The GATA2 transcriptional network is requisite for RAS oncogene-driven non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most frequent cause of cancer deaths worldwide; nearly half contain mutations in the receptor tyrosine kinase/RAS pathway. Here we show that RAS-pathway mutant NSCLC cells depend on the transcription factor GATA2. Loss of GATA2 reduced the viability of NSCLC cells with RAS-pathway mutations, whereas wild-type cells were unaffected. Integrated gene expression and genome occupancy analyses revealed GATA2 regulation of the proteasome, and IL-1-signaling, and Rho-signaling pathways. These pathways were functionally significant, as reactivation rescued viability after GATA2 depletion. In a Kras-driven NSCLC mouse model, Gata2 loss dramatically reduced tumor development. Furthermore, Gata2 deletion in established Kras mutant tumors induced striking regression. Although GATA2 itself is likely undruggable, combined suppression of GATA2-regulated pathways with clinically approved inhibitors caused marked tumor clearance. Discovery of the nononcogene addiction of KRAS mutant lung cancers to GATA2 presents a network of druggable pathways for therapeutic exploitation.

Treatment with inhaled aerosolised ethanol reduces viral load and potentiates macrophage responses in an established influenza mouse model.

AIM: Treatment options for viral lung infections are currently limited. We aimed to explore the safety and efficacy of inhaled ethanol in an influenza-infection mouse model. MATERIALS AND METHODS: In a safety and tolerability experiment, 80 healthy female BALB/c mice (20 per group) were exposed to nebulized saline (control) or three concentrations of ethanol (40/60/80% ethanol v/v in water) for 3x30-minute periods, with a two-hour break between exposures. In a separate subsequent experiment, 40 Female BALB/c mice were nasally inoculated with 104.5 plaque-forming units of immediate virulence "Mem71" influenza. Infection was established for 48-h before commencing treatment in 4 groups of 10 mice with either nebulized saline (control) or one of 3 different concentrations of ethanol (40/60/80% ethanol v/v in water) for 3x30-minute periods daily over three consecutive days. In both experiments, mouse behavior, clinical scores, weight change, bronchoalveolar lavage cell viability, cellular composition, and cytokine levels, were assessed 24-h following the final exposure, with viral load also assessed after the second experiment. RESULTS: In uninfected BALB/c mice, 3x30-minute exposures to nebulized 40%, 60%, and 80% ethanol resulted in no significant differences in mouse weights, cell counts/viability, cytokines, or morphometry measures. In Mem71-influenza infected mice, we observed a dose-dependent reduction in viral load in the 80%-treated group and potentiation of macrophage numbers in the 60%- and 80%-treated groups, with no safety concerns. CONCLUSIONS: Our data provides support for inhaled ethanol as a candidate treatment for respiratory infections.

Does pre-injury anticoagulation make chest tubes any less safe? A nationwide retrospective analysis.

BACKGROUND: Oral anticoagulation is becoming more common with the aging population, which raises concern for the risk of invasive procedures that can cause bleeding, such as chest tube placement (thoracostomy). With the increase in CT imaging, more pneumothoraces and hemothoraces are being identified. The relative risk of thoracostomy in the presence of anticoagulation is not well-established. The objective of this study was to determine whether pre-injury anticoagulation affects the relative risk of tube thoracostomy following significant chest trauma. METHODS: This retrospective cohort study used data from the 2019 American College of Surgeons-Trauma Quality Program (ACS-TQP) database using R version 4.2.2. Data from the database was filtered based on inclusion and exclusion criteria. Outcomes were then assessed with the population of interest. Demographics, vitals, comorbidities, and injury parameters were also collected for each patient. This study included all adult patients (≥18 years) presenting with traumatic hemothorax, pneumothorax, or hemopneumothorax. Patients with missing data in demographics, vitals, comorbidities, injury parameters, or outcomes, as well as those with no signs of life upon arrival, were excluded from the study. Patients were stratified into groups based on whether they had pre-injury anticoagulation and whether they had a chest tube placed in the hospital. The primary outcome was mortality, and the secondary outcome was hospital length of stay (LOS). Logistic and standard regressions were used by a statistician to control for age, sex, and Injury Severity Score (ISS). RESULTS: Our study population included 72,385 patients (4250 with pre-injury anticoagulation and 68,135 without pre-injury anticoagulation). Pre-injury anticoagulation and thoracostomy were each independently associated with increased mortality and LOS. However, there was a non-significant interaction term between pre-injury anticoagulation and thoracostomy for both outcomes, indicating that their combined effects on mortality and LOS did not differ significantly from the sum of their individual effects. CONCLUSION: This study suggests that both pre-injury anticoagulation and thoracostomy are risk factors for mortality and increased LOS in adult patients presenting with hemothorax, pneumothorax, or hemopneumothorax, but they do not interact with each other. We recommend further study of this phenomenon to potentially improve clinical guidelines. LEVEL OF EVIDENCE: Therapeutic, Level III.

