vast knowledge in a succinct manner. Between April 2020 and February 2023, the CIAO consortium exploited the Adverse Outcome Pathway (AOP) framework to comprehensively gather and systematically organize published scientific literature on COVID-19 pathology. The project considered 24 pathways relevant for COVID-19 by identifying essential key events (KEs) leading to 19 adverse outcomes observed in patients. While an individual AOP defines causally linked perturbed KEs towards an outcome, building an AOP network visually reflect the interrelatedness of the various pathways and outcomes. In this study, 17 of those COVID-19 AOPs were selected based on quality criteria to computationally derive an AOP network. This primary network highlighted the need to consider tissue specificity and helped to identify missing or redundant elements which were then manually implemented in the final network. Such a network enabled visualization of the complex interactions of the KEs leading to the various outcomes of the multifaceted COVID-19 and confirmed the central role of the inflammatory response in the disease. In addition, this study disclosed the importance of terminology harmonization and of tissue/organ specificity for network building. Furthermore the unequal completeness and quality of information contained in the AOPs highlighted the need for tighter implementation of the FAIR principles to improve AOP findability, accessibility, interoperability and re-usability. Finally, the study underlined that describing KEs specific to SARS-CoV-2 replication and discriminating physiological from pathological inflammation is necessary but requires adaptations to the framework. Hence, based on the challenges encountered, we proposed recommendations relevant for ongoing and future AOP-aligned consortia aiming to build computationally biologically meaningful AOP networks in the context of, but not limited to, viral diseases.

Abstract The anti-apoptotic BCL-2 protein family regulates cancer cell survival, thus it represents an important therapeutic target. Indeed, a drug class, called BH3-mimetics, have been developed to directly target BCL2 proteins and promote cancer cell death. Conventional wisdom suggests that the primary anti-cancer effect of BCL-2 inhibition is through induction of cancer cell death. However, a recent study by Zhao and colleagues describes that BCL-2 inhibition also enhances the function of classical dendritic cells, unleashing their role in immunosurveillance, promoting T cell immunity and tumour regression. Thus, inhibiting anti-apoptotic BCL-2 function may have a multi-pronged anti-tumour action.

Abstract Background Accurate estimation of SARS-CoV-2 re-infection is crucial to understanding the connection between infection burden and adverse outcomes. However, relying solely on PCR testing results in underreporting. We present a novel approach that includes longitudinal serologic data, and compared it against testing alone among people experiencing homelessness. Methods We recruited 736 individuals experiencing homelessness in Toronto, Canada, between June and September 2021. Participants completed surveys and provided saliva and blood serology samples every three months over 12 months of follow-up. Re-infections were defined as: positive PCR or rapid antigen test (RAT) results > 90 days after initial infection; new serologic evidence of infection among individuals with previous infection who sero-reverted; or increases in anti-nucleocapsid in seropositive individuals whose levels had begun to decrease. Results Among 381 participants at risk, we detected 37 re-infections through PCR/RAT and 98 re-infections through longitudinal serology. The comprehensive method identified 37.4 re-infection events per 100 person-years, more than four-fold more than the rate detected through PCR/RAT alone (9.0 events/100 person-years). Almost all test-confirmed re-infections (85%) were also detectable by longitudinal serology. Conclusions Longitudinal serology significantly enhances the detection of SARS-CoV-2 re-infections. Our findings underscore the importance and value of combining data sources for effective research and public health surveillance.

Abstract Background Few studies in China have examined correlates of internet health survey misreporting or the effect of interventions to mitigate misreporting. We conducted an experiment to: (1) identify correlates of survey misreporting, and (2) assess the impact of “watching eyes” images on survey misreporting. Exposure to watching eyes has been shown to discourage socially deviant behavior. Methods In 2022, a contract survey company recruited 1655 online survey respondents who were ≥ 18 years old and living in China. Participants were randomized to one of four arms. Participants randomized to arms 1 and 3 were asked to report their blood type. Participants randomized to arms 2 and 4 were also asked to report their blood type, but were additionally told they could end the survey early if they reported AB blood type. Participants randomized to arm 3 or 4 (but not arms 1 or 2) were shown an image of watching eyes before being asked to report their blood type. Results Among participants with lower educational attainment, the probability of reporting AB blood type was higher if incentivized to report AB blood (19.05% vs 9.26%), though this difference was not statistically significant (p = 0.189). Among participants incentivized to report AB blood type, the probability of reporting AB blood type was significantly greater among individuals shown watching eyes (19.93% vs 11.56%, p

