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Efforts to diversify STEM fields have not completely eliminated higher rates of women leaving certain science, technology, engineering, and mathematics (STEM) disciplines, such as geosciences. A diverse mentorship network is linked to persistence in STEM among college students, but little is known about how it leads to persistence. In particular, does a student's sense of belonging mediate the relationship between the diversity of one's mentor network and persistence in a field? This longitudinal study investigated whether students' university sense of belonging mediates the relationship between the diversity of mentor networks and interest in geoscience. 253 college women in STEM majors from nine U.S. universities reported on the diversity of their mentor networks, university belongingness, and interest in geoscience from Spring 2018 to Spring 2019. Consistent with our hypotheses, mediation analysis revealed a statistically and practically significant indirect effect of the diversity of mentor networks on interest development through university belonging.

Abstract Low‐grade epilepsy‐associated tumors (LEATs) are a common cause of drug‐resistant epilepsy in children. Herein, we demonstrate the feasibility of using tumor tissue derived from stereoelectroencephalography (sEEG) electrodes upon removal to molecularly characterize tumors and aid in diagnosis. An 18‐year‐old male with focal epilepsy and MRI suggestive of a dysembryoplastic neuroepithelial tumor (DNET) in the left posterior temporal lobe underwent implantation of seven peri‐tumoral sEEG electrodes for peri‐operative language mapping and demarcation of the peri‐tumoral ictal zone prior to DNET resection. Using electrodes that passed through tumor tissue, we show successful isolation of tumor DNA and subsequent analysis using standard methods for tumor classification by DNA, including Glioseq targeted sequencing and DNA methylation array analysis. This study provides preliminary evidence for the feasibility of molecular diagnosis of LEATs or other lesions using a minimally invasive method with microscopic tissue volumes. The implications of sEEG electrodes in tumor characterization are broad but would aid in diagnosis and subsequent targeted therapeutic strategies.

Kimberly Daniels,1 Stephan Lanes,1 Arlene Tave,1 Michael F Pollack,2 David M Mannino,3 Gerard Criner,4 Amanda Neikirk,1 Kirsty Rhodes,5 Norbert Feigler,2 Clementine Nordon5 1Safety and Epidemiology, Carelon Research, Wilmington, DE, USA; 2Global Medical Affairs, AstraZeneca, Wilmington, DE, USA; 3College of Medicine, University of Kentucky, Lexington, KY, USA; 4Thoracic Medicine and Surgery, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA; 5BioPharmaceuticals Medical, AstraZeneca, Cambridge, UKCorrespondence: Kimberly Daniels, Safety and Epidemiology, Carelon Research, 123 Justison Street, Suite 200, Wilmington, DE, 19801, USA, Tel +1 443-812-1731, Email Kimberly.Daniels@carelon.comPurpose: This study estimated the magnitude and duration of risk of cardiovascular events and mortality following acute exacerbations of chronic obstructive pulmonary disease (AECOPD), and whether risks varied by number and severity of exacerbation in a commercially insured population in the United States.Methods: This was a retrospective cohort study of newly diagnosed COPD patients ≥ 40 years old in the Healthcare Integrated Research Database from 2012 to 2019. Patients experiencing exacerbations comprised the “exacerbation cohort”. Moderate exacerbations were outpatient visits with contemporaneous antibiotic or glucocorticoid administration; severe exacerbations were emergency department visits or hospitalizations for AECOPD. Follow-up started on the exacerbation date. Distribution of time between diagnosis and first exacerbation was used to assign index dates to the “unexposed” cohort. Cox proportional hazards models estimated risks of a cardiovascular event or death following an exacerbation adjusted for medical and prescription history and stratified by follow-up time, type of cardiovascular event, exacerbation severity, and rank of exacerbation (first, second, or third).Results: Among 435,925 patients, 170,236 experienced ≥ 1 exacerbation. Risk of death was increased for 2 years following an exacerbation and was highest during the first 30 days (any exacerbation hazard ratio (HR)=1.79, 95% CI=1.58— 2.04; moderate HR=1.22, 95% CI=1.04— 1.43; severe HR=5.09, 95% CI=4.30— 6.03). Risks of cardiovascular events were increased for 1 year following an AECOPD and highest in the first 30-days (any exacerbation HR=1.34, 95% CI=1.23— 1.46; moderate HR=1.23 (95% CI 1.12— 1.35); severe HR=1.93 (95% CI=1.67— 2.22)). Each subsequent AECOPD was associated with incrementally higher rates of both death and cardiovascular events.Conclusion: Risk of death and cardiovascular events was greatest in the first 30 days and rose with subsequent exacerbations. Risks were elevated for 1– 2 years following moderate and severe exacerbations, highlighting a sustained increased cardiopulmonary risk associated with exacerbations.Keywords: COPD, cardiopulmonary, cardiac events, epidemiology, longitudinal studies

Preclinical and clinical studies indicate that psychostimulants, in addition to having abuse potential, may elicit brain dysfunctions and/or neurotoxic effects. Central toxicity induced by psychostimulants may pose serious health risks since the recreational use of these substances is on the rise among young people and adults. The present review provides an overview of recent research, conducted between 2018 and 2023, focusing on brain dysfunctions and neurotoxic effects elicited in experimental models and humans by amphetamine, cocaine, methamphetamine, 3,4-methylenedioxymethamphetamine, methylphenidate, caffeine, and nicotine. Detailed elucidation of factors and mechanisms that underlie psychostimulant-induced brain dysfunction and neurotoxicity is crucial for understanding the acute and enduring noxious brain effects that may occur in individuals who use psychostimulants for recreational and/or therapeutic purposes.