Exploring the structure of relative age effects research using citation network analysis.

Since the 1980s, research on relative age effects (RAEs) consistently shows that relatively older individuals are advantaged in sport and other contexts. With the recent proliferation of studies on RAEs, periodic knowledge synthesis becomes imperative. Our purpose was to conduct a cross-disciplinary citation network analysis of RAEs literature to enhance our knowledge of RAEs citation structures and the interconnectivity of RAEs studies. We analysed 484 RAEs articles found in Web of Science that were published before 2022. Descriptive results revealed a 12.6% annual growth rate for total RAEs articles published since 1980. The articles appeared in 151 journals, had 1,180 unique authors, and averaged 23.9 citations received. Three theoretical/review papers had the most substantial influence on the field. For the conceptual structure of the field, it was apparent that RAEs research focused mainly on sport performance, maturity, and competition. Regarding intellectual structure, three distinct clusters of articles were cited together, and 13 authorship clusters were detected with few between-cluster connections. The results describe a field with productivity but little interconnectivity among authors and papers. We offer insights into this trend and the role that influential authors/articles have in the field.

ED/hospital program contributions to community multi-disciplinary team meetings: Different models.

Elder mistreatment (EM) is a complex problem, with response and prevention requiring contributions from professionals from many disciplines. Community-based multi-disciplinary teams (MDTs) that conduct meetings to discuss challenging cases and coordinate services are a common strategy to ensure effective collaboration. Though they play an important role in EM identification, intervention, and prevention, hospitals and hospital-based healthcare professionals have been particularly difficult to engage in MDTs. Two hospitals in different communities recently launched Emergency Department (ED)/hospital-based response teams to consult in cases of potential EM, and both participate in MDTs. We explored similarities and differences between the MDTs in these communities including in the role of the ED/hospital-based response team. The comparison demonstrates both core common features as well as large variations. These differences reflect different circumstances in the models on which they were based, on MDT development in these communities, available resources and infrastructure, and the ED/hospital program's role.

Strategies for dissemination of ED/hospital elder mistreatment response team model.

Interdisciplinary Emergency Department/hospital-based teams represent a promising care model to improve identification of and intervention for elder mistreatment. Two institutions, Weill Cornell Medicine/NewYork-Presbyterian Hospital and the University of Colorado Anschutz Medical Campus have launched such programs and are exploring multiple strategies for effective dissemination. These strategies include: (1) program evaluation research, (2) framing as a new model of geriatric care, (3) understanding the existing incentives of health systems, EDs, and hospitals to align with them, (4) connecting to ongoing ED/hospital initiatives, (5) identifying and collaborating with communities with strong elder mistreatment response that want to integrate the ED/hospital, (6) developing and making easily accessible high-quality, comprehensive protocols and training materials, (7) offering technical assistance and support, (8) communications outreach to raise awareness, and (9) using an existing framework to inform implementation in new hospitals and health systems.

Elder abuse geriatrics: describing an important new medical specialist.

