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The purpose of this longitudinal study was to examine patterns in implementation of Tiers 2 and 3 school-wide positive behavioral interventions and supports (SWPBIS) systems to identify timings of installation that led to higher implementation of advanced tiers. Extant data from 776 schools in 27 states reporting on the first 3 years of Tier 2 implementation and 359 schools in 23 states reporting on the first year of Tier 3 implementation were analyzed. Using structural equation modeling, we found that higher Tier 1 implementation predicted subsequent Tier 2 and Tier 3 implementation. In addition, waiting 2 or 3 years after initial Tier 1 implementation to launch Tier 2 systems predicted higher initial Tier 2 implementation (compared with implementing the next year). Finally, we found that launching Tier 3 systems after Tier 2 systems, compared with launching both tiers simultaneously, predicted higher Tier 2 implementation in the second and third year, so long as Tier 3 systems were launched within 3 years of Tier 2 systems. These findings provide empirical guidance for when to launch Tiers 2 and 3 systems; however, we emphasize that delays in launching advanced systems should not equate to delays in more intensive supports for students.

In this article, the authors discuss zero tolerance policies and implications for those they affect most, namely students of color (e.g., Black, American Indian, Latino/a/e) and students with disabilities. First, we present a brief history of the use of zero tolerance policies in school discipline and review the literature on their effects. Although these policies seem race neutral, racial and ethnic disproportionality in their use is well documented. Then, the authors examine implicit bias as a contributor to a negative cycle of student-teacher interactions that influence disparate disciplinary outcomes. Lastly, the authors present recommendations for practice, including policy changes, systems for prevention, approaches for managing behavioral errors, and a promising approach to counteract bias in discipline decision making.

Technology has arisen as a powerful tool for enhancing student's learning and engagement in science education, particularly in the context of elementary inquiry-based science education (IBSE). This systematic review examines the use of technology in elementary IBSE over the past decade, analyzing 22 empirical studies to identify research trends, explore relationships among inquiry phases and process skills, and identify examples of technology utilization and affordances. The study reveals that technology has mainly been used to support students' observation and data interpretation skills during the investigation phase of inquiry. However, it also indicates that technology has the potential to support other science process skills in other phases of inquiry in a variety of ways. Supporting students to capture and collect data, providing learning materials, and linking the real-world context were the three predominant affordances. Furthermore, the analysis suggests research gaps in the use of emerging technology and insufficient attention paid to employing technology to support students' modeling processes and the use of simulations. These findings point to the need for further investigation to fully explore the potential of technology in supporting students' learning and engagement in elementary IBSE.

This paper describes the research protocol for the Educational and Developmental Gains in Early Childhood (EDGE) Study, which will examine the implementation of two years of funded kindergarten prior to the first year of school in Victoria, Australia. EDGE will examine whether children's language, cognitive, social-emotional, and behavioural outcomes are improved after two years of kindergarten compared to one year. The experiences of (and impacts on) teachers, service leaders, and families will also be examined. The study includes a cross-sectional cohort of 95 early childhood education and care (ECEC) services, and an embedded longitudinal observational cohort of children attending these services. Case studies of 15-20 ECEC services will also be collected, in addition to interviews with policy stakeholders.

This cross-sectional study analyzed data from 364,143 students in 492 high schools who completed the Georgia School Climate Survey during the 2017-2018 school year. Through latent profile analysis, we identified that student perceptions of school climate could be classified into three distinct profiles, including positive, moderate, and negative climate. Using multinomial logistic regression, we then identified school and student characteristics that predicted student classification in the student profiles using the total sample and subsamples by race/ethnicity. Among the key results, we found that most of the school characteristics (e.g., percent of students receiving free or reduced lunch, schools with higher percentages of minoritized students) predicting classification in the negative and positive school climate profiles were different for White students compared to minoritized students. For example, Black students in primarily non-White schools were more likely to view school climate positively, whereas the opposite was the case for White students. We also found that Black and Other (e.g., multiracial) students were more likely to be classified in the negative school climate profile and less likely to be classified in the positive school climate profile compared to White students. In contrast, Latino/a/e students were more likely to be classified in the positive school climate profile and less likely to be classified in the negative school climate profile. Implications for research and practice are discussed.

