The utility of antineutrophil cytoplasmic antibody (ANCA) levels to guide the management of patients with Wegener granulomatosis remains controversial.
To determine whether pro-proteinase 3 ...(PR3)-ANCA levels are a better measure of disease activity than mature-PR3-ANCA levels, whether decreases in either level are associated with shorter time to remission, and whether increases are followed by relapse.
Prospective, observational cohort study.
8 United States medical centers that participated in a treatment trial for Wegener granulomatosis.
156 patients with Wegener granulomatosis enrolled during periods of active disease.
PR3-ANCA levels (by capture enzyme-linked immunosorbent assay) and disease activity (by the Birmingham Vasculitis Activity Score for Wegener granulomatosis).
The ANCA levels were only weakly associated with disease activity across patients. The longitudinal association within patients was stronger, but changes in ANCA levels explained less than 10% of the variation in disease activity. Decreases in mature- and pro-PR3-ANCA levels were not statistically significantly associated with shorter time to remission, and increases in mature-PR3-ANCA levels (adjusted hazard ratio, 0.8 95% CI, 0.4 to 1.9; P = 0.67) and pro-PR3-ANCA levels (adjusted hazard ratio, 1.0 CI, 0.5 to 2.1; P = 0.99) were not associated with relapse. The proportion of patients who had relapse within 1 year of an increase in PR3-ANCA levels was 40% for mature-PR3 (CI, 18% to 56%) and 43% for pro-PR3 (CI, 22% to 58%).
Samples were collected approximately every 3 months. Sensitivity and specificity of ANCA levels for detecting remission and relapse could not be calculated because each patient had different follow-up times.
Pro-PR3-ANCA is no better than mature-PR3-ANCA as a measure of Wegener granulomatosis activity. Decreases in PR3-ANCA levels are not associated with shorter time to remission, and increases are not associated with relapse. These findings suggest that ANCA levels cannot be used to guide immunosuppressive therapy.
Unbiased data-driven omic approaches are revealing the molecular heterogeneity of Alzheimer disease. Here, we used machine learning approaches to integrate high-throughput transcriptomic, proteomic, ...metabolomic, and lipidomic profiles with clinical and neuropathological data from multiple human AD cohorts. We discovered 4 unique multimodal molecular profiles, one of them showing signs of poor cognitive function, a faster pace of disease progression, shorter survival with the disease, severe neurodegeneration and astrogliosis, and reduced levels of metabolomic profiles. We found this molecular profile to be present in multiple affected cortical regions associated with higher Braak tau scores and significant dysregulation of synapse-related genes, endocytosis, phagosome, and mTOR signaling pathways altered in AD early and late stages. AD cross-omics data integration with transcriptomic data from an SNCA mouse model revealed an overlapping signature. Furthermore, we leveraged single-nuclei RNA-seq data to identify distinct cell-types that most likely mediate molecular profiles. Lastly, we identified that the multimodal clusters uncovered cerebrospinal fluid biomarkers poised to monitor AD progression and possibly cognition. Our cross-omics analyses provide novel critical molecular insights into AD.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
A two-step multicomponent reaction oxidation protocol is reported herein, which affords novel tunable fluorescent tetracyclic indolizines. The procedure involves a novel 4-center-3-component ...reaction, which proceeds via a sequential Knoevenagel condensation, 4+1 cycloaddition, and imine condensation to afford imino-indolizines. Products then undergo cyclization and are oxidized in situ to afford fluorescent tetracycles, which are readily tunable through modification of diversity elements.
Efforts to identify meaningful functional imaging-based biomarkers are limited by the ability to reliably characterize inter-individual differences in human brain function. Although a growing number ...of connectomics-based measures are reported to have moderate to high test-retest reliability, the variability in data acquisition, experimental designs, and analytic methods precludes the ability to generalize results. The Consortium for Reliability and Reproducibility (CoRR) is working to address this challenge and establish test-retest reliability as a minimum standard for methods development in functional connectomics. Specifically, CoRR has aggregated 1,629 typical individuals' resting state fMRI (rfMRI) data (5,093 rfMRI scans) from 18 international sites, and is openly sharing them via the International Data-sharing Neuroimaging Initiative (INDI). To allow researchers to generate various estimates of reliability and reproducibility, a variety of data acquisition procedures and experimental designs are included. Similarly, to enable users to assess the impact of commonly encountered artifacts (for example, motion) on characterizations of inter-individual variation, datasets of varying quality are included.
