Nanostructural Diversity of Synapses in the Mammalian Spinal Cord

This work for funded by the Biotechnology and Biological Sciences Research Council (BBSRC; BB/M021793/1), RS MacDonald Charitable Trust, Motor Neurone Disease (MND) Association UK (Miles/Apr18/863-791), the Engineering and Physical Sciences Research Council (EPSRC; EP/P030017/1), Welcome Trust (202932/Z/16/Z), European Research Council (ERC; 695568) and the Simons Initiative for the Developing Brain.Functionally distinct synapses exhibit diverse and complex organisation at molecular and nanoscale levels. Synaptic diversity may be dependent on developmental stage, anatomical locus and the neural circuit within which synapses reside. Furthermore, astrocytes, which align with pre and post-synaptic structures to form “tripartite synapses”, can modulate neural circuits and impact on synaptic organisation. In this study, we aimed to determine which factors impact the diversity of excitatory synapses throughout the lumbar spinal cord. We used PSD95-eGFP mice, to visualise excitatory postsynaptic densities (PSDs) using high-resolution and super-resolution microscopy. We reveal a detailed and quantitative map of the features of excitatory synapses in the lumbar spinal cord, detailing synaptic diversity that is dependent on developmental stage, anatomical region and whether associated with VGLUT1 or VGLUT2 terminals. We report that PSDs are nanostructurally distinct between spinal laminae and across age groups. PSDs receiving VGLUT1 inputs also show enhanced nanostructural complexity compared with those receiving VGLUT2 inputs, suggesting pathway-specific diversity. Finally, we show that PSDs exhibit greater nanostructural complexity when part of tripartite synapses, and we provide evidence that astrocytic activation enhances PSD95 expression. Taken together, these results provide novel insights into the regulation and diversification of synapses across functionally distinct spinal regions and advance our general understanding of the ‘rules’ governing synaptic nanostructural organisation.Publisher PDFPeer reviewe

A multicenter assessment of interreader reliability of LI-RADS version 2018 for MRI and CT

Background: Various limitations have impacted research evaluating reader agreement for Liver Imaging-Reporting and Data System (LI-RADS). Purpose: To assess reader agreement of LI-RADS in an international multi-center, multireader setting using scrollable images. Materials and Methods: This retrospective study used de-identified clinical multiphase CT and MRI examinations and reports with at least one untreated observation from six institutions and three countries; only qualifying examinations were submitted. Examination dates were October 2017 – August 2018 at the coordinating center. One untreated observation per examination was randomly selected using observation identifiers, and its clinically assigned features were extracted from the report. The corresponding LI-RADS v2018 category was computed as a re-scored clinical read. Each examination was randomly assigned to two of 43 research readers who independently scored the observation. Agreement for an ordinal modified four-category LI-RADS scale (LR-1/2, LR-3, LR-4, LR-5/M/tumor in vein) was computed using intra-class correlation coefficients (ICC). Agreement was also computed for dichotomized malignancy (LR-4/LR5/LR-M/LR-tumor in vein), LR-5, and LR-M. Agreement was compared between researchversus-research reads and research-versus-clinical reads. Results: 484 patients (mean age, 62 years ±10 [SD]; 156 women; 93 CT, 391 MRI) were included. ICCs for ordinal LI-RADS, dichotomized malignancy, LR-5, and LR-M were 0.68 (95% CI: 0.62, 0.74), 0.63 (95% CI: 0.56, 0.71), 0.58 (95% CI: 0.50, 0.66), and 0.46 (95% CI: 0.31, 0.61) respectively. Research-versus-research reader agreement was higher than research-versus-clinical agreement for modified four-category LI-RADS (ICC, 0.68 vs. 0.62, P = .03) and for dichotomized malignancy (ICC, 0.63 vs. 0.53, P = .005), but not for LR-5 (P = .14) or LR-M (P = .94). Conclusion: There was moderate agreement for Liver Imaging-Reporting and Data System v2018 overall. For some comparisons, research-versus-research reader agreement was higher than research-versus-clinical reader agreement, indicating differences between the clinical and research environments that warrant further study

