A priority in cancer research is to innovate therapies that are not only effective against tumor progression but also address comorbidities such as cachexia that limit quality and quantity of life. ...We demonstrate that TLR7/8 agonist R848 induces anti-tumor responses and attenuates cachexia in murine models of pancreatic ductal adenocarcinoma (PDAC). In vivo, tumors from two of three cell lines were R848-sensitive, resulting in smaller tumor mass, increased immune complexity, increased CD8
T-cell infiltration and activity, and decreased Treg frequency. R848-treated mice demonstrated improvements in behavioral and molecular cachexia manifestations, resulting in a near-doubling of survival duration. Knockout mouse studies revealed that stromal, not neoplastic, TLR7 is requisite for R848-mediated responses. In patient samples, we found Tlr7 is ubiquitously expressed in stroma across all stages of pancreatic neoplasia, but epithelial Tlr7 expression is relatively uncommon. These studies indicate immune-enhancing approaches including R848 may be useful in PDAC and cancer-associated cachexia.
To mimic native insulin activity, materials have been developed that encapsulate insulin, glucose oxidase, and catalase for glucose-responsive insulin delivery. A major challenge, however, has been ...achieving the desired kinetics of both rapid and extended release. Here, we tune insulin release profiles from polymeric nanoparticles by altering the degree of modification of acid-degradable, acetalated-dextran polymers. Nanoparticles synthesized from dextran with a high acyclic acetal content (94% of residues) show rapid release kinetics, while nanoparticles from dextran with a high cyclic acetal content (71% of residues) release insulin more slowly. Thus, coformulation of these two materials affords both rapid and extended glucose-responsive insulin delivery. In vivo analyses using both streptozotocin-induced type 1 diabetic and healthy mouse models indicate that this delivery system has the ability to respond to glucose on a therapeutically relevant time scale. Importantly, the concentration of human insulin in mouse serum is enhanced more than 3-fold with elevated glucose levels, providing direct evidence of glucose-responsiveness in animals. We further show that a single subcutaneous injection provides 16 h of glycemic control in diabetic mice. We believe the nanoparticle formulations developed here may provide a generalized strategy for the development of glucose-responsive insulin delivery systems.
Landsat-based fire severity datasets are an invaluable resource for monitoring and research purposes. These gridded fire severity datasets are generally produced with pre- and post-fire imagery to ...estimate the degree of fire-induced ecological change. Here, we introduce methods to produce three Landsat-based fire severity metrics using the Google Earth Engine (GEE) platform: The delta normalized burn ratio (dNBR), the relativized delta normalized burn ratio (RdNBR), and the relativized burn ratio (RBR). Our methods do not rely on time-consuming a priori scene selection but instead use a mean compositing approach in which all valid pixels (e.g., cloud-free) over a pre-specified date range (pre- and post-fire) are stacked and the mean value for each pixel over each stack is used to produce the resulting fire severity datasets. This approach demonstrates that fire severity datasets can be produced with relative ease and speed compared to the standard approach in which one pre-fire and one post-fire scene are judiciously identified and used to produce fire severity datasets. We also validate the GEE-derived fire severity metrics using field-based fire severity plots for 18 fires in the western United States. These validations are compared to Landsat-based fire severity datasets produced using only one pre- and post-fire scene, which has been the standard approach in producing such datasets since their inception. Results indicate that the GEE-derived fire severity datasets generally show improved validation statistics compared to parallel versions in which only one pre-fire and one post-fire scene are used, though some of the improvements in some validations are more or less negligible. We provide code and a sample geospatial fire history layer to produce dNBR, RdNBR, and RBR for the 18 fires we evaluated. Although our approach requires that a geospatial fire history layer (i.e., fire perimeters) be produced independently and prior to applying our methods, we suggest that our GEE methodology can reasonably be implemented on hundreds to thousands of fires, thereby increasing opportunities for fire severity monitoring and research across the globe.
Abstract
The Genome Database for Rosaceae (GDR, https://www.rosaceae.org) is an integrated web-based community database resource providing access to publicly available genomics, genetics and breeding ...data and data-mining tools to facilitate basic, translational and applied research in Rosaceae. The volume of data in GDR has increased greatly over the last 5 years. The GDR now houses multiple versions of whole genome assembly and annotation data from 14 species, made available by recent advances in sequencing technology. Annotated and searchable reference transcriptomes, RefTrans, combining peer-reviewed published RNA-Seq as well as EST datasets, are newly available for major crop species. Significantly more quantitative trait loci, genetic maps and markers are available in MapViewer, a new visualization tool that better integrates with other pages in GDR. Pathways can be accessed through the new GDR Cyc Pathways databases, and synteny among the newest genome assemblies from eight species can be viewed through the new synteny browser, SynView. Collated single-nucleotide polymorphism diversity data and phenotypic data from publicly available breeding datasets are integrated with other relevant data. Also, the new Breeding Information Management System allows breeders to upload, manage and analyze their private breeding data within the secure GDR server with an option to release data publicly.
