Estimating human pharmacokinetic parameters forelectronic nicotine delivery system products from chemical analyses of their aerosols.

The ability of Electronic Nicotine Delivery Systems (ENDS) to deliver nicotine is central to their function to substitute for cigarettes, allowing people who smoke to switch away from smoking, thus reducing their exposure to harmful chemicals in cigarette smoke. The nicotine concentration in ENDS e-liquid has proved to be a poor predictor of nicotine uptake in users. Using meta-analytic methods to analyze 12 pharmacokinetic studies of nicotine-salt closed-system ENDS, this paper examines whether the mass of nicotine/puff of aerosol can predict Cmax in pharmacokinetic studies. Cmax values were available for 38 products, in 58 use conditions (including both controlled [3 s] and ad libitum puffing), comprising 1769 participant observations. Nicotine/puff data reflected chemical analyses of aerosol obtained under nonintense (3 s) or intense (6 s) machine puffing. Meta-regression analyses (weighted by reliability of Cmax estimate) assessed the relationship of nicotine/puff to Cmax. In some models, empirical data were used to impute the variation in Cmax or the nicotine/puff value under intense puffing. In simple linear models, Cmax was significantly associated with nicotine/puff under all combinations of intense/nonintense and controlled/ad-libitum conditions, with R2 values of 0.71-0.77. More complex models based on quadratic effects or log[nicotine/puff] did not generally improve upon more parsimonious linear models. Application of the model illustrates the divergence between nicotine concentration in e-liquids and expected Cmax when other ENDS parameters vary. The meta-analytic model may have utility in settings where clinical pharmacokinetic data are not available, including product development.

External vs Internal Focus of Attention in Procedural Skills Learning: A Randomized Study.

PURPOSE: The Optimizing Performance Through Intrinsic Motivation and Attention for Learning theory postulates that directing attention to the intended movement effect or outcome (external focus) is more effective than directing attention to the internal body motion or body part (internal focus). This study compared external vs internal focus of attention as novice students learned ultrasound-guided peripheral cannulation. The authors hypothesized that conditions promoting an external (vs internal) focus of attention would result in better performance on immediate and delayed (retention) testing. METHOD: The authors conducted a randomized, experimental study from October 2022 to February 2023 comparing external and internal focus using ultrasound-guided peripheral venous cannulation followed by practice using an ultrasound training block. Undergraduate health science students performed 4 practice trials with instructions to focus on the needle tip (external focus) or their hands (internal focus), followed by an immediate assessment and a retention assessment 2 weeks later. The primary outcome was time to successful cannulation. Results were compared using Kaplan-Meier curves and parametric survival analysis regression (accelerated failure time) models. RESULTS: Seventy participants completed the immediate assessment. The external focus group completed successful cannulation a mean of 2.33 times faster (95% CI = 1.47, 3.67; P < .001) than those in the internal focus group (median time, 12.0 vs 29.5 seconds). Results also favored the external focus group during practice, with the external focus group successfully completing the task a mean of 1.83 times faster (95% CI = 1.04, 3.21; P = .04) than the internal focus group. In the retention assessment, the external focus group successfully completed the task a mean of 2.37 times faster (95% CI = 1.19, 4.74; P = .02) than the internal focus group. CONCLUSIONS: External focus of attention compared with internal focus of attention improves medical motor skill learning in novice learners.

Macroscopic changes in aquaporin-4 underlie blast traumatic brain injury-related impairment in glymphatic function.

Mild traumatic brain injury (mTBI) has emerged as a potential risk factor for the development of neurodegenerative conditions such as Alzheimer's disease and chronic traumatic encephalopathy. Blast mTBI, caused by exposure to a pressure wave from an explosion, is predominantly experienced by military personnel and has increased in prevalence and severity in recent decades. Yet the underlying pathology of blast mTBI is largely unknown. We examined the expression and localization of AQP4 in human post-mortem frontal cortex and observed distinct laminar differences in AQP4 expression following blast exposure. We also observed similar laminar changes in AQP4 expression and localization and delayed impairment of glymphatic function that emerged 28 days following blast injury in a mouse model of repetitive blast mTBI. In a cohort of veterans with blast mTBI, we observed that blast exposure was associated with an increased burden of frontal cortical MRI-visible perivascular spaces, a putative neuroimaging marker of glymphatic perivascular dysfunction. These findings suggest that changes in AQP4 and delayed glymphatic impairment following blast injury may render the post-traumatic brain vulnerable to post-concussive symptoms and chronic neurodegeneration.