Multisite clinical validation of isothermal amplification-based SARS-CoV-2 detection assays using different sampling strategies

Isothermal amplification-based tests have been introduced as rapid, low-cost, and simple alternatives to real-time reverse transcriptase PCR (RT-PCR) tests for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) detection. The clinical performance of two isothermal amplification-based tests (Atila Biosystems iAMP coronavirus disease of 2019 [COVID-19] detection test and OptiGene COVID-19 direct plus RT-loop-mediated isothermal amplification [LAMP] test) was compared with that of clinical RT-PCR assays using different sampling strategies. A total of 1,378 participants were tested across 4 study sites. Compared with standard of care RT-PCR testing, the overall sensitivity and specificity of the Atila iAMP test for detection of SARS-CoV-2 were 76.2% and 94.9%, respectively, and increased to 88.8% and 89.5%, respectively, after exclusion of an outlier study site. Sensitivity varied based on the anatomic site from which the sample was collected. Sensitivity for nasopharyngeal sampling was 65.4% (range across study sites, 52.8% to 79.8%), for midturbinate was 88.2%, for saliva was 55.1% (range across study sites, 42.9% to 77.8%), and for anterior nares was 66.7% (range across study sites, 63.6% to 76.5%). The specificity for these anatomic collection sites ranged from 96.7% to 100%. Sensitivity improved in symptomatic patients (overall, 82.7%) and those with a higher viral load (overall, 92.4% for cycle threshold [CT] of #25). Sensitivity and specificity of the OptiGene direct plus RT-LAMP test, which was conducted at a single study site, were 25.5% and 100%, respectively. The Atila iAMP COVID test with midturbinate sampling is a rapid, low-cost assay for detecting SARS-CoV-2, especially in symptomatic patients and those with a high viral load, and could be used to reduce the risk of SARS-CoV-2 transmission in clinical settings. Variation of performance between study sites highlights the need for site-specific clinical validation of these assays before clinical adoption. IMPORTANCE Numerous SARS-CoV-2 detection assays have been developed and introduced into the market under emergency use authorizations (EUAs). EUAs are granted primarily based on small studies of analytic sensitivity and specificity with limited clinical validations. A thorough clinical performance evaluation of SARS-CoV-2 assays is important to understand the strengths, limitations, and specific applications of these assays. In this first large-scale multicentric study, we evaluated the clinical performance and operational characteristics of two isothermal amplification-based SARS-CoV-2 tests, namely, (i) iAMP COVID-19 detection test (Atila BioSystems, USA) and (ii) COVID-19 direct plus RT-LAMP test (OptiGene Ltd., UK), compared with those of clinical RT-PCR tests using different sampling strategies (i.e., nasopharyngeal, self-sampled anterior nares, self-sampled midturbinate, and saliva). An important specific use for these isothermal amplification-based, rapid, low-cost, and easy-to-perform SARS-CoV-2 assays is to allow for a safer return to preventive clinical encounters, such as cancer screening, particularly in low- and middle-income countries that have low SARS-CoV-2 vaccination rates