Elder mistreatment, including elder abuse and neglect, is a difficult diagnosis to make and manage for most providers. To address this, two elder abuse consultation teams were developed for patients in the hospital and emergency department settings. As these teams have developed, the providers involved have obtained specialized training and experience that we believe contributes to a new field of elder abuse geriatrics, a corollary to the well-established field of child abuse pediatrics. Providers working in this field require specialized training and have a specialized scope of practice that includes forensic evaluation, evaluation of cognition and capacity, care coordination and advocacy for victims of abuse, and collaboration with protective services and law enforcement. Here we describe the training, scope of practice, ethical role, and best practices for elder mistreatment medical consultation. We hope this will serve as a starting point for this new and important medical specialty.

Emergency department and hospital-based programs responding to elder mistreatment: developing consensus about an idea whose time has come.

Elder mistreatment is common, serious, and under-recognized, with Emergency Department and hospital clinical encounters offering a potential but currently unrealized opportunity to identify and help older adults experiencing mistreatment. Interdisciplinary emergency department and hospital-based response teams represent a promising care model to address this. This manuscript describes two such teams and introduces a special issue dedicated to this work.

Physical Educators' Perceptions and Experiences of Teaching Students With Mobility Disabilities.

Schools can support physical education (PE) among students with mobility disabilities (SMDs). However, previous research has indicated that people and resources in the school environment have served as facilitators and barriers to engaging SMDs in PE. Thus, the purpose of this pragmatic, qualitative study was to explore physical educators' perceptions and experiences of teaching SMDs to learn how to develop a PE environment supportive of SMDs. Eleven K-8 PE teachers who taught SMDs engaged in semistructured interviews. A thematic analysis revealed three themes describing facilitators and barriers of a supportive PE environment for SMDs: (a) teacher planning, (b) students in the PE environment, and (c) resources and support. These findings provide context to PE environments for SMDs and highlight a need for increased communication and collaboration with students with or without mobility disabilities, training or professional development for PE teachers to develop skills for adapted PE, and financial and personnel support.

The critical role of the specialized social worker as part of ED/hospital-based elder mistreatment response teams.

The emergency department and hospital provide a unique and important opportunity to identify elder mistreatment and offer intervention. To help manage these complex cases, multi-disciplinary response teams have been launched. In developing these teams, it quickly became clear that social workers play a critical role in responding to elder mistreatment. Their unique skillset allows them to establish close connections with community resources, collaborate with various hospital stakeholders, support patients/families/caregivers through challenging situations, navigate the legal and protective systems, and balance patient safety and quality of life in disposition decision-making. The role of the social worker on these multi-faceted teams includes conducting a comprehensive biopsychosocial assessment, helping to develop a safe discharge plan, and making appropriate referrals, among other responsibilities. Any institution considering developing a multi-disciplinary program should recognize the critical importance of social work.

Bidirectional epithelial-mesenchymal crosstalk provides self-sustaining profibrotic signals in pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is the prototypic progressive fibrotic lung disease with a median survival of 2 to 4 years. Injury to and/or dysfunction of the alveolar epithelium is strongly implicated in IPF disease initiation, but the factors that determine whether fibrosis progresses rather than normal tissue repair occurs remain poorly understood. We previously demonstrated that zinc finger E-box-binding homeobox 1-mediated epithelial-mesenchymal transition in human alveolar epithelial type II (ATII) cells augments transforming growth factor-ß-induced profibrogenic responses in underlying lung fibroblasts via paracrine signaling. Here, we investigated bidirectional epithelial-mesenchymal crosstalk and its potential to drive fibrosis progression. RNA-Seq of lung fibroblasts exposed to conditioned media from ATII cells undergoing RAS-induced epithelial-mesenchymal transition identified many differentially expressed genes including those involved in cell migration and extracellular matrix regulation. We confirmed that paracrine signaling between RAS-activated ATII cells and fibroblasts augmented fibroblast recruitment and demonstrated that this involved a zinc finger E-box-binding homeobox 1-tissue plasminogen activator axis. In a reciprocal fashion, paracrine signaling from transforming growth factor-ß-activated lung fibroblasts or IPF fibroblasts induced RAS activation in ATII cells, at least partially through the secreted protein acidic and rich in cysteine, which may signal via the epithelial growth factor receptor via epithelial growth factor-like repeats. Together, these data identify that aberrant bidirectional epithelial-mesenchymal crosstalk in IPF drives a chronic feedback loop that maintains a wound-healing phenotype and provides self-sustaining profibrotic signals.