Validation of the motivated strategies for learning questionnaire and instructional materials motivation survey.

PURPOSE: To validate the Motivated Strategies for Learning Questionnaire (MSLQ), which measures learner motivations; and the Instructional Materials Motivation Survey (IMMS), which measures the motivational properties of educational activities. METHODS: Participants (333 pharmacists, physicians, and advanced practice providers) completed the MSLQ, IMMS, Congruence-Personalization Questionnaire (CPQ), and a knowledge test immediately following an online learning module (April 2021). We randomly divided data for split-sample analysis using confirmatory factor analysis (CFA), exploratory factor analysis (EFA), and the multitrait-multimethod matrix. RESULTS: Cronbach alpha was ≥0.70 for most domains. CFA using sample 1 demonstrated suboptimal fit for both instruments, including 3 negatively-worded IMMS items with particularly low loadings. Revised IMMS (RIMMS) scores (which omit negatively-worded items) demonstrated better fit. Guided by EFA, we identified a novel 3-domain, 11-item 'MSLQ-Short Form-Revised' (MSLQ-SFR, with domains: Interest, Self-efficacy, and Attribution) and the 4-domain, 12-item RIMMS as the best models. CFA using sample 2 confirmed good fit. Correlations among MSLQ-SFR, RIMMS, and CPQ scores aligned with predictions; correlations with knowledge scores were small. CONCLUSIONS: Original MSLQ and IMMS scores show poor model fit, with negatively-worded items notably divergent. Revised, shorter models-the MSLQ-SFR and RIMMS-show satisfactory model fit (internal structure) and relations with other variables.

Developing a Novel Ontology for Cybersecurity in Internet of Medical Things-Enabled Remote Patient Monitoring.

IoT has seen remarkable growth, particularly in healthcare, leading to the rise of IoMT. IoMT integrates medical devices for real-time data analysis and transmission but faces challenges in data security and interoperability. This research identifies a significant gap in the existing literature regarding a comprehensive ontology for vulnerabilities in medical IoT devices. This paper proposes a fundamental domain ontology named MIoT (Medical Internet of Things) ontology, focusing on cybersecurity in IoMT (Internet of Medical Things), particularly in remote patient monitoring settings. This research will refer to similar-looking acronyms, IoMT and MIoT ontology. It is important to distinguish between the two. IoMT is a collection of various medical devices and their applications within the research domain. On the other hand, MIoT ontology refers to the proposed ontology that defines various concepts, roles, and individuals. MIoT ontology utilizes the knowledge engineering methodology outlined in Ontology Development 101, along with the structured life cycle, and establishes semantic interoperability among medical devices to secure IoMT assets from vulnerabilities and cyberattacks. By defining key concepts and relationships, it becomes easier to understand and analyze the complex network of information within the IoMT. The MIoT ontology captures essential key terms and security-related entities for future extensions. A conceptual model is derived from the MIoT ontology and validated through a case study. Furthermore, this paper outlines a roadmap for future research, highlighting potential impacts on security automation in healthcare applications.

Diverse methodological approaches to a Circumpolar multi-site case study which upholds and responds to local and Indigenous community research processes in the Arctic.

This paper outlines the methodological approaches to a multi-site Circumpolar case study exploring the impacts of COVID-19 on Indigenous and remote communities in 7 of 8 Arctic countries. Researchers involved with the project implemented a three-phase multi-site case study to assess the positive and negative societal outcomes associated with the COVID-19 pandemic in Arctic communities from 2020 to 2023. The goal of the multi-site case study was to identify community-driven models and evidence-based promising practices and recommendations that can help inform cohesive and coordinated public health responses and protocols related to future public health emergencies in the Arctic. Research sites included a minimum of 1 one community each from Canada (Nunavut,) United States of America (Alaska), Greenland, Iceland, Norway, Sweden, Finland. The approaches used for our multi-site case study provide a comprehensive, evidence-based account of the complex health challenges facing Arctic communities, offering insights into the effectiveness of interventions, while also privileging Indigenous local knowledge and voices. The mixed method multi-site case study approach enriched the understanding of unique regional health disparities and strengths during the pandemic. These methodological approaches serve as a valuable resource for policymakers, researchers, and healthcare professionals, informing future strategies and interventions.