Abstract Background Ferroptosis is a form of regulated cell death characterised by lipid peroxidation as the terminal endpoint and a requirement for iron. Although it protects against cancer and infection, ferroptosis is also implicated in causing neuronal death in degenerative diseases of the central nervous system (CNS). The precise role for ferroptosis in causing neuronal death is yet to be fully resolved. Methods To elucidate the role of ferroptosis in neuronal death we utilised co-culture and conditioned medium transfer experiments involving microglia, astrocytes and neurones. We ratified clinical significance of our cell culture findings via assessment of human CNS tissue from cases of the fatal, paralysing neurodegenerative condition of amyotrophic lateral sclerosis (ALS). We utilised the SOD1G37R mouse model of ALS and a CNS-permeant ferroptosis inhibitor to verify pharmacological significance in vivo. Results We found that sublethal ferroptotic stress selectively affecting microglia triggers an inflammatory cascade that results in non-cell autonomous neuronal death. Central to this cascade is the conversion of astrocytes to a neurotoxic state. We show that spinal cord tissue from human cases of ALS exhibits a signature of ferroptosis that encompasses atomic, molecular and biochemical features. Further, we show the molecular correlation between ferroptosis and neurotoxic astrocytes evident in human ALS-affected spinal cord is recapitulated in the SOD1G37R mouse model where treatment with a CNS-permeant ferroptosis inhibitor, CuII(atsm), ameliorated these markers and was neuroprotective. Conclusions By showing that microglia responding to sublethal ferroptotic stress culminates in non-cell autonomous neuronal death, our results implicate microglial ferroptotic stress as a rectifiable cause of neuronal death in neurodegenerative disease. As ferroptosis is currently primarily regarded as an intrinsic cell death phenomenon, these results introduce an entirely new pathophysiological role for ferroptosis in disease. Graphical Abstract

Counterfeit electronic components are known to enter supply chains through recycling, with these already-aged components creating serious reliability risks, particularly for critical infrastructure systems. A number of recycled integrated circuit (IC) risk mitigation approaches have been proposed, but these generally lack pragmatic feasibility. This work proposes a novel real-world deployable on-chip sensor that: 1) is tamper-resistant by exploiting persistent changes caused by hot carrier injection (HCI); 2) generates a DC signal measurable by common low-cost test equipment; and 3) reuses an existing I/O interface, including existing pins; while 4) requiring a very small footprint. Combining this sensor with a random sample-based testing strategy allows for low-cost and time efficient detection of fraudulently recycled batches of ICs. Through simulation-based validation using process-accurate models of a 65 nm technology we show that employing a random sample size as small as 130 is sufficient for identifying such batches with a statistical significance level of 0.01.

Objective: To determine the diagnostic accuracy of the initial telestroke consultation in a large academic hub-and-spoke telemedicine network. Patients and Methods: This retrospective study includes all patients evaluated for cerebral ischemia through video telestroke consultation in a large academic hub-and-spoke telemedicine network from January 1, 2019 to December 31, 2020. A detailed chart review was conducted to identify the initial suspected diagnosis and final diagnosis. Cerebral ischemia was defined as acute ischemic stroke and transient ischemic attack. All other diagnoses were defined as stroke mimics. Data were organized into continuous and categorical variables. Sensitivity, specificity, positive predictive value, negative predictive value, accuracy, area under the curve (AUC), and likelihood ratio (LR+) for the telestroke-consultation diagnosis were calculated while using the final diagnosis as the gold standard diagnosis. Results: A total of 1043 patients met the inclusion criteria. The final diagnosis of cerebral ischemia was made in 63.5% of all patients (539 of the 1043 with acute ischemic stroke,123 of the 1043 with transient ischemic attack). Stroke mimic was diagnosed in 36.5% patients (381 of the 1043). The sensitivity and specificity of telestroke evaluation for diagnosis of cerebral ischemia were 97.1% and 81.4%, respectively. Positive predictive value was 90.1%, and negative predictive value was 94.2%. Overall diagnostic accuracy was 91.4%, with an LR+ of 5.21 and AUC of 0.89. Conclusion: This study highlights the high diagnostic accuracy of telestroke providers in diagnosing cerebral ischemia. Further research exploring the application of teleneurology in the nonstroke setting and other medical subspecialties is warranted.