This article develops an index to measure the level of susceptibility of courses to cheating using ChatGPT (Chat Generative Pre-trained Transformer), an advanced text-based artificial intelligence (AI) language model. It demonstrates the application of the index to a sample of business courses in a mid-sized university. The study finds that the vulnerability index varies across disciplines and teaching modalities. As advanced language models become more common in academic settings and create new educational challenges, the study provides an intuitive and practical mechanism for instructors and academic units to measure and assess the vulnerability of their courses to various language-based predictive models.

There is yet a concerted effort directed to ameliorate mathematics anxiety (MA) among deaf learners especially in Nigeria. Hence, this study examined the effects of rational emotive behavioural and relaxation therapies on MA among deaf learners. The study adopted the quantitative quasi-experimental research design. A purposive sampling method was adopted to select three schools for the deaf in Oyo state. A random sampling procedure was employed to select 60 deaf learners who were assigned to two experimental groups and the control group. The Mathematics Anxiety Scale was used to screen participants, while a Mathematics Achievement Test was used for data collection. Data gathered were analysed using analysis of covariance and a descriptive chart. Findings revealed the efficacy of the two therapeutic interventions on the reduction of MA among the participants. The estimated mean difference between the treatments (rational emotive behavioural therapy = 5.537; relaxation therapy = 3.867) and control groups (1.670) showed higher potency of rational emotive behavioural therapy for reduction in MA among deaf learners than relaxation therapy. Based on the findings, it is important that mathematics teaching environment should be rich with tangible instructional materials that speak specifically to the emotion and cognitions of deaf learners.

Purpose: The purpose of this paper is to investigate the ending of fee-free higher education in Australia for overseas students in the 1980s, and the ways in which the government managed the diplomatic relationships that were affected by this policy shift. The introduction of fee-free higher education in Australia in 1974 was incredibly popular, and the end of the program in the late 1980s created difficulties for individuals, families and diplomatic relationships. Design/methodology/approach: Using a mix of secondary sources and archival documents, this paper has a historiographical element, and an element of analysis. Findings: This research finds that the ending of fee-free education created significant diplomatic issues with a number of Australia's regional neighbours. It also created issues for individual students and families. The solution to these problems was, in large part, a scholarship scheme called the Equity and Merit Scholarship Scheme (EMSS). The EMSS was designed, in part, to address the issues created by the end of the fee-free program. However, the design of the scholarship scheme also created its own diplomatic issues with a different cohort of nation states. Originality/value: There is limited scholarly research into the history of international education policy in Australia. This research draws on the work of some scholars of international scholarships, as well as historians of universities and education more broadly. This research adds to a growing body of work in the field of Australian international education history.

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia). P

BackgroundClonal hematopoiesis of indeterminate potential (CHIP) is an age-related somatic mutation associated with incident hematologic cancer. Environmental stressors which, like air pollution, generate oxidative stress at the cellular level, may induce somatic mutations and some mutations may provide a selection advantage for persistence and expansion of specific clones.MethodsWe used data from the Multi-Ethnic Study of Atherosclerosis (MESA) N = 4,379 and the Women's Health Initiative (WHI) N = 7,701 to estimate cross-sectional associations between annual average air pollution concentrations at participant address the year before blood draw using validated spatiotemporal models. We used covariate-adjusted logistic regression to estimate risk of CHIP per interquartile range increases in particulate matter (PM2.5; 4 μg/m3) and nitrogen dioxide (NO2; 10 ppb) as ORs (95% confidence intervals).ResultsPrevalence of CHIP at blood draw (variant allele fraction > 2%) was 4.4% and 8.7% in MESA and WHI, respectively. The most common CHIP driver mutation was in DNMT3A. Neither pollutant was associated with CHIP: ORMESA PM2.5 = 1.00 (0.68-1.45), ORMESA NO2 = 1.05 (0.69-1.61), ORWHI PM2.5 = 0.97 (0.86-1.09), ORWHI NO2 = 0.98 (0.88-1.10); or with DNMT3A-driven CHIP.ConclusionsWe did not find evidence that air pollution contributes to CHIP prevalence in two large observational cohorts.ImpactThis is the first study to estimate associations between air pollution and CHIP.