The RCO/DN Approach to Planning of Urban Growth Boundaries

ABSTRACT: Cities are faced with serious issues resulting from urban sprawl, and one way to manage this is through the implementation of urban growth boundaries (UGB). The complexity of cities makes long-term planning extremely difficult. The high level of uncertainty, currently inherent in any complex and long-term problem, makes this task even more formidable.Decision Network (DN) methodology has been developed to deal with complexity and Risk-Constrained Optimization® (RCO) is a system for long-term planning and risk management under radical uncertainty. This study integrated the two systems in the form of RCO/DN, resulting in the creation of a powerful tool to deal with the problems of urban planning. RCO/DN is meant to enhance the effectiveness of planning by taking into consideration both its intended goals and undesirable unintended consequences. As a second function, RCO/DN prevents the overextension of urban resources, physical, technological, financial, and human.RCO/DN presents the uncertainty associated with future events using multiple scenarios provided by city planners and simulations. Scenarios differ with regard to values of their parameters, such as annual land use or inflated costs of land within UGBs. Unfortunately, under radical uncertainty it is impossible to predict plan outcomes or reliably convert diverse outcomes into a single metric to allow a comparison of strategies. Finally, under such conditions there exists neither a “best solution”, nor a “best method” to select a solution.The only option is to develop a number of reasonably good and safe strategies. These strategies can then be presented to decision-makers for final selection, which they make according to their preferences and their attitudes toward various forms of risk.This approach seeks to identify good tradeoffs between various forms of risk, such as environmental, human safety-related, or financial. RCO/DN accomplishes this task by using an ensemble of novel techniques that includes enhanced stochastic multiscenario mathematical programming models, designed to reveal hidden dangers within unfavorable scenarios.With regard to the planning of UGBs, RCO/DN is a risk management system that allows the combination of time-driven and event-driven approaches to reduce costs by shortening the planning horizon.Simplified RCO/DN models can be standardized for small towns, while more complex models can be developed for large cities, in which UGBs are connected to multiple interrelated factors. This approach is particularly valuable in planning disaster mitigation actions as well as in dealing with economic crises. The more complex planning difficulties are, the greater the benefits of RCO/DN in realistic planning, risk management, and cost savings. KEYWORDS: Stainability, risk management, urban planning, urban growth boundaries, decision-making under radical uncertainty, stochastic multiscenario models, complexit

Polyglotton Medicum, eine Anleitung zur Verständigung des Arztes mit dem Kranken in sechs Sprachen, mit Rücksicht auf die Hauptsprachen der Völker des österreichischen Kaiserstaates, Deutsch, Böhmisch, Polnisch, Ungarisch, Italienisch, Französisch, enthaltend: eine systematische Zusammenstellung von Fragen, ... nach den Forderungen der Diagnose, Prognose und Therapie

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Comparison of Diffusion Tensor Imaging and Magnetic Resonance Perfusion Imaging in Differentiating Recurrent Brain Neoplasm From Radiation Necrosis

RATIONALE AND OBJECTIVES: To compare differences in diffusion tensor imaging (DTI) and dynamic susceptibility-weighted contrast-enhanced (DSC) magnetic resonance (MR) perfusion imaging characteristics of recurrent neoplasm and radiation necrosis in patients with brain tumors previously treated with radiotherapy with or without surgery and chemotherapy. MATERIALS AND METHODS: Patients with a history of brain neoplasm previously treated with radiotherapy with or without chemotherapy and surgery who developed a new enhancing lesion on posttreatment surveillance MRI were enrolled. DSC perfusion MRI and DTI were performed. Region of interest cursors were manually drawn in the contrast-enhancing lesions, in the perilesional white matter edema, and in the contralateral normal-appearing frontal lobe white matter. DTI and DSC perfusion MR indices were compared in recurrent tumor versus radiation necrosis. RESULTS: Twenty-two patients with 24 lesions were included. Sixteen (67%) lesions were placed into the recurrent neoplasm group and eight (33%) lesions were placed into the radiation necrosis group using biopsy results as the gold standard in all but three patients. Mean apparent diffusion coefficient values, mean parallel eigenvalues, and mean perpendicular eigenvalues in the contrast-enhancing lesion were significantly lower, and relative cerebral blood volume was significantly higher for the recurrent neoplasm group compared to the radiation necrosis group (P < 0.01, P = 0.03, P < 0.01, and P < 0.01, respectively). CONCLUSIONS: The combined assessment of DTI and DSC MR perfusion properties of new contrast-enhancing lesions is helpful in distinguishing recurrent neoplasm from radiation necrosis in patients with a history of brain neoplasm previously treated with radiotherapy with or without surgery and chemotherapy