Abstract Microphysical observations of precipitating particles are critical data sources for numerical weather prediction models and remote sensing retrieval algorithms. However, obtaining coherent data sets of particle microphysics is challenging as they are often unindexed, distributed across disparate institutions, and have not undergone a uniform quality control process. This work introduces a unified, comprehensive Northern Hemisphere particle microphysical data set from the National Aeronautics and Space Administration precipitation imaging package (PIP), accessible in a standardized data format and stored in a centralized, public repository. Data is collected from 10 measurement sites spanning 34° latitude (37°N–71°N) over 10 years (2014–2023), which comprise a set of 1,070,000 precipitating minutes. The provided data set includes measurements of a suite of microphysical attributes for both rain and snow, including distributions of particle size, vertical velocity, and effective density, along with higher‐order products including an approximation of volume‐weighted equivalent particle densities, liquid equivalent snowfall, and rainfall rate estimates. The data underwent a rigorous standardization and quality assurance process to filter out erroneous observations to produce a self‐describing, scalable, and achievable data set. Case study analyses demonstrate the capabilities of the data set in identifying physical processes like precipitation phase‐changes at high temporal resolution. Bulk precipitation characteristics from a multi‐site intercomparison also highlight distinct microphysical properties unique to each location. This curated PIP data set is a robust database of high‐quality particle microphysical observations for constraining future precipitation retrieval algorithms, and offers new insights toward better understanding regional and seasonal differences in bulk precipitation characteristics.

As health systems organize to deliver the highest quality stroke care to their patients, there is increasing emphasis being placed on prehospital stroke recognition, accurate diagnosis, and efficient triage to improve outcomes after stroke. Emergency medical services (EMS) personnel currently rely heavily on dispatch accuracy, stroke screening tools, bypass protocols and prehospital notification to care for patients with suspected stroke, but novel tools including mobile stroke units and telemedicine-enabled ambulances are already changing the landscape of prehospital stroke care. Herein, the authors provide our perspective on the current state of prehospital stroke diagnosis and triage including several of these emerging trends. Then, we provide commentary to highlight potential artificial intelligence (AI) applications to improve stroke detection, improve accurate and timely dispatch, enhance EMS training and performance, and develop novel stroke diagnostic tools for prehospital use.

Abstract Introduction Despite the Veterans Health Administration (VA) efforts to become a learning health system (LHS) and high‐reliability organization (HRO), interventions to build supportive learning environments within teams are not reliably implemented, contributing to high levels of burnout, turnover, and variation in care. Supportive learning environments build capabilities for teaching and learning, empower teams to safely trial and adapt new things, and adopt highly reliable work practices (eg, debriefs). Innovative approaches to create supportive learning environments are needed to advance LHS and HRO theory and research into practice. Methods To guide the identification of evidence‐based interventions that cultivate supportive learning environments, the authors used a longitudinal, mixed‐methods design and LHS and HRO frameworks. We partnered with the 81 VA cardiac catheterization laboratories and conducted surveys, interviews, and literature reviews that informed a Relational Playbook for Cardiology Teams. Results The Relational Playbook resources and 50 evidence‐based interventions are organized into five LHS and HRO‐guided chapters: Create a positive culture, teamwork, leading teams, joy in work, communication, and high reliability. The interventions are designed for managers to integrate into existing meetings or trainings to cultivate supportive learning environments. Conclusions LHS and HRO frameworks describe how organizations can continually learn and deliver nearly error‐free services. The Playbook resources and interventions translate LHS and HRO frameworks for real‐world implementation by healthcare managers. This work will cultivate supportive learning environments, employee well‐being, and Veteran safety while providing insights into LHS and HRO theory, research, and practice.

Background Portopulmonary hypertension (PoPH), associated with increased mortality, can limit treatment options for liver diseases. Data on the continuum of clinical risk related to cardiopulmonary hemodynamics in PoPH are lacking. Methods and Results As part of the United States national Veterans Affairs Clinical Assessment, Reporting, and Tracking database, we performed a retrospective cohort study of adults with cirrhosis undergoing right heart catheterization between October 1, 2017, and September 30, 2022. Pulmonary hypertension (mean pulmonary arterial pressure [mPAP] >20 mm Hg without PoPH) and PoPH (mPAP >20 mm Hg+pulmonary artery wedge pressure ≤15 mm Hg+pulmonary vascular resistance ≥3 WU) were defined by right heart catheterization hemodynamics. Multivariable Cox proportional hazards using natural splines for hemodynamic variables were used to evaluate the association between cardiopulmonary hemodynamics and mortality following right heart catheterization. A total of 4409 patients were included in the final analysis, predominantly men (96.3%), with a mean age of 68.5 years. Pulmonary hypertension and PoPH were observed in 71.6% and 10.2% of the cohort, respectively. Compared with a reference cardiac index of 2.5 L/min per m2, the hazard for mortality increased progressively with decreasing cardiac index, even after adjustment for mPAP and pulmonary vascular resistance. The minority of patients with PoPH (N=65, 14.5%) were prescribed pulmonary vasodilator therapy. Conclusions These data suggest that pulmonary hypertension and PoPH are prevalent in veterans with chronic liver disease, but low use of targeted PoPH therapy persists. Cardiac function discriminated mortality risk across a wide range of mPAP and pulmonary vascular resistance values and may diagnose and clarify prognosis in this patient population.