Interactive graphical genome browsers are essential tools in genomics, but they do not contain all the recent genome assemblies. We create Genome Archive (GenArk) collection of UCSC Genome Browsers from NCBI assemblies. Built on our established track hub system, this enables fast visualization of annotations. Assemblies come with gene models, repeat masks, BLAT, and in silico PCR. Users can add annotations via track hubs and custom tracks. We can bulk-import third-party resources, demonstrated with TOGA and Ensembl gene models for hundreds of assemblies.Three thousand two hundred sixty-nine GenArk assemblies are listed at https://hgdownload.soe.ucsc.edu/hubs/ and can be searched for on the Genome Browser gateway page.

Nonalcoholic fatty liver disease (NAFLD) is common and partially heritable and has no effective treatments. We carried out a genome-wide association study (GWAS) meta-analysis of imaging (n = 66,814) and diagnostic code (3,584 cases versus 621,081 controls) measured NAFLD across diverse ancestries. We identified NAFLD-associated variants at torsin family 1 member B (TOR1B), fat mass and obesity associated (FTO), cordon-bleu WH2 repeat protein like 1 (COBLL1)/growth factor receptor-bound protein 14 (GRB14), insulin receptor (INSR), sterol regulatory element-binding transcription factor 1 (SREBF1) and patatin-like phospholipase domain-containing protein 2 (PNPLA2), as well as validated NAFLD-associated variants at patatin-like phospholipase domain-containing protein 3 (PNPLA3), transmembrane 6 superfamily 2 (TM6SF2), apolipoprotein E (APOE), glucokinase regulator (GCKR), tribbles homolog 1 (TRIB1), glycerol-3-phosphate acyltransferase (GPAM), mitochondrial amidoxime-reducing component 1 (MARC1), microsomal triglyceride transfer protein large subunit (MTTP), alcohol dehydrogenase 1B (ADH1B), transmembrane channel like 4 (TMC4)/membrane-bound O-acyltransferase domain containing 7 (MBOAT7) and receptor-type tyrosine-protein phosphatase δ (PTPRD). Implicated genes highlight mitochondrial, cholesterol and de novo lipogenesis as causally contributing to NAFLD predisposition. Phenome-wide association study (PheWAS) analyses suggest at least seven subtypes of NAFLD. Individuals in the top 10% and 1% of genetic risk have a 2.5-fold to 6-fold increased risk of NAFLD, cirrhosis and hepatocellular carcinoma. These genetic variants identify subtypes of NAFLD, improve estimates of disease risk and can guide the development of targeted therapeutics.

Transcriptome prediction models built with data from European-descent individuals are less accurate when applied to different populations because of differences in linkage disequilibrium patterns and allele frequencies. We hypothesized that methods that leverage shared regulatory effects across different conditions, in this case, across different populations, may improve cross-population transcriptome prediction. To test this hypothesis, we made transcriptome prediction models for use in transcriptome-wide association studies (TWASs) using different methods (elastic net, joint-tissue imputation [JTI], matrix expression quantitative trait loci [Matrix eQTL], multivariate adaptive shrinkage in R [MASHR], and transcriptome-integrated genetic association resource [TIGAR]) and tested their out-of-sample transcriptome prediction accuracy in population-matched and cross-population scenarios. Additionally, to evaluate model applicability in TWASs, we integrated publicly available multiethnic genome-wide association study (GWAS) summary statistics from the Population Architecture using Genomics and Epidemiology (PAGE) study and Pan-ancestry genetic analysis of the UK Biobank (PanUKBB) with our developed transcriptome prediction models. In regard to transcriptome prediction accuracy, MASHR models performed better or the same as other methods in both population-matched and cross-population transcriptome predictions. Furthermore, in multiethnic TWASs, MASHR models yielded more discoveries that replicate in both PAGE and PanUKBB across all methods analyzed, including loci previously mapped in GWASs and loci previously not found in GWASs. Overall, our study demonstrates the importance of using methods that benefit from different populations' effect size estimates in order to improve TWASs for multiethnic or underrepresented populations.

