The underpinnings of cancer metastasis remain poorly understood, in part due to a lack of tools for probing their emergence at high resolution. Here we present macsGESTALT, an inducible ...CRISPR-Cas9-based lineage recorder with highly efficient single-cell capture of both transcriptional and phylogenetic information. Applying macsGESTALT to a mouse model of metastatic pancreatic cancer, we recover ∼380,000 CRISPR target sites and reconstruct dissemination of ∼28,000 single cells across multiple metastatic sites. We find that cells occupy a continuum of epithelial-to-mesenchymal transition (EMT) states. Metastatic potential peaks in rare, late-hybrid EMT states, which are aggressively selected from a predominately epithelial ancestral pool. The gene signatures of these late-hybrid EMT states are predictive of reduced survival in both human pancreatic and lung cancer patients, highlighting their relevance to clinical disease progression. Finally, we observe evidence for in vivo propagation of S100 family gene expression across clonally distinct metastatic subpopulations.
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•macsGESTALT is an inducible lineage recorder with efficient capture in single cells•Despite genetic competency, most cancer clones are not metastatic•Metastatic aggression peaks at specific late-hybrid EMT states•Expression of S100 genes is propagated across distinct metastatic subpopulations
Simeonov et al. develop an inducible lineage recorder, enabling simultaneous capture of lineages and transcriptomes from single cells. Lineage reconstruction in a metastatic pancreatic cancer model reveals extensive bottlenecking and subpopulation signaling, as well as specific transcriptional states associated with metastatic aggression and predictive of worse outcomes in human cancer.
This paper charted the cognitive and behavioural profiles from toddlerhood to middle childhood in 48 children diagnosed with ASD at 24-months. The Mullen Scales of Early Learning (MSEL) was ...administered at 24- and 48-months and the Wechsler Abbreviated Scale of Intelligence (WASI) at school age. Autism severity was derived using The Autism Diagnostic Observation Schedule (ADOS) Results: Developmental Disability/Intellectual Disability (DD/ID; Developmental Quotient <70) reduced from 64% at 24-months to 8% at outcome. Seventy-three percent of children continued to meet ADOS cut-off at school age. Conclusion: Diagnoses at 24-months, appear to be reliable and stable. Further research is needed to investigate whether early identification, which provides more opportunity to access early intervention, may in turn facilitate cognitive development over time.
Growing evidence links household air pollution exposure from biomass cookstoves with elevated blood pressure. We assessed cross‐sectional associations of 24‐hour mean concentrations of personal and ...kitchen fine particulate matter (PM2.5), black carbon (BC), and stove type with blood pressure, adjusting for confounders, among 147 women using traditional or cleaner‐burning Justa stoves in Honduras. We investigated effect modification by age and body mass index. Traditional stove users had mean (standard deviation) personal and kitchen 24‐hour PM2.5 concentrations of 126 μg/m3 (77) and 360 μg/m3 (374), while Justa stove users’ exposures were 66 μg/m3 (38) and 137 μg/m3 (194), respectively. BC concentrations were similarly lower among Justa stove users. Adjusted mean systolic blood pressure was 2.5 mm Hg higher (95% CI, 0.7‐4.3) per unit increase in natural log‐transformed kitchen PM2.5 concentration; results were stronger among women of 40 years or older (5.2 mm Hg increase, 95% CI, 2.3‐8.1). Adjusted odds of borderline high and high blood pressure (categorized) were also elevated (odds ratio = 1.5, 95% CI, 1.0‐2.3). Some results included null values and are suggestive. Results suggest that reduced household air pollution, even when concentrations exceed air quality guidelines, may help lower cardiovascular disease risk, particularly among older subgroups.
Deregulated CD8+ T cell cytotoxicity plays a central role in enhancing disease severity in several conditions. However, we have little understanding of the mechanisms by which immunopathology ...develops as a consequence of cytotoxicity. Using murine models of inflammation induced by the protozoan parasite leishmania, and data obtained from patients with cutaneous leishmaniasis, we uncovered a previously unrecognized role for NLRP3 inflammasome activation and IL-1β release as a detrimental consequence of CD8+ T cell-mediated cytotoxicity, ultimately resulting in chronic inflammation. Critically, pharmacological blockade of NLRP3 or IL-1β significantly ameliorated the CD8+ T cell-driven immunopathology in leishmania-infected mice. Confirming the relevance of these findings to human leishmaniasis, blockade of the NLRP3 inflammasome in skin biopsies from leishmania-infected patients prevented IL-1β release. Thus, these studies link CD8+ T cell cytotoxicity with inflammasome activation and reveal novel avenues of treatment for cutaneous leishmaniasis, as well as other of diseases where CD8+ T cell-mediated cytotoxicity induces pathology.
We measured 24-hour average personal exposure to fine particulate matter (PM2.5) among rural Honduran women using a lightweight, gravimetric monitor – the Ultrasonic Personal Aerosol Sampler (UPAS). ...Performance of the UPAS was compared with a commonly used gravimetric pump, cyclone, and filter sampling system. We observed strong agreement and correlation (Spearman ρ = 0.91; PM2.5 concentration range: 19–120 μg/m3) between 43 paired measures, supporting the use of the UPAS as a personal exposure monitor for household air pollution studies.