Single-Cell RNA Sequencing Reveals Repair Features of Human Umbilical Cord Mesenchymal Stromal Cells.

RATIONALE: The chronic lung disease bronchopulmonary dysplasia (BPD) is the most severe complication of extreme prematurity. BPD results in impaired lung alveolar and vascular development and long-term respiratory morbidity, for which only supportive therapies exist. Umbilical cord-derived mesenchymal stromal cells (UC-MSCs) improve lung structure and function in experimental BPD. Results of clinical trials with MSCs for many disorders do not yet match the promising preclinical studies. A lack of specific criteria to define functionally distinct MSCs persists. OBJECTIVES: To determine and correlate single-cell UC-MSC transcriptomic profile with therapeutic potential. METHODS: UC-MSCs from five term donors and human neonatal dermal fibroblasts (HNDFs, control cells of mesenchymal origin) transcriptomes were investigated by single-cell RNA sequencing analysis (scRNA-seq). The lung-protective effect of UC-MSCs with a distinct transcriptome and control HNDFs was tested in vivo in hyperoxia-induced neonatal lung injury in rats. MEASUREMENTS AND MAIN RESULTS: UC-MSCs showed limited transcriptomic heterogeneity, but were different from HNDFs. Gene ontology enrichment analysis revealed distinct - progenitor-like and fibroblast-like - UC-MSC subpopulations. Only the treatment with progenitor-like UC-MSCs improved lung function and structure and attenuated pulmonary hypertension in hyperoxia-exposed rat pups. Moreover, scRNA-seq identified major histocompatibility complex class I as a molecular marker of non-therapeutic cells and associated with decreased lung retention. CONCLUSIONS: UC-MSCs with a progenitor-like transcriptome, but not with a fibroblast-like transcriptome, provide lung protection in experimental BPD. High expression of major histocompatibility complex class I is associated with reduced therapeutic benefit. scRNA-seq may be useful to identify subsets of MSCs with superior repair capacity for clinical application.

Assessment of management reasoning: Design considerations drawn from analysis of simulated outpatient encounters.

PURPOSE: Management reasoning is a distinct subset of clinical reasoning. We sought to explore features to be considered when designing assessments of management reasoning. METHODS: This is a hybrid empirical research study, narrative review, and expert perspective. In 2021, we reviewed and discussed 10 videos of simulated (staged) physician-patient encounters, actively seeking actions that offered insights into assessment of management reasoning. We analyzed our own observations in conjunction with literature on clinical reasoning assessment, using a constant comparative qualitative approach. RESULTS: Distinguishing features of management reasoning that will influence its assessment include management scripts, shared decision-making, process knowledge, illness-specific knowledge, and tailoring of the encounter and management plan. Performance domains that merit special consideration include communication, integration of patient preferences, adherence to the management script, and prognostication. Additional facets of encounter variation include the clinical problem, clinical and nonclinical patient characteristics (including preferences, values, and resources), team/system characteristics, and encounter features. We cataloged several relevant assessment approaches including written/computer-based, simulation-based, and workplace-based modalities, and a variety of novel response formats. CONCLUSIONS: Assessment of management reasoning could be improved with attention to the performance domains, facets of variation, and variety of approaches herein identified.

Kink bands promote exceptional fracture resistance in a NbTaTiHf refractory medium-entropy alloy.

