MiRNAs from the Dlk1-Dio3 locus and miR-224/452 cluster contribute to glioblastoma tumor heterogeneity.

Glioblastoma is one of the most common and aggressive brain tumors and has seen few improvements in patient outcomes. Inter-tumor heterogeneity between tumors of different patients as well as intra-tumor heterogeneity of cells within the same tumor challenge the development of effective drugs. MiRNAs play an essential role throughout the developing brain and regulate many key genes involved in oncogenesis, yet their role in driving many of the processes underlying tumor heterogeneity remains unclear. In this study, we highlight miRNAs from the Dlk1-Dio3 and miR-224/452 clusters which may be expressed cell autonomously and have expression that is associated with cell state genes in glioblastoma, most prominently in neural progenitor-like and mesenchymal-like states respectively. These findings implicate these miRNA clusters as potential regulators of glioblastoma intra-tumoral heterogeneity and may serve as valuable biomarkers for cell state identification.

Beyond Men's Experiences: Scale Development and Psychometric Testing of the Fitness in Nursing Scale-Men (FiNS-M).

Background and Purpose: Men believe they are perceived as unfit for nursing. No scales exist to measure perceptions of men's fitness for nursing. Additionally, women have been largely excluded from this area of inquiry. This study's purpose was to develop and test the psychometric properties of the Fitness in Nursing Scale for Men. Methods: Six hundred thirty-five nurses participated. Scale development entailed concept clarification, item development, and scale testing. Results: Confirmatory factor analysis suggested a two-factor structure (F1: nursing fitness and F2: strengths of men in nursing) which demonstrated good model fit, root mean square error of approximation = .059, 90% CI (.056, .063), standardized root mean square residual = .055, comparative fit index = .932, Tucker-Lewis index = .927, and ωt = .98. Invariance held. Latent means were not significantly different for women (M = 5.90) compared with men (M = 5.92). Conclusions: Findings suggest men are perceived as fit for nursing, but results are inconsistent with men's qualitative experiences. Future research should attempt to reconcile the disagreement. Findings can inform cultural awareness strategies in the workplace and classroom.

In vivo activity of the second-generation proteasome inhibitor ixazomib against pediatric T-cell acute lymphoblastic leukemia xenografts.

The overall survival rate of patients with T-cell acute lymphoblastic leukemia (T-ALL) is now 90%, although patients with relapsed T-ALL face poor prognosis. The ubiquitin-proteasome system maintains normal protein homeostasis, and aberrations in this pathway are associated with T-ALL. Here we demonstrate the in vitro and in vivo activity of ixazomib, a second-generation orally available, reversible, and selective proteasome inhibitor against pediatric T-ALL cell lines and patient-derived xenografts (PDXs) grown orthotopically in immunodeficient NOD.Cg-PrkdcscidIL2rgtm1Wjl/SzJAusb (NSG) mice. Ixazomib was highly potent in vitro, with half-maximal inhibitory concentration (IC50) values in the low nanomolar range. As a monotherapy, ixazomib significantly extended mouse event-free survival of five out of eight T-ALL PDXs in vivo.

Nursing practice in modern healthcare environments: A systematic review of attributes, characteristics, and demonstrations.

AIM: To identify Attributes, Characteristics and Demonstrations of nursing practice from both nurses' and people perspectives in today's healthcare environments. A secondary aim was to identify relevant differences between female and male nurses in the context of ACDs. DESIGN: This systematic review was informed by the Joanna Briggs Institute Convergent Integrated Approach to Mixed Study Systematic Reviews. METHODS: The search included articles ranging from the years 2000 to 2023 across 10 electronic databases and multiple grey literature outlets. McMaster critical review forms and the Mixed Methods Appraisal Tool were used to appraise article quality. The Convergent Integrated Approach to Mixed Study Systematic Reviews was used to guide data synthesis. RESULTS: Twenty articles were included in this review, 13 qualitative, five quantitative and two mixed-methods studies. Three themes emerged, including knowledge, practice skills and interpersonal relationships. Differences in Attributes, Characteristics and Demonstrations of professional practice between women and men in nursing were also explored. CONCLUSION: Findings suggest that evolving healthcare environments challenge nurses to remain focused on patient-centred and compassionate care. The review also supports nurses caring in a manner that empowers people, increases well-being, and reduces suffering. IMPACT: Identified characteristics and attributes of nursing practice, including emphasis on continuous learning, interpersonal relationships and compassion, have a profound impact on nursing. Nurses should remain adaptable, compassionate and patient-focused in an ever-evolving healthcare environment. These foundational care principles are necessary for improving patient outcomes, enhancing trust between people and healthcare providers, and increasing inclusivity and diversity in the nursing workforce. WIDER GLOBAL COMMUNITY: Nurses worldwide should strive to embody these attributes to provide high-quality, patient-centred care in an inclusive environment in today's demanding healthcare environment. Gender-specific differences in the perception and expression of professional Attributes, Characteristics and Demonstrations can inform inclusion and diversity efforts in the workplace. REPORTING METHOD: This systematic review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. PATIENT OR PUBLIC CONTRIBUTION: No Patient or Public Contribution.