IntroductionThe U. S. Environmental Protection Agency’s Endocrine Disruptor Screening Program (EDSP) Tier 1 assays are used to screen for potential endocrine system–disrupting chemicals. A model integrating data from 16 high-throughput screening assays to predict estrogen receptor (ER) agonism has been proposed as an alternative to some low-throughput Tier 1 assays. Later work demonstrated that as few as four assays could replicate the ER agonism predictions from the full model with 98% sensitivity and 92% specificity. The current study utilized chemical clustering to illustrate the coverage of the EDSP Universe of Chemicals (UoC) tested in the existing ER pathway models and to investigate the utility of chemical clustering to evaluate the screening approach using an existing 4-assay model as a test case. Although the full original assay battery is no longer available, the demonstrated contribution of chemical clustering is broadly applicable to assay sets, chemical inventories, and models, and the data analysis used can also be applied to future evaluation of minimal assay models for consideration in screening.MethodsChemical structures were collected for 6,947 substances via the CompTox Chemicals Dashboard from the over 10,000 UoC and grouped based on structural similarity, generating 826 chemical clusters. Of the 1,812 substances run in the original ER model, 1,730 substances had a single, clearly defined structure. The ER model chemicals with a clearly defined structure that were not present in the EDSP UoC were assigned to chemical clusters using a k-nearest neighbors approach, resulting in 557 EDSP UoC clusters containing at least one ER model chemical.Results and DiscussionPerformance of an existing 4-assay model in comparison with the existing full ER agonist model was analyzed as related to chemical clustering. This was a case study, and a similar analysis can be performed with any subset model in which the same chemicals (or subset of chemicals) are screened. Of the 365 clusters containing >1 ER model chemical, 321 did not have any chemicals predicted to be agonists by the full ER agonist model. The best 4-assay subset ER agonist model disagreed with the full ER agonist model by predicting agonist activity for 122 chemicals from 91 of the 321 clusters. There were 44 clusters with at least two chemicals and at least one agonist based upon the full ER agonist model, which allowed accuracy predictions on a per-cluster basis. The accuracy of the best 4-assay subset ER agonist model ranged from 50% to 100% across these 44 clusters, with 32 clusters having accuracy ≥90%. Overall, the best 4-assay subset ER agonist model resulted in 122 false-positive and only 2 false-negative predictions compared with the full ER agonist model. Most false positives (89) were active in only two of the four assays, whereas all but 11 true positive chemicals were active in at least three assays. False positive chemicals also tended to have lower area under the curve (AUC) values, with 110 out of 122 false positives having an AUC value below 0.214, which is lower than 75% of the positives as predicted by the full ER agonist model. Many false positives demonstrated borderline activity. The median AUC value for the 122 false positives from the best 4-assay subset ER agonist model was 0.138, whereas the threshold for an active prediction is 0.1.ConclusionOur results show that the existing 4-assay model performs well across a range of structurally diverse chemicals. Although this is a descriptive analysis of previous results, several concepts can be applied to any screening model used in the future. First, the clustering of the chemicals provides a means of ensuring that future screening evaluations consider the broad chemical space represented by the EDSP UoC. The clusters can also assist in prioritizing future chemicals for screening in specific clusters based on the activity of known chemicals in those clusters. The clustering approach can be useful in providing a framework to evaluate which portions of the EDSP UoC chemical space are reliably covered by in silico and in vitro approaches and where predictions from either method alone or both methods combined are most reliable. The lessons learned from this case study can be easily applied to future evaluations of model applicability and screening to evaluate future datasets.