Coronary artery calcification (CAC), a measure of subclinical atherosclerosis, predicts future symptomatic coronary artery disease (CAD). Identifying genetic risk factors for CAC may point to new therapeutic avenues for prevention. Currently, there are only four known risk loci for CAC identified from genome-wide association studies (GWAS) in the general population. Here we conducted the largest multi-ancestry GWAS meta-analysis of CAC to date, which comprised 26,909 individuals of European ancestry and 8,867 individuals of African ancestry. We identified 11 independent risk loci, of which eight were new for CAC and five had not been reported for CAD. These new CAC loci are related to bone mineralization, phosphate catabolism and hormone metabolic pathways. Several new loci harbor candidate causal genes supported by multiple lines of functional evidence and are regulators of smooth muscle cell-mediated calcification ex vivo and in vitro. Together, these findings help refine the genetic architecture of CAC and extend our understanding of the biological and potential druggable pathways underlying CAC.

Each human genome has tens of thousands of rare genetic variants; however, identifying impactful rare variants remains a major challenge. We demonstrate how use of personal multi-omics can enable identification of impactful rare variants by using the Multi-Ethnic Study of Atherosclerosis, which included several hundred individuals, with whole-genome sequencing, transcriptomes, methylomes, and proteomes collected across two time points, 10 years apart. We evaluated each multi-omics phenotype's ability to separately and jointly inform functional rare variation. By combining expression and protein data, we observed rare stop variants 62 times and rare frameshift variants 216 times as frequently as controls, compared to 13-27 times as frequently for expression or protein effects alone. We extended a Bayesian hierarchical model, "Watershed," to prioritize specific rare variants underlying multi-omics signals across the regulatory cascade. With this approach, we identified rare variants that exhibited large effect sizes on multiple complex traits including height, schizophrenia, and Alzheimer's disease.

During May 2018‒December 2022, we reviewed transfusion-transmitted sepsis cases in the United States attributable to polymicrobial contaminated apheresis platelet components, including Acinetobacter calcoaceticus‒baumannii complex or Staphylococcus saprophyticus isolated from patients and components. Transfused platelet components underwent bacterial risk control strategies (primary culture, pathogen reduction or primary culture, and secondary rapid test) before transfusion. Environmental samples were collected from a platelet collection set manufacturing facility. Seven sepsis cases from 6 platelet donations from 6 different donors were identified in patients from 6 states; 3 patients died. Cultures identified Acinetobacter calcoaceticus‒baumannii complex in 6 patients and 6 transfused platelets, S. saprophyticus in 4 patients and 4 transfused platelets. Whole-genome sequencing showed environmental isolates from the manufacturer were closely related genetically to patient and platelet isolates, indicating the manufacturer was the most probable source of recurrent polymicrobial contamination. Clinicians should maintain awareness of possible transfusion-transmitted sepsis even when using bacterial risk control strategies.

PURPOSE OF REVIEW: The purpose of this review is to summarize current approaches and provide recommendations for imaging bone in pediatric populations using high-resolution peripheral quantitative computed tomography (HR-pQCT). RECENT FINDINGS: Imaging the growing skeleton is challenging and HR-pQCT protocols are not standardized across centers. Adopting a single-imaging protocol for all studies is unrealistic; thus, we present three established protocols for HR-pQCT imaging in children and adolescents and share advantages and disadvantages of each. Limiting protocol variation will enhance the uniformity of results and increase our ability to compare study results between different research groups. We outline special cases along with tips and tricks for acquiring and processing scans to minimize motion artifacts and account for growing bone. The recommendations in this review are intended to help researchers perform HR-pQCT imaging in pediatric populations and extend our collective knowledge of bone structure, architecture, and strength during the growing years.