Variation in the Bandgap of Amorphous Zinc Tin Oxide: Investigating the Thickness Dependence via In Situ STS.

Amorphous transparent conducting oxides (a-TCOs) have seen substantial interest in recent years due to the significant benefits that they can bring to transparent electronic devices. One such material of promise is amorphous ZnxSn1-xOy (a-ZTO). a-ZTO possesses many attractive properties for a TCO such as high transparency in the visible range, tunable charge carrier concentration, electron mobility, and only being composed of common and abundant elements. In this work, we employ a combination of UV-vis spectrophotometry, X-ray photoemission spectroscopy, and in situ scanning tunneling spectroscopy to investigate a 0.33 eV blue shift in the optical bandgap of a-ZTO, which we conclude to be due to quantum confinement effects.

High-performance p-type V2O3 films by spray pyrolysis for transparent conducting oxide applications.

High-quality epitaxial p-type V2O3 thin films have been synthesized by spray pyrolysis. The films exhibited excellent electrical performance, with measurable mobility and high carrier concentration. The conductivity of the films varied between 115 and 1079 Scm-1 while the optical transparency of the films ranged from 32 to 65% in the visible region. The observed limitations in thinner films' mobility were attributed to the nanosized granular structure and the presence of two preferred growth orientations. The 60 nm thick V2O3 film demonstrated a highly competitive transparency-conductivity figure of merit compared to the state-of-the-art.

A Review of Neural Data and Modelling to Explain How a Semicircular Canal Dehiscence (SCD) Causes Enhanced VEMPs, Skull Vibration Induced Nystagmus (SVIN), and the Tullio Phenomenon.

Angular acceleration stimulation of a semicircular canal causes an increased firing rate in primary canal afferent neurons that result in nystagmus in healthy adult animals. However, increased firing rate in canal afferent neurons can also be caused by sound or vibration in patients after a semicircular canal dehiscence, and so these unusual stimuli will also cause nystagmus. The recent data and model by Iversen and Rabbitt show that sound or vibration may increase firing rate either by neural activation locked to the individual cycles of the stimulus or by slow changes in firing rate due to fluid pumping ("acoustic streaming"), which causes cupula deflection. Both mechanisms will act to increase the primary afferent firing rate and so trigger nystagmus. The primary afferent data in guinea pigs indicate that in some situations, these two mechanisms may oppose each other. This review has shown how these three clinical phenomena-skull vibration-induced nystagmus, enhanced vestibular evoked myogenic potentials, and the Tullio phenomenon-have a common tie: they are caused by the new response of semicircular canal afferent neurons to sound and vibration after a semicircular canal dehiscence.

In vivo activity of the dual SYK/FLT3 inhibitor TAK-659 against pediatric acute lymphoblastic leukemia xenografts.