Ultrasonic scaling in COVID-era dentistry: A quantitative assessment of aerosol spread during simulated and clinical ultrasonic scaling procedures.

OBJECTIVE: Healthcare agencies recommend limited use of aerosol-generating procedures to mitigate disease (COVID-19) transmission. However, total dispersion patterns of aerosols, particularly respirable droplets, via dental ultrasonic units is unclear. The purpose of this study was to characterize and map total spatter, droplet and aerosol dispersion during ultrasonic scaling in simulated and clinical contexts. METHODS: Ultrasonic scaling was performed on dental simulation units using methylene blue dye-stained water. All resultant stain profiles were photoanalysed to calculate droplet size and travel distance/direction. Airborne particle concentrations were also documented 0-1.2 m (0-4ft.) and 1.2-2.4 m (4-8ft.) from patients during in vivo ultrasonic scaling with a saliva ejector. RESULTS: Stain profiles showed droplets between 25 and 50µm in diameter were most common, with smaller droplets closer to the mouth. In-vivo particle concentrations were uniformly low. The smallest (<1 µm, PM1) and largest (>10 µm, PM10+) particles were most common, especially within 1.2 m (4ft.) of the patient. Respirable particles (PM2.5) were uncommon. CONCLUSIONS: Tests showed the highest concentration of small droplets in zones nearest the patient. While uncommon, particles were detected up to 2.4 m (8ft.) away. Furthermore, observed particle sizes were consistent with those that can carry infectious agents. Efforts to mitigate the spread of inhalable aerosols should emphasize proximate regions nearest the procedure, including personal protective equipment and the use of evacuation devices.

The SIC Scale of Ageism: Confirmatory Factor Analysis, Measurement Invariance, and Revisions.

The present study seeks to confirm the factor structure of the succession, identity, and consumption (SIC) scale of prescriptive ageism as a modern measure of intergenerational ageism, with particular utility for institutionalized ageism and policy in health care, the workplace, and residential facilities. In addition, measurement invariance of the scale is tested for gender and racial/ethnic groups. Confirmatory factor analysis was performed on the scale as initially proposed, treating the items as categorical variables (see for treatment of Likert-type items as categorical). Modifications to the scale were explored using both theoretical and statistical criteria. Measurement invariance tests were run on both gender and racial/ethnic categories. Analyses indicated that the three-factor structure as initially proposed was validated in an undergraduate population. Minor modifications are proposed to improve the performance of the measure. Using comparative fit indices, measurement invariance was established for gender and racial/ethnic groups with mean level scale score differences discussed.

Immune biomarkers predicting bronchiolitis disease severity: A systematic review.

Bronchiolitis is one of the leading causes of hospitalisation in infancy, with highly variable clinical presentations ranging from mild disease safely managed at home to severe disease requiring invasive respiratory support. Identifying immune biomarkers that can predict and stratify this variable disease severity has important implications for clinical prognostication/disposition. A systematic literature search of the databases Embase, PubMed, ScienceDirect, Web of Science, and Wiley Online Library was performed. English language studies that assessed the association between an immune biomarker and bronchiolitis disease severity among children aged less than 24 months were included. 252 distinct biomarkers were identified across 90 studies. A substantial degree of heterogeneity was observed in the bronchiolitis definitions, measures of disease severity, and study designs. 99 biomarkers showed some significant association with disease severity, but only 18 were significant in multiple studies. However, all of these candidate biomarkers had comparable studies that reported conflicting results. Conclusion: The heterogeneity among included studies and the lack of a consistently significant biomarker highlight the need for consensus on bronchiolitis definitions and severity measures, as well as further studies assessing their clinical utility both in isolation and in combination.