Single-phase body-centered cubic (bcc) refractory medium- or high-entropy alloys can retain compressive strength at elevated temperatures but suffer from extremely low tensile ductility and fracture toughness. We examined the strength and fracture toughness of a bcc refractory alloy, NbTaTiHf, from 77 to 1473 kelvin. This alloy's behavior differed from that of comparable systems by having fracture toughness over 253 MPa·m1/2, which we attribute to a dynamic competition between screw and edge dislocations in controlling the plasticity at a crack tip. Whereas the glide and intersection of screw and mixed dislocations promotes strain hardening controlling uniform deformation, the coordinated slip of <111> edge dislocations with {110} and {112} glide planes prolongs nonuniform strain through formation of kink bands. These bands suppress strain hardening by reorienting microscale bands of the crystal along directions of higher resolved shear stress and continually nucleate to accommodate localized strain and distribute damage away from a crack tip.

Validation of the Learner Engagement Instrument for Continuing Professional Development.

PURPOSE: Learner engagement is the energy learners exert to remain focused and motivated to learn. The Learner Engagement Instrument (LEI) was developed to measure learner engagement in a short continuing professional development (CPD) activity. The authors validated LEI scores using validity evidence of internal structure and relationships with other variables. METHOD: Participants attended 1 of 4 CPD courses (1 in-person, 2 online livestreamed, and 1 either in-person or online) in 2018, 2020, 2021, and 2022. Confirmatory factor analysis was used to examine model fit for several alternative structural models, separately for each course. The authors also conducted a generalizability study to estimate score reliability. Associations were evaluated between LEI scores and Continuing Medical Education Teaching Effectiveness (CMETE) scores and participant demographics. All statistical methods accounted for repeated measures by participants. RESULTS: 415 unique participants attended 203 different CPD presentations and completed the LEI 11,567 times. The originally hypothesized 4-domain model of learner engagement (domains: emotional, behavioral, cognitive in-class, cognitive out-of-class) demonstrated best model fit in all 4 courses, with Comparative Fit Index ≥0.99, Standardized Root Mean Square Residual ≤0.031, and Root Mean Square Error of Approximation ≤0.047. The reliability for overall scores and domain scores were all acceptable (50-rater G-coefficient ≥ 0.74) except for the cognitive-in-class domain (50-rater G-coefficient 0.55 to 0.66). All findings were similar for both in-person and online delivery modalities. Correlation of LEI scores with teaching effectiveness was confirmed (rho 0.58), and a small correlation was found with participant age (rho 0.19); other associations were small and not statistically significant. Using these findings, we generated a shortened 4-item instrument, the LEI Short Form. CONCLUSIONS: This study confirms a 4-domain model of learner engagement, and provides validity evidence that supports using LEI scores to measure learner engagement in both in-person and livestreamed CPD activities.

Maggots cannot live on meat meal alone: production parameters for mass rearing of the ovoviviparous blowfly, Calliphora dubia (Diptera: Calliphoridae).

This study determined a cost-effective larval diet for rearing Calliphora dubia Macquart for use as a potential managed pollinator in Australia. This fly has potential as a pollination species to support honey bees (Apis mellifera). Larvae of C. dubia were reared mostly in meat meals with varying amounts of either whole egg powder, whole eggs (+ shell), bran flakes, skimmed milk powder, brewer's yeast, or poultry oil. This was done from an economic and production perspective to support commercial rearing. Several laboratory-based studies determined the growth and output from various ingredient combinations. Larvae fed 90% meat meal and 10% whole egg powder developed rapidly through to pupation with a high pupation rate, adult size, and percent adult emergence. Given the high cost and difficulty in sourcing whole egg powder, media comprising mostly meat meals with the addition of bran flakes and whole eggs also supported rapid larval development, pupation rate, and adult emergence. The ideal amount of media/larvae was 0.5 g/larvae to support high pupation rates and adult emergence. Adult eclosion occurred over 4-5 days, even when larvae were laid and fed within 1 h on ample media. Commercial mass rearing would then require daily cohorts of larvae to ensure peak adult fly emergence over 1-2 days for release into a crop. Mass-rearing C. dubia should use meat meal as the base ingredient with bran flakes and whole eggs added and fed at 0.5 g of media/larvae. Based on the current media ingredient costs, rearing 1-m adult C. dubia would cost just over $500 (US$342).