BACKGROUND: While children with acute lymphoblastic leukemia (ALL) experience close to a 90% likelihood of cure, the outcome for certain high-risk pediatric ALL subtypes remains dismal. Spleen tyrosine kinase (SYK) is a prominent cytosolic nonreceptor tyrosine kinase in pediatric B-lineage ALL (B-ALL). Activating mutations or overexpression of Fms-related receptor tyrosine kinase 3 (FLT3) are associated with poor outcome in hematological malignancies. TAK-659 (mivavotinib) is a dual SYK/FLT3 reversible inhibitor, which has been clinically evaluated in several other hematological malignancies. Here, we investigate the in vivo efficacy of TAK-659 against pediatric ALL patient-derived xenografts (PDXs). METHODS: SYK and FLT3 mRNA expression was quantified by RNA-seq. PDX engraftment and drug responses in NSG mice were evaluated by enumerating the proportion of human CD45+ cells (%huCD45+ ) in the peripheral blood. TAK-659 was administered per oral at 60 mg/kg daily for 21 days. Events were defined as %huCD45+ ≥ 25%. In addition, mice were humanely killed to assess leukemia infiltration in the spleen and bone marrow (BM). Drug efficacy was assessed by event-free survival and stringent objective response measures. RESULTS: FLT3 and SYK mRNA expression was significantly higher in B-lineage compared with T-lineage PDXs. TAK-659 was well tolerated and significantly prolonged the time to event in six out of eight PDXs tested. However, only one PDX achieved an objective response. The minimum mean %huCD45+ was significantly reduced in five out of eight PDXs in TAK-659-treated mice compared with vehicle controls. CONCLUSIONS: TAK-659 exhibited low to moderate single-agent in vivo activity against pediatric ALL PDXs representative of diverse subtypes.

In vivo activity of the dual PI3Kδ and PI3Kγ inhibitor duvelisib against pediatric acute lymphoblastic leukemia xenografts.

BACKGROUND: Acute lymphoblastic leukemia (ALL) remains one of the most common causes of cancer-related mortality in children. Phosphoinositide 3-kinases (PI3Ks) are a family of lipid kinases, and aberrations in the PI3K pathway are associated with several hematological malignancies, including ALL. Duvelisib (Copiktra) is an orally available, small molecule dual inhibitor of PI3Kδ and PI3Kγ, that is Food and Drug Administration (FDA) approved for the treatment of relapsed/refractory chronic lymphocytic leukemia and small lymphocytic lymphoma. Here, we report the efficacy of duvelisib against a panel of pediatric ALL patient-derived xenografts (PDXs). PROCEDURES: Thirty PDXs were selected for a single mouse trial based on PI3Kδ (PIK3CD) and PI3Kγ (PIK3CG) expression and mutational status. PDXs were grown orthotopically in NSG (NOD.Cg-Prkdcscid IL2rgtm1Wjl /SzJAusb) mice, and engraftment was evaluated by enumerating the proportion of human versus mouse CD45+ cells (%huCD45+ ) in the peripheral blood. Treatment commenced when the %huCD45+ reached greater than or equal to 1%, and events were predefined as %huCD45+ greater than or equal to 25% or leukemia-related morbidity. Duvelisib was administered per oral (50 mg/kg, twice daily for 28 days). Drug efficacy was assessed by event-free survival and stringent objective response measures. RESULTS: PI3Kδ and PI3Kγ mRNA expression was significantly higher in B-lineage than T-lineage ALL PDXs (p-values <.0001). Duvelisib was well-tolerated and reduced leukemia cells in the peripheral blood in four PDXs, but with only one objective response. There was no obvious relationship between duvelisib efficacy and PI3Kδ or PI3Kγ expression or mutation status, nor was the in vivo response to duvelisib subtype dependent. CONCLUSIONS: Duvelisib demonstrated limited in vivo activity against ALL PDXs.

First evidence of the link between internal and external structure of the human inner ear otolith system using 3D morphometric modeling.

Our sense of balance is among the most central of our sensory systems, particularly in the evolution of human positional behavior. The peripheral vestibular system (PVS) comprises the organs responsible for this sense; the semicircular canals (detecting angular acceleration) and otolith organs (utricle and saccule; detecting linear acceleration, vibration, and head tilt). Reconstructing vestibular evolution in the human lineage, however, is problematic. In contrast to considerable study of the canals, relationships between external bone and internal membranous otolith organs (otolith system) remain largely unexplored. This limits our understanding of vestibular functional morphology. This study combines spherical harmonic modeling and landmark-based shape analyses to model the configuration of the human otolith system. Our approach serves two aims: (1) test the hypothesis that bony form covaries with internal membranous anatomy; and (2) create a 3D morphometric model visualizing bony and membranous structure. Results demonstrate significant associations between bony and membranous tissues of the otolith system. These data provide the first evidence that external structure of the human otolith system is directly related to internal anatomy, suggesting a basic biological relationship. Our results visualize this structural relationship, offering new avenues into vestibular biomechanical modeling and assessing the evolution of the human balance system.