PURPOSE: Proximal fibula fractures are often associated with tibial plateau fractures, but their relationship is poorly characterized. The purpose of this study was to better define the relationship between tibial plateau injury severity and presence of associated soft tissue injuries. METHODS: A retrospective review was performed on all operatively treated tibial plateau fractures at a Level 1 trauma center over a 5-year period. Patient demographics, injury radiographs, CT scans, operative reports and follow-up were reviewed. RESULTS: Queried tibial plateau fractures from 2014 to 2019 totaled 217 fractures in 215 patients. Fifty-two percent were classified as AO/OTA 41B and 48% were AO/OTA 41C. Thirty-nine percent had an associated proximal fibula fracture. The presence of a proximal fibula fracture had significant correlation with AO/OTA 41C fractures, as compared with AO/OTA 41B fractures (chi-square, p

Chronic nonhealing wounds are debilitating and diminish one's quality of life, necessitating the development of improved strategies for effective treatment. Biomaterial- and cell-based therapies offer an alternative treatment compared to conventional wound care for regenerating damaged tissues. Cell-based approaches frequently utilize endothelial cells (ECs) to promote vascularization and mesenchymal stromal cells (MSCs) for their potent secretome that promotes host cell recruitment. Spheroids have improved therapeutic potential over monodisperse cells, while degradable scaffolds can influence cellular processes conducive to long-term tissue regeneration. However, the role of biomaterial degradation on the therapeutic potential of heterotypic EC-MSC spheroids for wound healing is largely unknown. We formed poly(ethylene) glycol (PEG) hydrogels with varying ratios of matrix metalloproteinase (MMP)-degradable and non-degradable crosslinkers to develop three distinct constructs - fully degradable, partially degradable, and non-degradable - and interrogate the influence of degradation rate on engineered cell carriers for wound healing. We found that the vulnerability to degradation was critical for cellular proliferation, while inhibition of degradation impaired spheroid metabolic activity. Higher concentrations of degradable crosslinker promoted robust cell spreading, outgrowth, and secretion of proangiogenic cytokines (i.e., VEGF, HGF) that are critical in wound healing. The degree of degradation dictated the unique secretory profile of spheroids. When applied to a clinically relevant full-thickness ex vivo skin model, degradable spheroid-loaded hydrogels restored stratification of the epidermal layer, confirming the efficacy of scaffolds to promote wound healing. These results highlight the importance of matrix remodeling and its essential role in the therapeutic potential of heterotypic spheroids.

K-12 schools are the largest energy consumers in the public sector, with their HVAC energy consumption representing the largest portion of their total energy use. While transitioning these schools to grid-interactive HVAC system operation through advanced controls offers significant financial and environmental benefits, and model predictive control (MPC) has been identified as a promising solution to achieve that, very few MPCs are affordable and have been deployed in K-12 schools. This situation raises concerns about the unclear real-world benefits of MPC technology among facility managers and industries. To address this gap, this paper presents a low-cost MPC solution that requires minimal control infrastructure costs and a unique field demonstration at a K-12 school, conducted for both cooling and heating seasons. This work adopted a previously developed MPC and extended it for use in the school application. The MPC aims to coordinate multiple packaged units to eliminate unnecessary peaks and shift cooling or heating loads in response to grid signals based on load conditions, while maintaining thermostat temperatures within school-defined bounds. Throughout the field tests, the MPC achieved a 24% reduction in peak demand during the cooling season and shifted cooling or heating loads by up to 16% in response to the school's utility tariff, considering load conditions, while also allowing end-users to override thermostat setpoints. The paper also discusses the limitations of this study and future research directions for better performance of the MPC at K-12 schools.