Clinical electromagnetic brain scanner.

Stroke is a leading cause of death and disability worldwide, and early diagnosis and prompt medical intervention are thus crucial. Frequent monitoring of stroke patients is also essential to assess treatment efficacy and detect complications earlier. While computed tomography (CT) and magnetic resonance imaging (MRI) are commonly used for stroke diagnosis, they cannot be easily used onsite, nor for frequent monitoring purposes. To meet those requirements, an electromagnetic imaging (EMI) device, which is portable, non-invasive, and non-ionizing, has been developed. It uses a headset with an antenna array that irradiates the head with a safe low-frequency EM field and captures scattered fields to map the brain using a complementary set of physics-based and data-driven algorithms, enabling quasi-real-time detection, two-dimensional localization, and classification of strokes. This study reports clinical findings from the first time the device was used on stroke patients. The clinical results on 50 patients indicate achieving an overall accuracy of 98% in classification and 80% in two-dimensional quadrant localization. With its lightweight design and potential for use by a single para-medical staff at the point of care, the device can be used in intensive care units, emergency departments, and by paramedics for onsite diagnosis.

Normal Clinical Laboratory Ranges by Age and Sex, and Impact on Study Screening Outcomes in Rural Mali.

The interpretation of a laboratory test result requires an appropriate reference range established in healthy subjects, and normal ranges may vary by factors such as geographic region, sex, and age. We examined hematological and clinical chemistry parameters in healthy residents at two rural vaccine trial sites: Bancoumana and Doneguebougou in Mali, West Africa. During screening of clinical studies in 2018 and 2019, peripheral blood samples from 1,192 apparently healthy individuals age 6 months to 82 years were analyzed at a laboratory accredited by the College of American Pathologists for a complete blood count, and creatinine and/or alanine aminotransferase levels. Based on manufacturers' reference range values, which are currently used in Malian clinical laboratories, abnormal values were common in this healthy population. In fact, 30.4% of adult participants had abnormal neutrophil levels and 19.8% had abnormal hemoglobin levels. Differences by sex were observed in those who were older, but not in those younger than 10 years, for several parameters, including hemoglobin, platelet, and absolute neutrophil counts in hematology, and creatinine in biochemistry. The site-specific reference intervals we report can be used in malaria vaccine clinical trials and other interventional studies, as well as in routine clinical care, to identify abnormalities in hematological and biochemical parameters among healthy Malian trial participants.

CSF ß-Amyloid and Tau Biomarker Changes in Veterans With Mild Traumatic Brain Injury.

BACKGROUND AND OBJECTIVES: Moderate-to-severe traumatic brain injuries (TBI) have been reported to increase the risk of Alzheimer disease (AD). Whether mild TBI (mTBI) in veterans confers a similar increased risk of AD is less known. This study investigated early AD changes using CSF biomarkers in veterans with blast mTBI. METHODS: This was a cross-sectional case-control study of veterans with mTBI and non-mTBI veterans and civilians from 2 study sources. Blast-mTBI veterans had at least 1 war zone blast or combined blast/impact mTBI meeting Veterans Affairs (VA) and Department of Defense (DoD) criteria for mTBI. Non-mTBI participants had no lifetime history of TBI. All participants underwent standardized clinical and neuropsychological assessments and lumbar puncture for collection of the CSF. CSF biomarkers were measured using MesoScale Discovery assays for Aß40 and Aß42 and INNOTEST ELISAs for phosphorylated tau181 (p-tau181) and total tau (t-tau). RESULTS: Our sample comprised 51 participants with mTBI and 85 non-mTBI participants with mean (SD) ages 34.0 (10.1) and 33.5 years (8.9), respectively. All participants but 1 (99%) were male. Differences in CSF AD biomarkers between mTBI and non-mTBI groups were age dependent and most pronounced at older ages (omnibus test p ≤ 0.08). At age 50 years, the mTBI group had lower mean [95% CI] CSF Aß42 and Aß40 than the non-mTBI group by 154 [-12 to 319] and 1864 [610-3,118] pg/mL, respectively. By contrast, CSF p-tau181 and t-tau mean levels remained relatively constant with age in participants with mTBI, while tending to be higher at older ages for the non-mTBI group. The mTBI group also demonstrated poorer cognitive performance at older ages (omnibus p < 0.08): at age 50 years, the mean TMT-B time was higher by 34 seconds [10-58] and the mean CVLT-II short-delay recall was lower by 4.2 points [1.9-6.6]. Poorer verbal memory and verbal fluency performance were associated with lower CSF Aß42 (p ≤ 0.05) in older participants. DISCUSSION: CSF Aß levels decreased in middle-aged veterans with blast-related mTBI. These data suggest that chronic neuropathologic processes associated with blast mTBI share properties in common with pathogenic processes known to portend AD onset, thus raising concern that veterans with blast-related mTBI may develop a dementing disorder later in life.