•Common methods for measuring personal exposure to PM mass have involved devices that are cumbersome to wear•We compared the performance of Ultrasonic Personal Aerosol Samplers to standard methods for 24-h PM2.5 among biomass users•Given strong observed, the UPAS may be viable for personal PM2.5 assessments, particularly for cookstove-related studies
l-menthol (menthol) is an organic compound derived from peppermint which imparts a refreshing mint flavor and aroma to oral hygiene products, chewing gum, and topical analgesics. Menthol has been ...identified as a non-thermal sensory cooling strategy for athletes when ingested or mouth-rinsed during exercise in hot environments. Therefore, sports nutrition products delivering a controlled concentration of menthol could be beneficial for athletes exercising in the heat. We sought to test the performance and perceptual outcomes of a novel menthol energy gel during treadmill running in the heat (33 °C, 49% RH). Fourteen trained runners (mean ± SD; age: 31 ± 6 years, VO
: 56.5 ± 10.1 mL·kg
·min
, BMI: 23.2 ± 2.4 kg/m
; six female) participated in a randomized, crossover, double-blind, and placebo-controlled study. A menthol-enhanced energy gel (0.5% concentration; MEN) or flavor-matched placebo (PLA) was ingested 5 min before and again at 20 and 40 min of a 40 min treadmill exercise preload at 60% VO
, followed by a 20 min self-paced time trial. The total distance, vertical distance, perceptual measures (thermal comfort, thermal sensation, rating of perceived exertion, and affect), and cognitive performance via computerized neurocognitive assessment were measured. No difference between 20 min self-paced time trial total distance (MEN: 4.22 ± 0.54 km, PLA: 4.22 ± 0.55 km,
= 0.867), vertical distance (MEN: 49.2 ± 24.6 m, PLA: 44.4 ± 11.4 m,
= 0.516), or any perceptual measures was observed (all
> 0.05). Cognitive performance was not different between the trials (all
> 0.05). These results suggest that a menthol energy gel is not superior to a non-menthol gel in terms of performance or perception during treadmill running in the heat. More research is needed to confirm whether these findings translate to ecologically valid settings, including outdoor exercise in ambient heat and during competition.
Background There is increasing interest in implementing comprehensive perioperative protocols, including preoperative optimization and education, perioperative goal-directed fluid management, and ...postoperative fast tracking, to enhance recovery after surgery. Data on the outcomes of these protocols in pancreatic surgery, however, are limited. Study Design A retrospective review of a prospectively maintained pancreas surgery database at a single institution from August 2012 to April 2015 was undertaken. An enhanced recovery protocol was initiated in October 2014, and patients were divided into groups according to preprotocol or postprotocol implementation. Preoperative, intraoperative, and postoperative data were tabulated. Statistical analysis was performed with Student's t -test and Fisher's exact tests, as well as equality of variances where appropriate, using SAS System software (SAS Institute). Results Three hundred and seventy-eight patients (181 men, mean age 54 years, BMI 28 kg/m2 ) underwent elective pancreatic surgery during the study period, 297 patients preprotocol and 81 postprotocol. There were no significant differences in preoperative or intraoperative characteristics. Mean postoperative length of stay was significantly lower in the Enhanced Recovery After Surgery group (7.4 vs 9.2 days; p < 0.0001). Hospital costs were similarly lower in the Enhanced Recovery After Surgery group ($23,307.90 vs $27,387.80; p < 0.0001). Readmission (29% vs 32%) and pancreatic fistula (26% vs 28%) rates were similar between groups. Delayed gastric emptying was lower in the Enhanced Recovery After Surgery group (26% vs 13%; p = 0.03). Conclusions Implementation of an enhanced recovery after pancreatic surgery protocol significantly decreased length of stay and hospital cost without increasing readmission or morbidity. Despite patient complexity and the potential need for individualization of care, enhanced recovery protocols can be valuable and effective in high-risk patient populations, including pancreatic surgery patients.
This study explored the attitudes of parents and professionals who work with children with autism spectrum disorder (ASD) toward the utilization of iPads and use of iPad applications by children with ...ASD. A survey of parents (n = 90) and professionals (n = 31) assessed information and communication technology (ICT) anxiety and self-efficacy, attitude toward ICT and iPad applications, and iPad utilization. Both parents and professionals held positive attitudes toward ICT and iPad use for children with ASD. Parents reported high use of iPads by their children, and professionals reported some, albeit limited, utilization as part of their practice. These findings suggest that iPad applications are not being used by professionals to a degree that is consistent with their favorable attitudes toward them. iPad use has been enthusiastically adopted by many parents; however, there appears a need for training in their use and research to establish an evidence base. Author abstract
The number of healthcare professionals leaving clinical practice and transitioning to alternative careers in health professions education is increasing. Among these non-practicing healthcare ...professionals, concerns have been reported regarding tensions in relation to identity, role, and credibility in their new field. There are suggestions that this is a particularly pressing issue for minoritised professionals who make this transition. Support is critical to attract and retain diverse talent within health professions education teaching and research. The purpose of this scoping review is to explore the career experiences of non-practicing healthcare professionals who work in health professions education internationally.
Arksey and O'Malley's framework has been utilised to guide the design of this scoping review process and will be used throughout the course of the review. A comprehensive search of seven electronic databases and limited search of Google Scholar will be conducted, as well as a hand search of eligible article reference lists. Two reviewers will independently screen all articles based on inclusion criteria, with conflicts resolved by a third reviewer. Data from included articles will be charted, collated, and analysed thematically. Meta-data will be summarised quantitatively.
This scoping review aims to explore the role and experiences of non-practicing healthcare professionals working within health professions education. The review will follow established scoping review guidelines and will include studies from various regions and languages, provided an English translation is available. The study remit will be broad, including both quantitative and qualitative studies, as well as reviews and opinion papers. Limitations may include the exclusion of non-English articles and potential difficulty of identifying papers which discuss the experiences of non-practicing clinicians. However, the review will provide insight into the current knowledge on what it is like to be a non-practicing clinician working within health professions education and identify gaps for both future research, and future support for those making this career transition.
Open Science Framework Registration https://doi.org/10.17605/OSF.IO/485Z3.
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