Osteosarcoma (OS) is the most common primary malignant bone cancer in children and adolescents. While numerous other cancers now have promising therapeutic advances, treatment options for OS have remained unchanged since the advent of standard chemotherapeutics and offer less than a 25% 5-y survival rate for those with metastatic disease. This dearth of clinical progress underscores a lack of understanding of OS progression and necessitates the study of this disease in an innovative system. Here, we adapt a previously described engineered bone marrow (eBM) construct for use as a three-dimensional platform to study how microenvironmental and immune factors affect OS tumor progression. We form eBM by implanting acellular bone-forming materials in mice and explanting the cellularized constructs after 8 wk for study. We interrogate the influence of the anatomical implantation site on eBM tissue quality, test ex vivo stability under normoxic (5% O2) and standard (21% O2) culture conditions, culture OS cells within these constructs, and compare them to human OS samples. We show that eBM stably recapitulates the composition of native bone marrow. OS cells exhibit differential behavior dependent on metastatic potential when cultured in eBM, thus mimicking in vivo conditions. Furthermore, we highlight the clinical applicability of eBM as a drug-screening platform through doxorubicin treatment and show that eBM confers a protective effect on OS cells that parallel clinical responses. Combined, this work presents eBM as a cellular construct that mimics the complex bone marrow environment that is useful for mechanistic bone cancer research and drug screening.

BACKGROUND: Stem cell products are increasingly entering early stage clinical trials for treating retinal degeneration. The field is learning from experience about comparability of cells proposed for preclinical and clinical use. Without this, preclinical data supporting translation to a clinical study might not adequately reflect the performance of subsequent clinical-grade cells in patients. METHODS: Research-grade human neural progenitor cells (hNPC) and clinical-grade hNPC (termed CNS10-NPC) were injected into the subretinal space of the Royal College of Surgeons (RCS) rat, a rodent model of retinal degeneration such as retinitis pigmentosa. An investigational new drug (IND)-enabling study with CNS10-NPC was performed in the same rodent model. Finally, surgical methodology for subretinal cell delivery in the clinic was optimized in a large animal model with Yucatan minipigs. RESULTS: Both research-grade hNPC and clinical-grade hNPC can survive and provide functional and morphological protection in a dose-dependent fashion in RCS rats and the optimal cell dose was defined and used in IND-enabling studies. Grafted CNS10-NPC migrated from the injection site without differentiation into retinal cell phenotypes. Additionally, CNS10-NPC showed long-term survival, safety and efficacy in a good laboratory practice (GLP) toxicity and tumorigenicity study, with no observed cell overgrowth even at the maximum deliverable dose. Finally, using a large animal model with the Yucatan minipig, which has an eye size comparable to the human, we optimized the surgical methodology for subretinal cell delivery in the clinic. CONCLUSIONS: These extensive studies supported an approved IND and the translation of CNS10-NPC to an ongoing Phase 1/2a clinical trial (NCT04284293) for the treatment of retinitis pigmentosa.

Clonal hematopoiesis of indeterminate potential (CHIP) is associated with an increased risk of cardiovascular diseases (CVDs), putatively via inflammasome activation. We pursued an inflammatory gene modifier scan for CHIP-associated CVD risk among 424,651 UK Biobank participants. We identified CHIP using whole-exome sequencing data of blood DNA and modeled as a composite, considering all driver genes together, as well as separately for common drivers (DNMT3A, TET2, ASXL1, and JAK2). We developed predicted gene expression scores for 26 inflammasome-related genes and assessed how they modify CHIP-associated CVD risk. We identified IL1RAP as a potential key molecule for CHIP-associated CVD risk across genes and increased AIM2 gene expression leading to heightened JAK2- and ASXL1-associated CVD risk. We show that CRISPR-induced Asxl1-mutated murine macrophages had a particularly heightened inflammatory response to AIM2 agonism, associated with an increased DNA damage response, as well as increased IL-10 secretion, mirroring a CVD-protective effect of IL10 expression in ASXL1 CHIP. Our study supports the role of inflammasomes in CHIP-associated CVD and provides evidence to support gene-specific strategies to address CHIP-associated CVD risk.