Implications of the three-dimensional chromatin organization for genome evolution in a fungal plant pathogen.

The spatial organization of eukaryotic genomes is linked to their biological functions, although it is not clear how this impacts the overall evolution of a genome. Here, we uncover the three-dimensional (3D) genome organization of the phytopathogen Verticillium dahliae, known to possess distinct genomic regions, designated adaptive genomic regions (AGRs), enriched in transposable elements and genes that mediate host infection. Short-range DNA interactions form clear topologically associating domains (TADs) with gene-rich boundaries that show reduced levels of gene expression and reduced genomic variation. Intriguingly, TADs are less clearly insulated in AGRs than in the core genome. At a global scale, the genome contains bipartite long-range interactions, particularly enriched for AGRs and more generally containing segmental duplications. Notably, the patterns observed for V. dahliae are also present in other Verticillium species. Thus, our analysis links 3D genome organization to evolutionary features conserved throughout the Verticillium genus.

Gender Differences in Autonomy Granted to Residents and Fellows During Procedural Training: A Systematic Review and Meta-Analysis.

PURPOSE: Supervisors may be prone to implicit (unintentional) bias when granting procedural autonomy to trainees due to the subjectivity of autonomy decisions. The authors aimed to conduct a systematic review and meta-analysis to assess the differences in perceptions of procedural autonomy granted to physician trainees based on gender and/or race. METHOD: MEDLINE, Embase, CENTRAL, Scopus, and Web of Science were searched (search date: January 5, 2022) for studies reporting quantitative gender- or race-based differences in perceptions of procedural autonomy of physician trainees. Reviewers worked in duplicate for article selection and data abstraction. Primary measures of interest were self-reported and observer-rated procedural autonomy. Meta-analysis pooled differences in perceptions of procedural autonomy based on trainee gender. RESULTS: The search returned 2,714 articles, of which 16 were eligible for inclusion. These reported data for 6,109 trainees (median 90 per study) and 2,763 supervisors (median 54 per study). No studies investigated differences in perceptions of autonomy based on race. In meta-analysis of disparities between genders in autonomy ratings (positive number favoring female trainees), pooled standardized mean differences were -0.12 (95% confidence interval [CI] = -0.19, -0.04; P = .003; n = 10 studies) for trainee self-rated autonomy and -0.05 (95% CI = -0.11, 0.01; P = .07; n = 9 studies) for supervisor ratings of autonomy. CONCLUSIONS: Limited evidence suggests that female trainees perceived that they received less procedural autonomy than did males. Further research exploring the degree of gender- and race-based differences in procedural autonomy, and factors that influence these differences, is warranted.

COVID-19 and local community resilience in the Westfjords of Iceland.

Remote Arctic communities have often been depicted as being particularly vulnerable to the challenges of disasters, with their location and lack of infrastructure exacerbating risk. This study explores the characteristics of local resilience in the Arctic using the case study of the communities of the north-western Westfjords. A total of 42 semi-structured interviews were carried out with various community members, seeking to uncover the features of inbuilt resilience that contribute to successes and vulnerabilities. These were transcribed, coded, and categorised in relation to an integrated framework for assessing community resilience in disaster management, which groups topics via the themes of environmental, social, governance, economic, and infrastructure. All themes played a role in the success of local coping strategies, with easy access to the natural environment central to physical and mental well-being. Despite this, vulnerabilities of the community were evident, including insufficient local healthcare workers during a severe COVID-19 outbreak in a care home, the absence of a local quarantine hotel, and insufficient information in foreign languages for non-natives of Iceland. The general trend of following rules and expert advice was demonstrative of strong social capital, with locals trusting those in charge, nationally and locally, to manage the pandemic.

