There are many studies of local communities during their heydays, but the life of a community in decline is rarely studied. The Once and Future Silver Queen of the Rockies delves into the life of ...Georgetown, Colorado, after the turn of the twentieth century as mining in Clear Creek County steadily declined and ultimately collapsed.
One of the earliest mining communities in the state, Georgetown began to struggle for survival as the nineteenth century drew to a close. The price of silver dropped precipitously while other mining camps were still opening around the region. The new, bright future once envisioned for the "Silver Queen of the Rockies" began to fade. Yet the community managed to survive and re-create itself in the new world of the twentieth century. Tourism, skiing, and historic preservation replaced mineral extraction as the basis of the regional economy. Today, Georgetown maintains the aesthetic feel of a nineteenth-century mining town and stands as an example of community-supported historic preservation.
This richly illustrated sequel to The Rise of the Silver Queen tells the compelling story of Georgetown's survival, and ultimate flourishing, after the loss of its principal industry. It is an interesting and engaging addition to the history of Colorado and the West.
Existing methods to improve detection of circulating tumor DNA (ctDNA) have focused on genomic alterations but have rarely considered the biological properties of plasma cell-free DNA (cfDNA). We ...hypothesized that differences in fragment lengths of circulating DNA could be exploited to enhance sensitivity for detecting the presence of ctDNA and for noninvasive genomic analysis of cancer. We surveyed ctDNA fragment sizes in 344 plasma samples from 200 patients with cancer using low-pass whole-genome sequencing (0.4×). To establish the size distribution of mutant ctDNA, tumor-guided personalized deep sequencing was performed in 19 patients. We detected enrichment of ctDNA in fragment sizes between 90 and 150 bp and developed methods for in vitro and in silico size selection of these fragments. Selecting fragments between 90 and 150 bp improved detection of tumor DNA, with more than twofold median enrichment in >95% of cases and more than fourfold enrichment in >10% of cases. Analysis of size-selected cfDNA identified clinically actionable mutations and copy number alterations that were otherwise not detected. Identification of plasma samples from patients with advanced cancer was improved by predictive models integrating fragment length and copy number analysis of cfDNA, with area under the curve (AUC) >0.99 compared to AUC <0.80 without fragmentation features. Increased identification of cfDNA from patients with glioma, renal, and pancreatic cancer was achieved with AUC > 0.91 compared to AUC < 0.5 without fragmentation features. Fragment size analysis and selective sequencing of specific fragment sizes can boost ctDNA detection and could complement or provide an alternative to deeper sequencing of cfDNA.
Previous studies have shown that iconic graphical signs can evolve into symbols through repeated usage within dyads and interacting communities. Here we investigate the evolution of graphical signs ...over chains of participants. In these chains (or "replacement microsocieties"), membership of an interacting group changed repeatedly such that the most experienced members were continually replaced by naïve participants. Signs rapidly became symbolic, such that they were mutually incomprehensible across experienced members of different chains, and new entrants needed to learn conventionalised meanings. An objective measure of graphical complexity (perimetric complexity) showed that the signs used within the microsocieties were becoming progressively simplified over successive usage. This is the first study to show that the signs that evolve in graphical communication experiments can be transmitted to, and spontaneously adopted by, naïve participants. This provides critical support for the view that human communicative symbols could have evolved culturally from iconic representations.
The objectives of this review are to: 1) appraise the methodological quality of clinical practice guidelines (CPGs) in juvenile idiopathic arthritis (JIA) providing pharmacological and/or ...non-pharmacological intervention recommendations, and 2) summarize the recommendations provided by the included CPGs and compare them where possible.
A systematic search was performed. Three trained appraisers independently evaluated the methodological quality of the CPGs using a validated and reliable instrument, the Appraisal of Guidelines in Research and Evaluation II. Six domains were considered: 1) score and purpose; 2) stakeholder involvement; 3) rigor of development; 4) clarity of presentation; 5) applicability; and 6) editorial independence. The domains consist of a total of 23 items each scored on a 7-point scale. High quality CPGs were identified if they had a domain score above 60% in rigor of development, and two other domains.
Of the three included CPGs, the Royal Australian College of General Practitioners (RACGP) and American College of Rheumatology (ACR) CPGs were considered to be of high quality, but the German Society for Pediatric Rheumatology was of lower quality. Domains one to four had high domain scores across the guidelines (mean (standard deviation)): 72.76 (13.80); 66.67 (9.81); 64.67 (7.77); and 87.00 (9.64), respectively. Lower scores were obtained for applicability (14.00 (5.57)) and editorial independence (43.44 (7.02)). Recommendations varied across CPGs due to differences in context, target audience (general practitioners, rheumatologists, and other multidisciplinary healthcare professionals) and patients' disease presentations. Despite this variability, progression of pharmacological treatment did not conflict between CPGs. Recommendations for non-pharmacological interventions were vague and the interventions considered varied between CPGs.