Aerosol formation and production yields from 11 carbonyls (carbonyl concentration per aerosol mass unit) were investigated (1) from a fourth-generation (4th gen) e-cigarette device at different coil resistances and coil age (0-5000 puffs) using unflavored e-liquid with 2% benzoic acid nicotine salt, (2) between a sub-ohm third-generation (3rd gen) tank mod at 0.12 Ω and a 4th gen pod at 1.2 Ω using e-liquid with nicotine salt, together with nicotine yield, and (3) from 3rd gen coils of different metals (stainless steel, kanthal, nichrome) using e-liquid with freebase nicotine. Coil resistance had an inverse relationship with coil temperature, and coil temperature was directly proportional to aerosol mass formation. Trends in carbonyl yields depended on carbonyl formation mechanisms. Carbonyls produced primarily from thermal degradation chemistry (e.g., formaldehyde, acetaldehyde, acrolein, propionaldehyde) increased per aerosol mass with higher coil resistances, despite lower coil temperature. Carbonyls produced primarily from chemistry initiated by reactive oxygen species (ROS) (e.g., hydroxyacetone, dihydroxyacetone, methylglyoxal, glycolaldehyde, lactaldehyde) showed the opposite trend. Coil age did not alter coil temperature nor aerosol mass formation but had a significant effect on carbonyl formation. Thermal carbonyls were formed optimally at 500 puffs in our study and then declined to a baseline, whereas ROS-derived carbonyls showed a slow rise to a maximum trend with coil aging. The 3rd gen versus 4th gen device comparison mirrored the trends in coil resistance. Nicotine yields per aerosol mass were consistent between 3rd and 4th gen devices. Coil material did not significantly alter aerosol formation nor carbonyl yield when adjusted for wattage. This work shows that sub-ohm coils may not necessarily produce higher carbonyl yields even when they produce more aerosol mass. Furthermore, carbonyl formation is dynamic and not generalizable during the coils lifetime. Finally, studies that compare data across different e-cigarette devices, coil age, and coil anatomy should account for the aerosol chemistry trends that depend on these parameters.

BackgroundCommon genetic variants are associated with risk for hypertrophic cardiomyopathy and dilated cardiomyopathy and with left ventricular (LV) traits. Whether these variants are associated with myocardial fibrosis, an important pathophysiological mediator of cardiomyopathy, is unknown.MethodsMulti-Ethnic Study of Atherosclerosis participants with T1-mapping cardiac magnetic resonance imaging in-whom extracellular volume was assessed, and genotyping information was available were included (N=1255). Log extracellular volume (%) was regressed on 50 candidate single nucleotide polymorphisms (previously identified to be associated with hypertrophic cardiomyopathy, dilated cardiomyopathy, and LV traits) adjusting for age, sex, diabetes, blood pressure, and principal components of ancestry. Ancestry-specific results were pooled by fixed-effect meta-analyses. Gene knockdown experiments were performed in human cardiac fibroblasts.ResultsThe SMARCB1 rs2186370 intronic variant (minor allele frequency: 0.18 in White and 0.50 in Black participants), previously identified as a risk variant for dilated cardiomyopathy and hypertrophic cardiomyopathy, was significantly associated with increased extracellular volume (P=0.0002) after adjusting for confounding clinical variables. The SMARCB1 rs2070458 locus previously associated with increased LV wall thickness and mass was similarly significantly associated with increased extracellular volume (P=0.0002). The direction of effect was similar in all 4 ancestry groups, but the effect was strongest in Black participants. The variants are strong expression quantitative loci in human LV tissue and associated with genotype-dependent decreased expression of SMARCB1 (P=7.3×10-22). SMARCB1 knockdown in human cardiac fibroblasts resulted in increased TGF (transforming growth factor)-β1-mediated α-smooth muscle actin and collagen expression.ConclusionsCommon genetic variation in SMARCB1 previously associated with risk for cardiomyopathies and increased LV wall thickness is associated with increased cardiac magnetic resonance imaging-based myocardial fibrosis and increased TGF-β1 mediated myocardial fibrosis in vitro. Whether these findings suggest a pathophysiologic link between myocardial fibrosis and cardiomyopathy risk remains to be proven.