Eastern equine encephalitis virus (EEEV) is mosquito-borne virus that produces fatal encephalitis in humans. We recently conducted a first of its kind study to investigate EEEV clinical disease ...course following aerosol challenge in a cynomolgus macaque model utilizing the state-of-the-art telemetry to measure critical physiological parameters. Here, we report the results of a comprehensive pathology study of NHP tissues collected at euthanasia to gain insights into EEEV pathogenesis. Viral RNA and proteins as well as microscopic lesions were absent in the visceral organs. In contrast, viral RNA and proteins were readily detected throughout the brain including autonomic nervous system (ANS) control centers and spinal cord. However, despite presence of viral RNA and proteins, majority of the brain and spinal cord tissues exhibited minimal or no microscopic lesions. The virus tropism was restricted primarily to neurons, and virus particles (~61-68 nm) were present within axons of neurons and throughout the extracellular spaces. However, active virus replication was absent or minimal in majority of the brain and was limited to regions proximal to the olfactory tract. These data suggest that EEEV initially replicates in/near the olfactory bulb following aerosol challenge and is rapidly transported to distal regions of the brain by exploiting the neuronal axonal transport system to facilitate neuron-to-neuron spread. Once within the brain, the virus gains access to the ANS control centers likely leading to disruption and/or dysregulation of critical physiological parameters to produce severe disease. Moreover, the absence of microscopic lesions strongly suggests that the underlying mechanism of EEEV pathogenesis is due to neuronal dysfunction rather than neuronal death. This study is the first comprehensive investigation into EEEV pathology in a NHP model and will provide significant insights into the evaluation of countermeasure.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Non-cholera Vibrio bacteria are a major cause of foodborne illness in the United States. Raw oysters are commonly implicated in gastroenteritis caused by pathogenic Vibrio parahaemolyticus. In ...response to outbreaks in 1997–1998, the US Food and Drug Administration developed a nation-wide quantitative microbial risk assessment (QMRA) of V. parahaemolyticus in raw oysters in 2005. The QMRA identified information gaps that new research may address. Incidence of sporadic V. parahaemolyticus illness has recently increased and, as oyster consumption increases and sea temperatures rise, V. parahaemolyticus outbreaks may become more frequent, posing health concerns. Updated and region-specific QMRAs will improve the accuracy and precision of risk of infection estimates.
We identify research to support an updated QMRA of V. parahaemolyticus from oysters harvested in Chesapeake Bay and Puget Sound, focusing on observational and experimental research on post-harvest practices (PHPs) published from 2004 to 2019.
A predefined search strategy was applied to PubMed, Embase, Scopus, Science.gov, NAL Agricola, and Google Scholar. Study eligibility criteria were defined using a population, intervention, comparator, and outcome statement. Reviewers independently coded abstracts for inclusion/exclusion using predefined criteria. Data were extracted and study quality and relevance evaluated based on published guidance for food safety risk assessments. Findings were synthesized using a weight of evidence approach.
Of 12,174 articles retrieved, 93 were included for full-text review. Twenty-seven studies were found to be high quality and high relevance, including studies on cold storage, high hydrostatic pressure, depuration, and disinfectant, and other PHPs. High hydrostatic pressure consistently emerged as the most effective PHP in reducing abundance of V. parahaemolyticus.
Limitations of the knowledge base and review approach involve the type and quantity of data reported. Future research should focus on PHPs for which few or no high quality and high relevance studies exist, such as irradiation and relaying.
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•We systematically reviewed post-harvest intervention studies for Vibrio parahaemolyticus.•93 studies were included for full-text review and 27 studies were high quality and high relevance.•High hydrostatic pressure consistently emerged as the most effective post-harvest practice.