Overall, recommendations were based on a paucity of evidence and weak study designs. Further research is needed on interventions in JIA, as well as higher quality CPGs to facilitate implementation of the best evidence-based recommendations in clinical practice.
Trichoplax adhaerens is the best-known member of the phylum Placozoa, one of the earliest-diverging metazoan phyla. It is a small disk-shaped animal that glides on surfaces in warm oceans to feed on ...algae. Prior anatomical studies of Trichoplax revealed that it has a simple three-layered organization with four somatic cell types.
We reinvestigate the cellular organization of Trichoplax using advanced freezing and microscopy techniques to identify localize and count cells. Six somatic cell types are deployed in stereotyped positions. A thick ventral plate, comprising the majority of the cells, includes ciliated epithelial cells, newly identified lipophil cells packed with large lipid granules, and gland cells. Lipophils project deep into the interior, where they alternate with regularly spaced fiber cells whose branches contact all other cell types, including cells of the dorsal and ventral epithelium. Crystal cells, each containing a birefringent crystal, are arrayed around the rim. Gland cells express several proteins typical of neurosecretory cells, and a subset of them, around the rim, also expresses an FMRFamide-like neuropeptide.
Structural analysis of Trichoplax with significantly improved techniques provides an advance in understanding its cell types and their distributions. We find two previously undetected cell types, lipohil and crystal cells, and an organized body plan in which different cell types are arranged in distinct patterns. The composition of gland cells suggests that they are neurosecretory cells and could control locomotor and feeding behavior.
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•Trichoplax has six cell types, each arrayed in a distinct pattern•Structural cryotechniques reveal two new cell types, lipophils, and crystal cells•Lipophils contain large lipid granules; crystal cells contain one birefringent crystal•Gland cells express proteins and a peptide characteristic of neurosecretory cells
The cell types and body plan of the early-diverging metazoan Trichoplax adhaerens are revealed by advanced electron microscopic and immunofluorescence cryotechniques. There are six, including two novel, somatic cell types, arranged in distinct numbers and patterns. Gland cells arrayed around the rim package peptides in their secretory granules.
To seek pathways of retinal pigment epithelium (RPE) fate in age-related macular degeneration via a morphology grading system; provide nomenclature, visualization targets, and metrics for clinical ...imaging and model systems.
Donor eyes with geographic atrophy (GA) or choroidal neovascularization (CNV) and one GA eye with previous clinical spectral-domain optical coherence tomography (SDOCT) imaging were processed for histology, photodocumented, and annotated at predefined locations. Retinal pigment epithelial cells contained spindle-shaped melanosomes, apposed a basal lamina or basal laminar deposit (BLamD), and exhibited recognizable morphologies. Thicknesses and unbiased estimates of frequencies were obtained.
In 13 GA eyes (449 locations), 'Shedding,' 'Sloughed,' and 'Dissociated' morphologies were abundant; 22.2% of atrophic locations had 'Dissociated' RPE. In 39 CNV eyes (1363 locations), 37.3% of locations with fibrovascular/fibrocellular scar had 'Entombed' RPE; 'Sloughed,' 'Dissociated,' and 'Bilaminar' morphologies were abundant. Of abnormal RPE, CNV and GA both had ~35% 'Sloughed'/'Intraretinal,' with more Intraretinal in CNV (9.5% vs. 1.8%). 'Shedding' cells associated with granule aggregations in BLamD. The RPE layer did not thin, and BLamD remained thick, with progression. Granule-containing material consistent with three morphologies correlated to SDOCT hyperreflective foci in the previously examined GA patient.
Retinal pigment epithelium morphology indicates multiple pathways in GA and CNV. Atrophic/scarred areas have numerous cells capable of transcribing genes and generating imaging signals. Shed granule aggregates, possibly apoptotic, are visible in SDOCT, as are 'Dissociated' and 'Sloughed' cells. The significance of RPE phenotypes is addressable in longitudinal, high-resolution imaging in clinic populations. Data can motivate future molecular phenotyping studies.
In the current study, we examined the relationship between Big Five personality traits, cognitive flexibility, and life satisfaction. We expected that the Big Five traits would predict cognitive ...flexibility, cognitive flexibility would predict life satisfaction, and cognitive flexibility would mediate the relationship between four of the Big Five traits (conscientiousness, extraversion, agreeableness, and neuroticism) and life satisfaction. We sampled 258 U. S. participants through MTurk, where they completed a series of self-report measures. Using path analysis, we found support for each of our predictions. Future research should examine the role of affect and cognition in the Big Five traits, and how those might predict cognitive flexibility and life satisfaction.
Objectives
Risk stratification of emergency department (ED) patients with upper gastrointestinal bleeding (UGIB) using preendoscopic risk scores can aid ED physicians in disposition decision‐making. ...We conducted a systematic review to assess the predictive value of preendoscopic risk scores for 30‐day serious adverse events.