Little is known about the effect of meteorological conditions and geographical location on bacterial colonization rates particularly of antibiotic-resistant Gram-positive bacteria. We aimed to ...evaluate the effect of season, meteorological factors, and geographic location on methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE) colonization.
The prospective cohort included all adults admitted to 20 geographically-dispersed ICUs across the US from September 1, 2011 to October 4, 2012. Nasal and perianal swabs were collected at admission and tested for MRSA and VRE colonization respectively. Poisson regression models using monthly aggregated colonization counts as the outcome and mean temperature, relative humidity, total precipitation, season, and/or latitude as predictors were constructed for each pathogen.
A total of 24,704 ICU-admitted patients were tested for MRSA and 24,468 for VRE. On admission, 10% of patients were colonized with MRSA and 12% with VRE. For MRSA and VRE, a 10% increase in relative humidity was associated with approximately a 9% increase in prevalence rate. Southerly latitudes in the US were associated with higher MRSA colonization, while northerly latitudes were associated with higher VRE colonization. In contrast to MRSA, the association between VRE colonization and latitude was observed only after adjusting for relative humidity, which demonstrates how this effect is highly driven by this meteorological factor.
To our knowledge, we are the first to study the effect of meteorological factors and geographical location/latitude on MRSA and VRE colonization in adults. Increasing humidity was associated with greater MRSA and VRE colonization. Southerly latitudes in the US were associated with greater MRSA and less VRE. The effect of these factors on MRSA and VRE rates has the potential not only to inform patient management and treatment, but also infection prevention interventions.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The mastery of fundamental movement skills (FMS) has been purported as contributing to children's physical, cognitive and social development and is thought to provide the foundation for an active ...lifestyle. Commonly developed in childhood and subsequently refined into context- and sport-specific skills, they include locomotor (e.g. running and hopping), manipulative or object control (e.g. catching and throwing) and stability (e.g. balancing and twisting) skills. The rationale for promoting the development of FMS in childhood relies on the existence of evidence on the current or future benefits associated with the acquisition of FMS proficiency. The objective of this systematic review was to examine the relationship between FMS competency and potential health benefits in children and adolescents. Benefits were defined in terms of psychological, physiological and behavioural outcomes that can impact public health. A systematic search of six electronic databases (EMBASE, OVID MEDLINE, PsycINFO, PubMed, Scopus and SportDiscus®) was conducted on 22 June 2009. Included studies were cross-sectional, longitudinal or experimental studies involving healthy children or adolescents (aged 3-18 years) that quantitatively analysed the relationship between FMS competency and potential benefits. The search identified 21 articles examining the relationship between FMS competency and eight potential benefits (i.e. global self-concept, perceived physical competence, cardio-respiratory fitness CRF, muscular fitness, weight status, flexibility, physical activity and reduced sedentary behaviour). We found strong evidence for a positive association between FMS competency and physical activity in children and adolescents. There was also a positive relationship between FMS competency and CRF and an inverse association between FMS competency and weight status. Due to an inadequate number of studies, the relationship between FMS competency and the remaining benefits was classified as uncertain. More longitudinal and intervention research examining the relationship between FMS competency and potential psychological, physiological and behavioural outcomes in children and adolescents is recommended.
IMI Risk Factors for Myopia Morgan, Ian G; Wu, Pei-Chang; Ostrin, Lisa A ...
Investigative ophthalmology & visual science,
04/2021, Letnik:
62, Številka:
5
Journal Article
Recenzirano
Odprti dostop
Risk factor analysis provides an important basis for developing interventions for any condition. In the case of myopia, evidence for a large number of risk factors has been presented, but they have ...not been systematically tested for confounding. To be useful for designing preventive interventions, risk factor analysis ideally needs to be carried through to demonstration of a causal connection, with a defined mechanism. Statistical analysis is often complicated by covariation of variables, and demonstration of a causal relationship between a factor and myopia using Mendelian randomization or in a randomized clinical trial should be aimed for. When strict analysis of this kind is applied, associations between various measures of educational pressure and myopia are consistently observed. However, associations between more nearwork and more myopia are generally weak and inconsistent, but have been supported by meta-analysis. Associations between time outdoors and less myopia are stronger and more consistently observed, including by meta-analysis. Measurement of nearwork and time outdoors has traditionally been performed with questionnaires, but is increasingly being pursued with wearable objective devices. A causal link between increased years of education and more myopia has been confirmed by Mendelian randomization, whereas the protective effect of increased time outdoors from the development of myopia has been confirmed in randomized clinical trials. Other proposed risk factors need to be tested to see if they modulate these variables. The evidence linking increased screen time to myopia is weak and inconsistent, although limitations on screen time are increasingly under consideration as interventions to control the epidemic of myopia.