Compost is widely used in agriculture as fertilizer while providing a practical option for solid municipal waste disposal. However, compost may also contain per- and polyfluoroalkyl substances (PFAS), potentially impacting soils and leading to PFAS entry into food chains and ultimately human exposure risks via dietary intake. This study examined how compost affects the bioavailability and uptake of eight PFAS (two ethers, three fluorotelomer sulfonates, and three perfluorosulfonates) by lettuce (Lactuca sativa) grown in commercial organic compost-amended, PFAS spiked soils. After 50 days of greenhouse experiment, PFAS uptake by lettuce decreased (by up to 90.5 %) with the increasing compost amendment ratios (0–20 %, w/w), consistent with their decreased porewater concentrations (by 30.7–86.3 %) in compost-amended soils. Decreased bioavailability of PFAS was evidenced by the increased in-situ soil-porewater distribution coefficients (Kd) (by factors of 1.5–7.0) with increasing compost additions. Significant negative (or positive) correlations (R2 ≥ 0.55) were observed between plant bioaccumulation (or Kd) and soil organic carbon content, suggesting that compost amendment inhibited plant uptake of PFAS mainly by increasing soil organic carbon and enhancing PFAS sorption. However, short-chain PFAS alternatives (e.g., perfluoro-2-methoxyacetic acid (PFMOAA)) were effectively translocated to shoots with translocation factors > 2.9, increasing their risks of contamination in leafy vegetables. Our findings underscore the necessity for comprehensive risk assessment of compost-borne PFAS when using commercial compost products in agricultural lands.

A unique acoustic call type was identified and attributed to Bryde’s whales in the central North Pacific in 2015, but little is known about the distribution, calling behavior, or swimming behavior of Bryde’s whales in the region. Acoustic detections attributed to Bryde’s whales were used to localize and track individual whales on the U.S. Pacific Missile Range Facility (PMRF) in Kaua‘i, Hawai‘i. This study included 150 acoustically derived tracks from recordings spanning the years 2011–2022 with recording effort in nearly every month. Bryde’s whale movement was examined relative to calendar year, day of year, hour of day, wind speed, and acoustic calling rate. Hidden Markov models were used to identify two kinematic states (slower, less directional movement and faster, more directional movement). The findings indicate that Bryde’s whales were more likely to travel in a faster and more directional state during the daytime than at night and between May and August when compared to other times of year. The along-track acoustic cue rate was examined for 118 tracks, and the findings indicate a possible lengthening of the median inter-call interval over the duration of the study period. These results are an important first step in understanding more about behavior in Bryde’s whales, a relatively under-studied species.

Abstract Thermospheric polar warming (TPW) is observed conclusively for the first time at Mars during the aphelion/Northern Summer season using solar occultation (SO) measurements made by the Extreme Ultraviolet Monitor (EUVM) onboard the Mars Atmosphere and Volatile EvolutioN (MAVEN) orbiter. Aphelion data from Mars Year (MY) 33–36 are analyzed revealing TPW to be present at dawn but not dusk. This is consistent with an earlier analysis of accelerometer data from the Mars Global Surveyor that showed aphelion TPW is also not evident at 15 hr local time. Separating the data into individual MYs reveals TPW is observed during each year except MY 35. TPW is markedly intensified during MY 34, which is attributed to enhanced circulation caused by a northern‐hemisphere dust storm coinciding with the observations. Simulations from the Mars Climate Database predict the large TPW enhancement in MY 34 relative to MY 33 observed by EUVM SO, but predicts approximately 20K less overall TPW for both years than that observed by EUVM SO.

Streptococcus pyogenes is a human-specific pathogen that commonly colonizes the upper respiratory tract and skin, causing a wide variety of diseases ranging from pharyngitis to necrotizing fasciitis and toxic shock syndrome. S. pyogenes has a repertoire of secreted virulence factors that promote infection and evasion of the host immune system including the cytolysins streptolysin O (SLO) and streptolysin S (SLS). S. pyogenes does not naturally infect the upper respiratory tract of mice although mice transgenic for MHC class II human leukocyte antigens (HLA) become highly susceptible. Here we used HLA-transgenic mice to assess the role of both SLO and SLS during both nasopharyngeal and skin infection. Using S. pyogenes MGAS8232 as a model strain, we found that an SLS-deficient strain exhibited a 100-fold reduction in bacterial recovery from the nasopharynx and a 10-fold reduction in bacterial burden in the skin, whereas an SLO-deficient strain did not exhibit any infection defects in these models. Furthermore, depletion of neutrophils significantly restored the bacterial burden of the SLS-deficient bacteria in skin, but not in the nasopharynx. In mice nasally infected with the wildtype S. pyogenes, there was a marked change in localization of the tight junction protein ZO-1 at the site of infection, demonstrating damage to the nasal epithelia that was absent in mice infected with the SLS-deficient strain. Overall, we conclude that SLS is required for the establishment of nasopharyngeal infection and skin infection in HLA-transgenic mice by S. pyogenes MGAS8232 and provide evidence that SLS contributes to nasopharyngeal infection through the localized destruction of nasal epithelia.