The Ice, Cloud, and Land Elevation Satellite - 2 Mission: A Global Geolocated Photon Product Derived From the Advanced Topographic Laser Altimeter System.

The Ice, Cloud, and land Elevation Satellite - 2 (ICESat-2) observatory was launched on 15 September 2018 to measure ice sheet and glacier elevation change, sea ice freeboard, and enable the determination of the heights of Earth's forests. ICESat-2's laser altimeter, the Advanced Topographic Laser Altimeter System (ATLAS) uses green (532 nm) laser light and single-photon sensitive detection to measure time of flight and subsequently surface height along each of its six beams. In this paper, we describe the major components of ATLAS, including the transmitter, the receiver and the components of the timing system. We present the major components of the ICESat-2 observatory, including the Global Positioning System, star trackers and inertial measurement unit. The ICESat-2 Level 1B data product (ATL02) provides the precise photon round-trip time of flight, among other data. The ICESat-2 Level 2A data product (ATL03) combines the photon times of flight with the observatory position and attitude to determine the geodetic location (i.e. the latitude, longitude and height) of the ground bounce point of photons detected by ATLAS. The ATL03 data product is used by higher-level (Level 3A) surface-specific data products to determine glacier and ice sheet height, sea ice freeboard, vegetation canopy height, ocean surface topography, and inland water body height.

Exposure to chorioamnionitis alters the monocyte transcriptional response to the neonatal pathogen Staphylococcus epidermidis.

Preterm infants are uniquely susceptible to late-onset sepsis that is frequently caused by the skin commensal Staphylococcus epidermidis. Innate immune responses, particularly from monocytes, are a key protective mechanism. Impaired cytokine production by preterm infant monocytes is well described, but few studies have comprehensively assessed the corresponding monocyte transcriptional response. Innate immune responses in preterm infants may be modulated by inflammation such as prenatal exposure to histologic chorioamnionitis which complicates 40-70% of preterm pregnancies. Chorioamnionitis alters the risk of late-onset sepsis, but its effect on monocyte function is largely unknown. Here, we aimed to determine the impact of exposure to chorioamnionitis on the proportions and phenotype of cord blood monocytes using flow cytometry, as well as their transcriptional response to live S. epidermidis. RNA-seq was performed on purified cord blood monocytes from very preterm infants (<32 weeks gestation, with and without chorioamnionitis-exposure) and term infants (37-40 weeks), pre- and postchallenge with live S. epidermidis. Preterm monocytes from infants without chorioamnionitis-exposure did not exhibit an intrinsically deficient transcriptional response to S. epidermidis compared to term infants. In contrast, chorioamnionitis-exposure was associated with hypo-responsive transcriptional phenotype regarding a subset of genes involved in antigen presentation and adaptive immunity. Overall, our findings suggest that prenatal exposure to inflammation may alter the risk of sepsis in preterm infants partly by modulation of monocyte responses to pathogens.

Influences of population size and density on birthplace effects.

Contextual influences on talent development (e.g., birthplace effects) have become a topic of interest for sport scientists. Birthplace effects occur when being born in a certain city size leads to participation or performance advantages, typically for those born in smaller or mid-sized cities. The purpose of this study was to investigate birthplace effects in Portuguese volleyball players by analysing city size, as well as population density - an important but infrequently used variable. Participants included 4062 volleyball players (Mage = 33), 53.2% of whom were men. Using Portuguese national census data from 1981, we compared participants (within each sex) across five population categories. In addition, we used ANOVAs to study expertise and population density. Results indicated that men and women athletes born in districts of 200,000-399,999 were 2.4 times more likely to attain elite volleyball status, while all other districts decreased the odds of expert development. For men, being born in high-density areas resulted in less chance of achieving expertise, whereas there were no differences for women. The results suggest that athletes' infrastructure and social structure play an important role in talent development, and that these structures are influenced by total population and population density, respectively.