Methods
We searched MEDLINE, PubMed, Embase, and the Cochrane Database of Systematic Reviews from inception to March 2015. We included studies involving adult ED UGIB patients evaluating preendoscopic risk scores and excluded reviews, case reports, and animal studies. The composite outcome included 30‐day mortality, recurrent bleeding, and need for intervention. In two phases (screening and full review), two reviewers independently screened articles for inclusion and extracted patient‐level data. The consensus data were used for analysis. We reported sensitivity, specificity, positive and negative predictive value, and positive and negative likelihood ratios with 95% confidence intervals.
Results
We identified 3,173 articles, of which 16 were included: three studied Glasgow Blatchford score (GBS); one studied clinical Rockall score (cRockall); two studied AIMS65; six compared GBS and cRockall; three compared GBS, a modification of the GBS, and cRockall; and one compared the GBS and AIMS65. Overall, the sensitivity and specificity of the GBS were 0.98 and 0.16, respectively; for the cRockall they were 0.93 and 0.24, respectively; and for the AIMS65 they were 0.79 and 0.61, respectively. The GBS with a cutoff point of 0 had a sensitivity of 0.99 and a specificity of 0.08.
Conclusion
The GBS with a cutoff point of 0 was superior over other cutoff points and risk scores for identifying low‐risk patients but had a very low specificity. None of the risk scores identified by our systematic review were robust and, hence, cannot be recommended for use in clinical practice. Future prospective studies are needed to develop robust new scores for use in ED patients with UGIB.
Smoke is an important abiotic cue for plant regeneration in postfire landscapes. Karrikins are a class of compounds discovered in smoke that promote seed germination and influence early development ...of many plants by an unknown mechanism. A genetic screen for karrikin-insensitive mutants in Arabidopsis thaliana revealed that karrikin signaling requires the F-box protein MAX2, which also mediates responses to the structurally-related strigolactone family of phytohormones. Karrikins and the synthetic strigolactone GR24 trigger similar effects on seed germination, seedling photomorphogenesis, and expression of a small set of genes during these developmental stages. Karrikins also repress MAX4 and IAA1 transcripts, which show negative feedback regulation by strigolactone. We demonstrate that all of these common responses are abolished in max2 mutants. Unlike strigolactones, however, karrikins do not inhibit shoot branching in Arabidopsis or pea, indicating that plants can distinguish between these signals. These results suggest that a MAX2-dependent signal transduction mechanism was adapted to mediate responses to two chemical cues with distinct roles in plant ecology and development.
Impairment of methylation status (ie, methionine to homocysteine ratio) may be a modifiable risk factor for structural brain changes and incident dementia.
To investigate the association of serum ...markers of methylation status and sulfur amino acids with risk of incident dementia, Alzheimer disease (AD), and the rate of total brain tissue volume loss during 6 years.
This population-based longitudinal study was performed from March 21, 2001, to October 10, 2010, in a sample of 2570 individuals aged 60 to 102 years from the Swedish Study on Aging and Care in Kungsholmen who were dementia free at baseline and underwent comprehensive examinations and structural brain magnetic resonance imaging (MRI) on 2 to 3 occasions during 6 years. Data analysis was performed from March 1, 2018, to October 1, 2018.
Incident dementia, AD, and the rate of total brain volume loss.
This study included 2570 individuals (mean SD age, 73.1 10.4 years; 1331 56.5% female). The methionine to homocysteine ratio was higher in individuals who consumed vitamin supplements (median, 1.9; interquartile range IQR, 1.5-2.6) compared with those who did not (median, 1.8; IQR, 1.3-2.3; P < .001) and increased per each quartile increase of vitamin B12 or folate. In the multiadjusted model, an elevated baseline serum total homocysteine level was associated with an increased risk of dementia and AD during 6 years: for the highest homocysteine quartile compared with the lowest, the hazard ratios (HRs) were 1.60 (95% CI, 1.01-2.55) for dementia and 2.33 (95% CI, 1.26-4.30) for AD. In contrast, elevated concentrations of methionine were associated with a decreased risk of dementia (HR, 0.54; 95% CI, 0.36-0.81) for the highest quartile compared with the lowest. Higher values of the methionine to homocysteine ratio were significantly associated with lower risk of dementia and AD: for the fourth methionine-homocysteine quartile compared with the first quartile, the HR was 0.44 (95% CI, 0.27-0.71) for incident dementia and 0.43 (95% CI, 0.23-0.80) for AD. In the multiadjusted linear mixed models, a higher methionine to homocysteine ratio was associated with a decreased rate of total brain tissue volume loss during the study period (β SE per 1-SD increase, 0.038 0.014; P = .007).
The methionine to homocysteine status was associated with dementia development and structural brain changes during the 6-year study period, suggesting that a higher methionine to homocysteine ratio may be important in reducing the rate of brain atrophy and decreasing the risk of dementia in older adults.
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