BACKGROUND: In men with a detectable prostate-specific antigen (PSA) level after prostatectomy for prostate cancer, salvage prostate bed radiotherapy (PBRT) results in about 70% of patients being free of progression at 5 years. A three-group randomised trial was designed to determine whether incremental gains in patient outcomes can be achieved by adding either 4-6 months of short-term androgen deprivation therapy (ADT) to PBRT, or both short-term ADT and pelvic lymph node radiotherapy (PLNRT) to PBRT. METHODS: The international, multicentre, randomised, controlled SPPORT trial was done at 283 radiation oncology cancer treatment centres in the USA, Canada, and Israel. Eligible patients (aged ≥18 years) were those who after prostatectomy for adenocarcinoma of the prostate had a persistently detectable or an initially undetectable and rising PSA of between 0·1 and 2·0 ng/mL. Patients with and without lymphadenectomy (N0/Nx) were eligible if there was no clinical or pathological evidence of lymph node involvement. Other eligibility criteria included pT2 or pT3 disease, prostatectomy Gleason score of 9 or less, and a Zubrod performance status of 0-1. Eligible patients were randomly assigned to receive PBRT alone at a dose of 64·8-70·2 Gy at 1·8 Gy per fraction daily (group 1), PBRT plus short-term ADT (group 2), or PLNRT (45 Gy at 1·8 Gy per fraction, and then a volume reduction made to the planning target volume for the remaining 19·8-25 ·2 Gy) plus PBRT plus short-term ADT (group 3). The primary endpoint was freedom from progression, in which progression was defined as biochemical failure according to the Phoenix definition (PSA ≥2 ng/mL over the nadir PSA), clinical failure (local, regional, or distant), or death from any cause. A planned interim analysis of 1191 patents with minimum potential follow-up time of 5 years applied a Haybittle-Peto boundary of p3 months after radiotherapy) did not differ significantly between the groups, apart from more late grade 2 or worse blood or bone marrow events in group 3 versus group 2 (one-sided p=0·0060) attributable to the addition of PLNRT in this group. INTERPRETATION: The results of this randomised trial establish the benefit of adding short-term ADT to PBRT to prevent progression in prostate cancer. To our knowledge, these are the first such findings to show that extending salvage radiotherapy to treat the pelvic lymph nodes when combined with short-term ADT results in meaningful reductions in progression after prostatectomy in patients with prostate cancer. FUNDING: National Cancer Institute.

Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.

The tumor immune microenvironment (TIME) is commonly infiltrated by diverse collections of myeloid cells. Yet, the complexity of myeloid-cell identity and plasticity has challenged efforts to define bona fide populations and determine their connections to T-cell function and their relationship to patient outcome. Here, we have leveraged single-cell RNA-sequencing analysis of several mouse and human tumors and found that monocyte-macrophage diversity is characterized by a combination of conserved lineage states as well as transcriptional programs accessed along the differentiation trajectory. We also found in mouse models that tumor monocyte-to-macrophage progression was profoundly tied to regulatory T cell (Treg) abundance. In human kidney cancer, heterogeneity in macrophage accumulation and myeloid composition corresponded to variance in, not only Treg density, but also the quality of infiltrating CD8+ T cells. In this way, holistic analysis of monocyte-to-macrophage differentiation creates a framework for critically different immune states.

PurposeFunctional outcomes have been proposed for assessing quality of pediatric trauma care. Outcomes assessments often rely on Abbreviated Injury Scale (AIS) severity scores to adjust for injury characteristics, but the relationship between AIS severity and functional impairment is unknown. This study's primary aim was to quantify functional impairment associated with increasing AIS severity scores within body regions. The secondary aim was to assess differences in impairment between body regions based on AIS severity.MethodsChildren with serious (AIS≥ 3) isolated body region injuries enrolled in a multicenter prospective study were analyzed. The primary outcome was functional status at discharge measured using the Functional Status Scale (FSS). Discharge FSS was compared (1) within each body region across increasing AIS severity scores, and (2) between body regions for injuries with matching AIS scores.ResultsThe study included 266 children, with 16% having abnormal FSS at discharge. Worse FSS was associated with increasing AIS severity only for spine injuries. Abnormal FSS was observed in a greater proportion of head injury patients with a severely impaired initial Glasgow Coma Scale (GCS) (GCS

BackgroundLower respiratory tract infections (LRTI) are a leading cause of critical illness and mortality in mechanically ventilated children; however, the pathogenic microbes frequently remain unknown. We combined traditional diagnostics with metagenomic next generation sequencing (mNGS) to evaluate the cause of LRTI in critically ill children.MethodsWe conducted a prospective, multicentre cohort study of critically ill children aged 31 days to 17 years with respiratory failure requiring mechanical ventilation (>72 h) in the USA. By combining bacterial culture and upper respiratory viral PCR testing with mNGS of tracheal aspirate collected from all patients within 24 h of intubation, we determined the prevalence, age distribution, and seasonal variation of viral and bacterial respiratory pathogens detected by either method in children with or without LRTI.FindingsBetween Feb 26, 2015, and Dec 31, 2017, of the 514 enrolled patients, 397 were eligible and included in the study (276 children with LRTI and 121 with no evidence of LRTI). A presumptive microbiological cause was identified in 255 (92%) children with LRTI, with respiratory syncytial virus (127 [46%]), Haemophilus influenzae (70 [25%]), and Moraxella catarrhalis (65 [24%]) being most prevalent. mNGS identified uncommon pathogens including Ureaplasma parvum and Bocavirus. Co-detection of viral and bacterial pathogens occurred in 144 (52%) patients. Incidental carriage of potentially pathogenic microbes occurred in 82 (68%) children without LRTI, with rhinovirus (30 [25%]) being most prevalent. Respiratory syncytial virus (p