Introduction: Computational models using data from high-throughput screening assays have promise for prioritizing and screening chemicals for testing under the U.S. Environmental Protection Agency’s Endocrine Disruptor Screening Program (EDSP). The purpose of this work was to demonstrate a data processing method for the determination of optimal minimal assay batteries from a larger comprehensive model, to provide a uniform method of evaluating the performance of future minimal assay batteries compared with the androgen receptor (AR) pathway model, and to incorporate chemical cluster analysis into this evaluation. Although several of the assays in the AR pathway model are no longer available through the original vendor, this approach could be used for future evaluations of minimal assay models for prioritization and screening.Methods: We compared two previously published models and found that an expanded 14-assay model had higher sensitivity for antagonists, whereas the original 11-assay model had slightly higher sensitivity for agonists. We then investigated subsets of assays in the original AR pathway model to optimize overall testing strategies that minimize cost while maintaining sensitivity across a broad chemical space.Results and Discussion: Evaluation of the critical assays across subset models derived from the 14-assay model identified three critical assays for predicting antagonism and two critical assays for predicting agonism. A minimum of nine assays is required for predicting agonism and antagonism with high sensitivity (95%). However, testing workflows guided by chemical structure–based clusters can reduce the average number of assays needed per chemical by basing the assays selected for testing on the likelihood of a chemical being an AR agonist, according to its structure. Our results show that a multi-stage testing workflow can provide 95% sensitivity while requiring only 48% of the resources required for running all assays from the original full models. The resources can be reduced further by incorporating in silico activity predictions.Conclusion: This work illustrates a data-driven approach that incorporates chemical clustering and simultaneous consideration of antagonism and agonism mechanisms to more efficiently screen chemicals. This case study provides a proof of concept for prioritization and screening strategies that can be utilized in future analyses to minimize the overall number of assays needed for predicting AR activity, which will maximize the number of chemicals that can be tested and allow data-driven prioritization of chemicals for further screening under the EDSP.

This case study describes how a music therapist (Stephen) and a music therapy intern (Sahitya) worked conjointly with a client and her granddaughter in a remote part of North India. The description provides a unique insight into conditions, culture, and lifestyle in this location, and how these two clinicians were able to merge broader arts-based and holistic approaches, on a journey towards client-centered and functional neurologic music therapy exercises to help the client regain more independence. The background to initial work undertaken by the music therapist, which lasted for one year and eleven months, is followed by a summary of five weekly conjoint sessions with the intern, including the evolution of exercises, rationale, and client responses, illustrated with embedded video excerpts. The communication, relationship, and trust-building with the client and her granddaughter, together with the intern joining the dynamic, paved the way for assimilating music therapy theoretical models that were new to them, and adapting neurologic music therapy approaches using an electronic keyboard that incorporated preferred facilitating music. This resulted in greater client engagement with higher levels of motivation and adherence and increased hand use in daily activities.

Abstract It is uncommon for risk groups defined by statistical or artificial intelligence (AI) models to be chosen by jointly considering model performance and potential interventions available. We develop a framework to rapidly guide choice of risk groups in this manner, and apply it to guide breast cancer screening intervals using an AI model. Linear programming is used to define risk groups that minimize expected advanced cancer incidence subject to resource constraints. In the application risk stratification performance is estimated from a case–control study (2044 cases, 1:1 matching), and other parameters are taken from screening trials and the screening programme in England. Under the model, re-screening in 1 year for the highest 4% AI model risk, in 3 years for the middle 64%, and in 4 years for 32% of the population at lowest risk, was expected to reduce the number of advanced cancers diagnosed by approximately 18 advanced cancers per 1000 diagnosed with triennial screening, for the same average number of screens in the population as triennial screening for all. Sensitivity analyses found the choice of thresholds was robust to model parameters, but the estimated reduction in advanced cancers was not precise and requires further evaluation. Our framework helps define thresholds with the greatest chance of success for reducing the population health burden of cancer when used in risk-adapted screening, which should be further evaluated such as in health-economic modelling based on computer simulation models, and real-world evaluations.