Objective: To examine the clinical and radiographic features in men and women in the Prospective Study of Outcomes in Ankylosing Spondylitis cohort, a large well-defined cross-sectional study of ...patients with AS, in order to understand the influence of gender in determining the severity of ankylosing spondylitis. Methods: Extensive clinical assessments and spine radiographs were performed in 302 men and 100 women with AS of ⩾20 years duration. Radiographs were scored using the Bath Ankylosing Spondylitis Radiographic Index Spine (BASRI-spine) score (range 2–12). Functional impairment was measured by the Bath Ankylosing Spondylitis Functional Index (BASFI) and the Health Assessment Questionnaire for the Spondyloarthropathies (HAQ-S). Results: Radiographic severity was worse among men. The unadjusted median BASRI-spine score for men was 10, compared with 6.5 for women (p<0.001). Functional disability, as measured by the BASFI and HAQ-S, was not different between men and women. However, after adjusting for radiographic spinal damage, women were found to report worse functioning than men at any given level of radiographic damage. Women had a slightly earlier age of disease onset; however, disease duration was identical in both groups. Women more frequently reported family histories of AS in first-degree relatives and were more likely to be treated with intra-articular steroids, sulphasalazine and prednisone. Conclusions: Among patients with longstanding AS, men have more severe radiographic changes; findings of treatment differences suggest that women may have more peripheral arthritis. At any given level of radiographic damage, self-reported functional limitations were worse for women.
The Chandra Source Catalog Evans, Ian N; Primini, Francis A; Glotfelty, Kenny J ...
The Astrophysical journal. Supplement series,
07/2010, Letnik:
189, Številka:
1
Journal Article
Recenzirano
Odprti dostop
The Chandra Source Catalog (CSC) is a general purpose virtual X-ray astrophysics facility that provides access to a carefully selected set of generally useful quantities for individual X-ray sources, ...and is designed to satisfy the needs of a broad-based group of scientists, including those who may be less familiar with astronomical data analysis in the X-ray regime. The first release of the CSC includes information about 94,676 distinct X-ray sources detected in a subset of public Advanced CCD Imaging Spectrometer imaging observations from roughly the first eight years of the Chandra mission. This release of the catalog includes point and compact sources with observed spatial extents {approx}<30''. The catalog (1) provides access to the best estimates of the X-ray source properties for detected sources, with good scientific fidelity, and directly supports scientific analysis using the individual source data; (2) facilitates analysis of a wide range of statistical properties for classes of X-ray sources; and (3) provides efficient access to calibrated observational data and ancillary data products for individual X-ray sources, so that users can perform detailed further analysis using existing tools. The catalog includes real X-ray sources detected with flux estimates that are at least 3 times their estimated 1{sigma} uncertainties in at least one energy band, while maintaining the number of spurious sources at a level of {approx}<1 false source per field for a 100 ks observation. For each detected source, the CSC provides commonly tabulated quantities, including source position, extent, multi-band fluxes, hardness ratios, and variability statistics, derived from the observations in which the source is detected. In addition to these traditional catalog elements, for each X-ray source the CSC includes an extensive set of file-based data products that can be manipulated interactively, including source images, event lists, light curves, and spectra from each observation in which a source is detected.
The mechanical response of multicomponent borosilicate glasses has drawn significant attention in the design of damage‐resistant glasses. In this work, we investigate the plasticity of two ...borosilicate glasses, Borofloat®33 (Boro33) and N‐BK7®, by implementing a uniaxial tension test using molecular dynamics simulations. A bond‐switching mechanism is found to be responsible for the plastic response of both glasses and is governed by the increasing rate of non‐bridging oxygen (NBO) production during the uniaxial tension. We found that the amount of B4OSi4 linkages in the glass governs the stress drop after yielding, due to its higher tendency to create NBOs compared to Si4OSi4. Also, the initial existence of NBOs weakens the critical stress for breaking the B4‐O bond in B4OSi4, which in turn lowers the yield strength of the glass. The local atomic constraints are analyzed in the two glasses, and high anti‐correlation between the concentration of rigid constraints and plastic deformation is observed.
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