We present here a novel surface mass spectrometry strategy to perform untargeted metabolite profiling of formalin-fixed paraffin-embedded pediatric ependymoma archives. Sequential Orbitrap secondary ...ion mass spectrometry (3D OrbiSIMS) and liquid extraction surface analysis-tandem mass spectrometry (LESA-MS/MS) permitted the detection of 887 metabolites (163 chemical classes) from pediatric ependymoma tumor tissue microarrays (diameter: <1 mm; thickness: 4 μm). From these 163 classes, 60 classes were detected with both techniques, whilst LESA-MS/MS and 3D OrbiSIMS individually allowed the detection of another 83 and 20 unique metabolite classes, respectively. Through data fusion and multivariate analysis, we were able to identify key metabolites and corresponding pathways predictive of tumor relapse, which were retrospectively confirmed by gene expression analysis with publicly available data. Altogether, this sequential mass spectrometry strategy has shown to be a versatile tool to perform high-throughput metabolite profiling on sample-limited tissue archives.
IMPORTANCE: Accurate diagnosis is essential to proper patient care. OBJECTIVE: To explore practitioner understanding of diagnostic reasoning. DESIGN, SETTING, AND PARTICIPANTS: In this survey study, ...723 practitioners at outpatient clinics in 8 US states were asked to estimate the probability of disease for 4 scenarios common in primary care (pneumonia, cardiac ischemia, breast cancer screening, and urinary tract infection) and the association of positive and negative test results with disease probability from June 1, 2018, to November 26, 2019. Of these practitioners, 585 responded to the survey, and 553 answered all of the questions. An expert panel developed the survey and determined correct responses based on literature review. RESULTS: A total of 553 (290 resident physicians, 202 attending physicians, and 61 nurse practitioners and physician assistants) of 723 practitioners (76.5%) fully completed the survey (median age, 32 years; interquartile range, 29-44 years; 293 female 53.0%; 296 53.5% White). Pretest probability was overestimated in all scenarios. Probabilities of disease after positive results were overestimated as follows: pneumonia after positive radiology results, 95% (evidence range, 46%-65%; comparison P < .001); breast cancer after positive mammography results, 50% (evidence range, 3%-9%; P < .001); cardiac ischemia after positive stress test result, 70% (evidence range, 2%-11%; P < .001); and urinary tract infection after positive urine culture result, 80% (evidence range, 0%-8.3%; P < .001). Overestimates of probability of disease with negative results were also observed as follows: pneumonia after negative radiography results, 50% (evidence range, 10%-19%; P < .001); breast cancer after negative mammography results, 5% (evidence range, <0.05%; P < .001); cardiac ischemia after negative stress test result, 5% (evidence range, 0.43%-2.5%; P < .001); and urinary tract infection after negative urine culture result, 5% (evidence range, 0%-0.11%; P < .001). Probability adjustments in response to test results varied from accurate to overestimates of risk by type of test (imputed median positive and negative likelihood ratios LRs for practitioners for chest radiography for pneumonia: positive LR, 4.8; evidence, 2.6; negative LR, 0.3; evidence, 0.3; mammography for breast cancer: positive LR, 44.3; evidence range, 13.0-33.0; negative LR, 1.0; evidence range, 0.05-0.24; exercise stress test for cardiac ischemia: positive LR, 21.0; evidence range, 2.0-2.7; negative LR, 0.6; evidence range, 0.5-0.6; urine culture for urinary tract infection: positive LR, 9.0; evidence, 9.0; negative LR, 0.1; evidence, 0.1). CONCLUSIONS AND RELEVANCE: This survey study suggests that for common diseases and tests, practitioners overestimate the probability of disease before and after testing. Pretest probability was overestimated in all scenarios, whereas adjustment in probability after a positive or negative result varied by test. Widespread overestimates of the probability of disease likely contribute to overdiagnosis and overuse.
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