Pro- and anti-tumour effects of B cells and antibodies in cancer: a comparison of clinical studies and preclinical models.

The primary immune role of B cells is to produce antibodies, but they can also influence T cell function via antigen presentation and, in some contexts, immune regulation. Whether their roles in tumour immunity are similar to those in other chronic immune responses such as autoimmunity and chronic infection, where both pro- and anti-inflammatory roles have been described, remains controversial. Many studies have aimed to define the role of B cells in antitumor immune responses, but despite this considerable body of work, it is not yet possible to predict how they will affect immunity to any given tumour. In many human cancers, the presence of tumour-infiltrating B cells and tumour-reactive antibodies correlates with extended patient survival, and this clinical observation is supported by data from some animal models. On the other hand, T cell responses can be adversely affected by B cell production of immunoregulatory cytokines, a phenomenon that has been demonstrated in humans and in animal models. The isotype and concentration of tumour-reactive antibodies may also influence tumour progression. Recruitment of B cells into tumours may directly reflect the subtype and strength of the anti-tumour T cell response. As the response becomes chronic, B cells may attenuate T cell responses in an attempt to decrease host damage, similar to their described role in chronic infection and autoimmunity. Understanding how B cell responses in cancer are related to the effectiveness of the overall anti-tumour response is likely to aid in the development of new therapeutic interventions against cancer.

Wood dust exposure and lung cancer risk: a meta-analysis.

Occupational lung cancers represent a major health burden due to their increasing prevalence and poor long-term outcomes. While wood dust is a confirmed human carcinogen, its association with lung cancer remains unclear due to inconsistent findings in the literature. We aimed to clarify this association using meta-analysis. We performed a search of 10 databases to identify studies published until June 2014. We assessed the lung cancer risk associated with wood dust exposure as the primary outcome and with wood dust-related occupations as a secondary outcome. Random-effects models were used to pool summary risk estimates. 85 publications were included in the meta-analysis. A significantly increased risk for developing lung cancer was observed among studies that directly assessed wood dust exposure (RR 1.21, 95% CI 1.05 to 1.39, n=33) and that assessed wood dust-related occupations (RR 1.15, 95% CI 1.07 to 1.23, n=59). In contrast, a reduced risk for lung cancer was observed among wood dust (RR 0.63, 95% CI 0.39 to 0.99, n=5) and occupation (RR 0.96, 95% CI 0.95 to 0.98, n=1) studies originating in Nordic countries, where softwood dust is the primary exposure. These results were independent of the presence of adjustment for smoking and exposure classification methods. Only minor differences in risk between the histological subtypes were identified. This meta-analysis provides strong evidence for an association between wood dust and lung cancer, which is critically influenced by the geographic region of the study. The reasons for this region-specific effect estimates remain to be clarified, but may suggest a differential effect for hardwood and softwood dusts.

Randomized Prospective Clinical Trial Comparing Room Temperature and Warmed Intravenous Fluid Boluses on Pediatric Patients' Comfort.

A common complaint among pediatric patients receiving an intravenous (IV) fluid bolus is that their arm feels cold and uncomfortable. The purpose of this study is to test if administering warmed IV fluids, as compared to room temperature IV fluids, results in increased comfort among pediatric patients seeking care in an emergency department. A blinded randomized controlled trial was conducted and 126 pediatric patients were enrolled. Each patient's overall comfort, arm comfort, and arm temperature were measured prior to IV fluid administration, 15 minutes after the beginning of the infusion, and at the end of the 60-minute infusion. After the first 15 minutes of IV fluid administration, the patients who received warmed IV fluids reported higher comfort than the patients who received room temperature IV fluids, t(118)=2.04, p=0.04. Additionally, patients who received the room temperature IV fluids reported that their arms felt cooler than patients who received the warmed fluids, t(118)=3.25, p=0.0015. Warming IV fluids has the potential to improve the experience of IV bolus administration for pediatric patients.