Symptom experiences in hypertension: a mixed methods systematic review.

AIM: Understanding patients' hypertension (HTN) symptoms can assist healthcare professionals' awareness of individual, cultural, and behavioral responses and improve diagnostic accuracy to optimize treatment. The purpose of this review was to evaluate and synthesize current literature exploring HTN symptoms. METHODS: Databases searched included MEDLINE (PubMed), CINAHL (EBSCO), Scopus, and Web of Science from January 2010 to January 2022. The search followed the Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. The McMaster critical review forms were used to determine the quality of both qualitative and quantitative articles. Synthesis of the data was guided by the Joanna Briggs Institute Convergent Integrated Approach to Mixed Study Systematic Reviews. RESULTS: In total, 41 articles were included, nine qualitative studies and 32 quantitative. The quality of the articles varied. Symptoms included commonly reported symptoms and some less prevalent, including some reporting absence of symptoms. Factors that affected symptoms included culture, beliefs, psychosocial factors, and knowledge. We also found that there may be a bidirectional relationship between symptoms and behaviors that may lead to self-management. CONCLUSION: HTN is common and symptoms are frequently reported. HTN management is related to multiple factors. Symptoms continue in a number of individuals after initial diagnosis. Evaluating symptoms after initial diagnosis may help to optimally manage and meet blood pressure guidelines.

Location of out-of-hospital cardiac arrests and automated external defibrillators in relation to schools in an English ambulance service region.

Introduction: This study sought to identify the availability of automated external defibrillators (AEDs) in schools in the region served by West Midlands Ambulance Service University NHS Trust (WMAS), United Kingdom, and the number of out-of-hospital cardiac arrests (OHCA) that occurred at or near to schools. A secondary aim was to explore the cost effectiveness of school-based defibrillators. Methods: This observational study used data from the national registry for OHCA (University of Warwick) to identify cases occurring at or near schools between January 2014 and December 2016 in WMAS region (n = 11,399). A school survey (n = 2,453) was carried out in September 2017 to determine the presence of AEDs and their registration status with WMAS. Geographical Information System mapping software identified OHCAs occurring within a 300-metre radius of a school. An economic analysis calculated the cost effectiveness of school-based AEDs. Results: A total of 39 (0.34%) of all OHCAs occurred in schools, although 4,250 (37.3%) of OHCAs in the region were estimated to have occurred within 300 metres of a school. Of 323 school survey responses, 184 (57%) had an AED present, of which 24 (13.0%) were available 24 h/day. Economic modelling of a school-based AED programme showed additional quality-adjusted life years (QALY) of 0.26 over the lifetime of cardiac arrest survivors compared with no AED programme. The incremental cost-effectiveness ratio (ICER) was £8,916 per QALY gained. Conclusion: Cardiac arrests in schools are rare. Registering AEDs with local Emergency Medical Services and improving their accessibility within their local community would increase their utility.

Insights into Inner Ear Function and Disease Through Novel Visualization of the Ductus Reuniens, a Seminal Communication Between Hearing and Balance Mechanisms.

The sensory end-organs responsible for hearing and balance in the mammalian inner ear are connected via a small membranous duct known as the ductus reuniens (also known as the reuniting duct (DR)). The DR serves as a vital nexus linking the hearing and balance systems by providing the only endolymphatic connection between the cochlea and vestibular labyrinth. Recent studies have hypothesized new roles of the DR in inner ear function and disease, but a lack of knowledge regarding its 3D morphology and spatial configuration precludes testing of such hypotheses. We reconstructed the 3D morphology of the DR and surrounding anatomy using osmium tetroxide micro-computed tomography and digital visualizations of three human inner ear specimens. This provides a detailed, quantitative description of the DR's morphology, spatial relationships to surrounding structures, and an estimation of its orientation relative to head position. Univariate measurements of the DR, inner ear, and cranial planes were taken using the software packages 3D Slicer and Zbrush. The DR forms a narrow, curved, flattened tube varying in lumen size, shape, and wall thickness, with its middle third being the narrowest. The DR runs in a shallow bony sulcus superior to the osseus spiral lamina and adjacent to a ridge of bone that we term the "crista reuniens" oriented posteromedially within the cranium. The DR's morphology and structural configuration relative to surrounding anatomy has important implications for understanding aspects of inner ear function and disease, particularly after surgical alteration of the labyrinth and potential causative factors for Ménière's disease.