FGL2 promotes tumour growth and attenuates infiltration of activated immune cells in melanoma and ovarian cancer models.

The tumour microenvironment is infiltrated by immunosuppressive cells, such as regulatory T cells (Tregs), which contribute to tumour escape and impede immunotherapy outcomes. Soluble fibrinogen-like protein 2 (sFGL2), a Treg effector protein, inhibits immune cell populations, via receptors FcγRIIB and FcγRIII, leading to downregulation of CD86 in antigen presenting cells and limiting T cell activation. Increased FGL2 expression is associated with tumour progression and poor survival in several different cancers, such as glioblastoma multiforme, lung, renal, liver, colorectal, and prostate cancer. Querying scRNA-seq human cancer data shows FGL2 is produced by cells in the tumour microenvironment (TME), particularly monocytes and macrophages as well as T cells and dendritic cells (DCs), while cancer cells have minimal expression of FGL2. We studied the role of FGL2 exclusively produced by cells in the TME, by leveraging Fgl2 knockout mice. We tested two murine models of cancer in which the role of FGL2 has not been previously studied: epithelial ovarian cancer and melanoma. We show that absence of FGL2 leads to a more activated TME, including activated DCs (CD86+, CD40+) and T cells (CD25+, TIGIT+), as well as demonstrating for the first time that the absence of FGL2 leads to more activated natural killer cells (DNAM-1+, NKG2D+) in the TME. Furthermore, the absence of FGL2 leads to prolonged survival in the B16F10 melanoma model, while the absence of FGL2 synergizes with oncolytic virus to prolong survival in the ID8-p53-/-Brca2-/- ovarian cancer model. In conclusion, targeting FGL2 is a promising cancer treatment strategy alone and in combination immunotherapies.

The Neurovascular Unit as a Locus of Injury in Low-Level Blast-Induced Neurotrauma.

Blast-induced neurotrauma has received much attention over the past decade. Vascular injury occurs early following blast exposure. Indeed, in animal models that approximate human mild traumatic brain injury or subclinical blast exposure, vascular pathology can occur in the presence of a normal neuropil, suggesting that the vasculature is particularly vulnerable. Brain endothelial cells and their supporting glial and neuronal elements constitute a neurovascular unit (NVU). Blast injury disrupts gliovascular and neurovascular connections in addition to damaging endothelial cells, basal laminae, smooth muscle cells, and pericytes as well as causing extracellular matrix reorganization. Perivascular pathology becomes associated with phospho-tau accumulation and chronic perivascular inflammation. Disruption of the NVU should impact activity-dependent regulation of cerebral blood flow, blood-brain barrier permeability, and glymphatic flow. Here, we review work in an animal model of low-level blast injury that we have been studying for over a decade. We review work supporting the NVU as a locus of low-level blast injury. We integrate our findings with those from other laboratories studying similar models that collectively suggest that damage to astrocytes and other perivascular cells as well as chronic immune activation play a role in the persistent neurobehavioral changes that follow blast injury.

Society for Simulation in Healthcare Guidelines for Simulation Training.

BACKGROUND: Simulation has become a staple in the training of healthcare professionals with accumulating evidence on its effectiveness. However, guidelines for optimal methods of simulation training do not currently exist. METHODS: Systematic reviews of the literature on 16 identified key questions were conducted and expert panel consensus recommendations determined using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. OBJECTIVE: These evidence-based guidelines from the Society for Simulation in Healthcare intend to support healthcare professionals in decisions on the most effective methods for simulation training in healthcare. RESULTS: Twenty recommendations on 16 questions were determined using GRADE. Four expert recommendations were also provided. CONCLUSIONS: The first evidence-based guidelines for simulation training are provided to guide instructors and learners on the most effective use of simulation in healthcare.