BACKGROUND: Previous studies have identified pulmonary hypertension (PH) as a relatively common diagnosis in children with in-hospital cardiac arrest (IHCA), and preclinical laboratory studies have found poor outcomes and low systemic blood pressures during CPR for PH-associated cardiac arrest. The objective of this study was to determine the prevalence of PH among children with IHCA and the association between PH diagnosis and intra-arrest physiology and survival outcomes. METHODS: This was a prospectively designed secondary analysis of patients enrolled in the ICU-RESUS clinical trial (NCT02837497). The primary exposure was a pre-arrest diagnosis of PH. The primary survival outcome was survival to hospital discharge with favorable neurologic outcome (Pediatric Cerebral Performance Category score 1-3 or unchanged from baseline). The primary physiologic outcome was event-level average diastolic blood pressure (DBP) during CPR. RESULTS: Of 1276 patients with IHCAs during the study period, 1129 index IHCAs were enrolled; 184 (16.3%) had PH and 101/184 (54.9%) were receiving inhaled nitric oxide at the time of IHCA. Survival with favorable neurologic outcome was similar between patients with and without PH on univariate (48.9% vs. 54.4%; p = 0.17) and multivariate analyses (aOR 0.82 [95%CI: 0.56, 1.20]; p = 0.32). There were no significant differences in CPR event outcome or survival to hospital discharge. Average DBP, systolic BP, and end-tidal carbon dioxide during CPR were similar between groups. CONCLUSIONS: In this prospective study of pediatric IHCA, pre-existing PH was present in 16% of children. Pre-arrest PH diagnosis was not associated with statistically significant differences in survival outcomes or intra-arrest physiologic measures.

PURPOSE: To compare the evaluation metrics for deep learning methods that were developed using imbalanced imaging data in osteoarthritis studies. MATERIALS AND METHODS: This retrospective study utilized 2996 sagittal intermediate-weighted fat-suppressed knee MRIs with MRI Osteoarthritis Knee Score readings from 2467 participants in the Osteoarthritis Initiative study. We obtained probabilities of the presence of bone marrow lesions (BMLs) from MRIs in the testing dataset at the sub-region (15 sub-regions), compartment, and whole-knee levels based on the trained deep learning models. We compared different evaluation metrics (e.g., receiver operating characteristic (ROC) and precision-recall (PR) curves) in the testing dataset with various class ratios (presence of BMLs vs. absence of BMLs) at these three data levels to assess the models performance. RESULTS: In a subregion with an extremely high imbalance ratio, the model achieved a ROC-AUC of 0.84, a PR-AUC of 0.10, a sensitivity of 0, and a specificity of 1. CONCLUSION: The commonly used ROC curve is not sufficiently informative, especially in the case of imbalanced data. We provide the following practical suggestions based on our data analysis: 1) ROC-AUC is recommended for balanced data, 2) PR-AUC should be used for moderately imbalanced data (i.e., when the proportion of the minor class is above 5% and less than 50%), and 3) for severely imbalanced data (i.e., when the proportion of the minor class is below 5%), it is not practical to apply a deep learning model, even with the application of techniques addressing imbalanced data issues.

Although many novel gene-metabolite and gene-protein associations have been identified using high-throughput biochemical profiling, systematic studies that leverage human genetics to illuminate causal relationships between circulating proteins and metabolites are lacking. Here, we performed protein-metabolite association studies in 3,626 plasma samples from three human cohorts. We detected 171,800 significant protein-metabolite pairwise correlations between 1,265 proteins and 365 metabolites, including established relationships in metabolic and signaling pathways such as the protein thyroxine-binding globulin and the metabolite thyroxine, as well as thousands of new findings. In Mendelian randomization (MR) analyses, we identified putative causal protein-to-metabolite associations. We experimentally validated top MR associations in proof-of-concept plasma metabolomics studies in three murine knockout strains of key protein regulators. These analyses identified previously unrecognized associations between bioactive proteins and metabolites in human plasma. We provide publicly available data to be leveraged for studies in human metabolism and disease.