Effectiveness of alternative shock strategies for out-of-hospital cardiac arrest: A systematic review.

Aim: To determine the optimal first-shock energy level for biphasic defibrillation and whether fixed or escalating protocols for subsequent shocks are most effective. Methods: We searched Medline, Embase, Cochrane CENTRAL, CINAHL, the Web of Science and national and international trial registry databases for papers published from database inception to January 2022. We reviewed reference lists of key papers to identify additional references. The population included adults sustaining non traumatic out-of-hospital cardiac arrest subject to attempted defibrillation. Studies of internal or monophasic defibrillation and studies other than randomised controlled trials or prospective cohorts were excluded. Two reviewers assessed study relevance. Data extraction and risk of bias assessment, using the ROBINS-I tool, were conducted by one reviewer and checked by a second reviewer. Data underwent intention-to-treat analysis. Results: We identified no studies evaluating first shock energy. Only one study (n = 738) comparing fixed versus escalating energy met eligibility criteria: a prospective cohort analysis of a randomised controlled trial of manual versus mechanical CPR. High fixed (360 J) energy was compared with an escalating (200-200/300-360 J) strategy. Researchers found 27.5% (70/255) of patients in the escalating energy group and 27.61% (132/478) in the fixed high energy group survived to hospital discharge (unadjusted risk ratio 0.99, 95% CI 0.73, 1.23). Results were of very low certainty as the study was at serious risk of bias. Conclusion: This systematic review did not identify an optimal first-shock energy for biphasic defibrillation. We identified no survival advantage at 30 days when comparing 360 J fixed with 200 J escalating strategy.

Nasopharyngeal morphology contributes to understanding the "muddle in the middle" of the Pleistocene hominin fossil record.

The late archeologist Glynn Isaac first applied the term "muddle in the middle" to a poorly understood period in the Middle Pleistocene human fossil record. This study uses the nasopharyngeal boundaries as a source of traits that may inform this unclear period of human evolution. The nasopharynx lies at the nexus of several vital physiological systems, yet relatively little is known about its importance in human evolution. We analyzed a geographically diverse contemporary Homo sapiens growth series (n = 180 adults, 237 nonadults), Homo neanderthalensis (La Chapelle aux Saints 1, La Ferrassie 1, Forbes Quarry 1, Monte Circeo 1, and Saccopastore 1), mid-Pleistocene Homo (Atapuerca 5, Kabwe 1, Petralona 1, and Steinheim 1), and two Homo erectus sensu lato (KNM-ER 3733 and Sangiran 17). Methods include traditional (Analysis 1) and 3D geometric morphometric analysis (Analysis 2). H. erectus exhibited tall, narrow nasopharyngeal shape, a robust, ancestral morphology. Kabwe 1 and Petralona 1 plotted among H. sapiens in Analysis 2, exhibiting relatively shorter and vertical cartilaginous Eustachian tubes and vertical medial pterygoid plates. Atapuerca 5 and Steinheim 1 exhibited horizontal vomeral orientation similar to H. neanderthalensis, indicating greater relative soft palate length and anteroposterior nasopharynx expansion. They may exhibit synapomorphies with H. neanderthalensis, supporting the accretionary hypothesis. Species-level differences were found among H. sapiens and H. neanderthalensis, including relatively longer dilator tubae muscles and extreme facial airorhynchy among Neanderthals. Furthermore, H. neanderthalensis were autapomorphic in exhibiting horizontal pterygoid plate orientation similar to human infants, suggesting that they may have had inferiorly low placement of the torus tubarius and Eustachian tube orifice on the lateral nasopharyngeal wall in life. This study supports use of osseous nasopharyngeal boundaries both for morphological characters and understanding evolution of otitis media susceptibility in living humans.

Optimizing outcomes after out-of-hospital cardiac arrest with innovative approaches to public-access defibrillation: A scientific statement from the International Liaison Committee on Resuscitation.

Out-of-hospital cardiac arrest is a global public health issue experienced by ≈3.8 million people annually. Only 8% to 12% survive to hospital discharge. Early defibrillation of shockable rhythms is associated with improved survival, but ensuring timely access to defibrillators has been a significant challenge. To date, the development of public-access defibrillation programs, involving the deployment of automated external defibrillators into the public space, has been the main strategy to address this challenge. Public-access defibrillator programs have been associated with improved outcomes for out-of-hospital cardiac arrest; however, the devices are used in <3% of episodes of out-of-hospital cardiac arrest. This scientific statement was commissioned by the International Liaison Committee on Resuscitation with 3 objectives: (1) identify known barriers to public-access defibrillator use and early defibrillation, (2) discuss established and novel strategies to address those barriers, and (3) identify high-priority knowledge gaps for future research to address. The writing group undertook systematic searches of the literature to inform this statement. Innovative strategies were identified that relate to enhanced public outreach, behavior change approaches, optimization of static public-access defibrillator deployment and housing, evolved automated external defibrillator technology and functionality, improved integration of public-access defibrillation with existing emergency dispatch protocols, and exploration of novel automated external defibrillator delivery vectors. We provide evidence- and consensus-based policy suggestions to enhance public-access defibrillation and guidance for future research in this area.

A systematic meta-review of systematic reviews about interprofessional collaboration: facilitators, barriers, and outcomes.

Interprofessional collaboration (IPC) is a practice model to promote healthcare quality. Since the World Health Organization highlighted the importance of IPC in 2010, a large volume of IPC-related research has been published. Multiple systematic reviews have been conducted to synthesize the literature from varying perspectives. Although systematic reviews are a compelling approach to synthesizing primary research, a systematic meta-review was needed to summarize the systematic reviews to offer information for healthcare professionals, researchers, and policymakers. This systematic meta-review was designed to synthesize the systematic reviews of IPC, emphasizing the IPC-related facilitators, barriers, and outcomes between 2010 and 2020. An electronic search for systematic reviews was performed in December 2020. The databases searched included PubMed, CINAHL, PsycINFO, and Cochrane Database of Systematic Reviews. Thirty-six systematic reviews met the inclusion criteria. Factors facilitating or impeding IPC were classified into three levels: organization, team, and individual. Major outcomes related to patients, healthcare professionals, and organizations. The facilitators, barriers, and outcomes are mutually interrelated. Highly effective collaboration is a process from relationship building to working together and collaborating. Improving IPC requires organizational, teams, and individuals' combined efforts. When highly effective collaborations occur, all stakeholders can benefit - organizations, professionals, and patients.

Optimizing Outcomes After Out-of-Hospital Cardiac Arrest With Innovative Approaches to Public-Access Defibrillation: A Scientific Statement From the International Liaison Committee on Resuscitation.

Out-of-hospital cardiac arrest is a global public health issue experienced by ≈3.8 million people annually. Only 8% to 12% survive to hospital discharge. Early defibrillation of shockable rhythms is associated with improved survival, but ensuring timely access to defibrillators has been a significant challenge. To date, the development of public-access defibrillation programs, involving the deployment of automated external defibrillators into the public space, has been the main strategy to address this challenge. Public-access defibrillator programs have been associated with improved outcomes for out-of-hospital cardiac arrest; however, the devices are used in <3% of episodes of out-of-hospital cardiac arrest. This scientific statement was commissioned by the International Liaison Committee on Resuscitation with 3 objectives: (1) identify known barriers to public-access defibrillator use and early defibrillation, (2) discuss established and novel strategies to address those barriers, and (3) identify high-priority knowledge gaps for future research to address. The writing group undertook systematic searches of the literature to inform this statement. Innovative strategies were identified that relate to enhanced public outreach, behavior change approaches, optimization of static public-access defibrillator deployment and housing, evolved automated external defibrillator technology and functionality, improved integration of public-access defibrillation with existing emergency dispatch protocols, and exploration of novel automated external defibrillator delivery vectors. We provide evidence- and consensus-based policy suggestions to enhance public-access defibrillation and guidance for future research in this area.