Regional cerebral blood flow single photon emission computed tomography for detection of Frontotemporal dementia in people with suspected dementia.

BACKGROUND: In the UK, dementia affects 5% of the population aged over 65 years and 25% of those over 85 years. Frontotemporal dementia (FTD) represents one subtype and is thought to account for up to 16% of all degenerative dementias. Although the core of the diagnostic process in dementia rests firmly on clinical and cognitive assessments, a wide range of investigations are available to aid diagnosis.Regional cerebral blood flow (rCBF) single-photon emission computed tomography (SPECT) is an established clinical tool that uses an intravenously injected radiolabelled tracer to map blood flow in the brain. In FTD the characteristic pattern seen is hypoperfusion of the frontal and anterior temporal lobes. This pattern of blood flow is different to patterns seen in other subtypes of dementia and so can be used to differentiate FTD.It has been proposed that a diagnosis of FTD, (particularly early stage), should be made not only on the basis of clinical criteria but using a combination of other diagnostic findings, including rCBF SPECT. However, more extensive testing comes at a financial cost, and with a potential risk to patient safety and comfort. OBJECTIVES: To determine the diagnostic accuracy of rCBF SPECT for diagnosing FTD in populations with suspected dementia in secondary/tertiary healthcare settings and in the differential diagnosis of FTD from other dementia subtypes. SEARCH METHODS: Our search strategy used two concepts: (a) the index test and (b) the condition of interest. We searched citation databases, including MEDLINE (Ovid SP), EMBASE (Ovid SP), BIOSIS (Ovid SP), Web of Science Core Collection (ISI Web of Science), PsycINFO (Ovid SP), CINAHL (EBSCOhost) and LILACS (Bireme), using structured search strategies appropriate for each database. In addition we searched specialised sources of diagnostic test accuracy studies and reviews including: MEDION (Universities of Maastricht and Leuven), DARE (Database of Abstracts of Reviews of Effects) and HTA (Health Technology Assessment) database.We requested a search of the Cochrane Register of Diagnostic Test Accuracy Studies and used the related articles feature in PubMed to search for additional studies. We tracked key studies in citation databases such as Science Citation Index and Scopus to ascertain any further relevant studies. We identified 'grey' literature, mainly in the form of conference abstracts, through the Web of Science Core Collection, including Conference Proceedings Citation Index and Embase. The most recent search for this review was run on the 1 June 2013.Following title and abstract screening of the search results, full-text papers were obtained for each potentially eligible study. These papers were then independently evaluated for inclusion or exclusion. SELECTION CRITERIA: We included both case-control and cohort (delayed verification of diagnosis) studies. Where studies used a case-control design we included all participants who had a clinical diagnosis of FTD or other dementia subtype using standard clinical diagnostic criteria. For cohort studies, we included studies where all participants with suspected dementia were administered rCBF SPECT at baseline. We excluded studies of participants from selected populations (e.g. post-stroke) and studies of participants with a secondary cause of cognitive impairment. DATA COLLECTION AND ANALYSIS: Two review authors extracted information on study characteristics and data for the assessment of methodological quality and the investigation of heterogeneity. We assessed the methodological quality of each study using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool. We produced a narrative summary describing numbers of studies that were found to have high/low/unclear risk of bias as well as concerns regarding applicability. To produce 2 x 2 tables, we dichotomised the rCBF SPECT results (scan positive or negative for FTD) and cross-tabulated them against the results for the reference standard. These tables were then used to calculate the sensitivity and specificity of the index test. Meta-analysis was not performed due to the considerable between-study variation in clinical and methodological characteristics. MAIN RESULTS: Eleven studies (1117 participants) met our inclusion criteria. These consisted of six case-control studies, two retrospective cohort studies and three prospective cohort studies. Three studies used single-headed camera SPECT while the remaining eight used multiple-headed camera SPECT. Study design and methods varied widely. Overall, participant selection was not well described and the studies were judged as having either high or unclear risk of bias. Often the threshold used to define a positive SPECT result was not predefined and the results were reported with knowledge of the reference standard. Concerns regarding applicability of the studies to the review question were generally low across all three domains (participant selection, index test and reference standard).Sensitivities and specificities for differentiating FTD from non-FTD ranged from 0.73 to 1.00 and from 0.80 to 1.00, respectively, for the three multiple-headed camera studies. Sensitivities were lower for the two single-headed camera studies; one reported a sensitivity and specificity of 0.40 (95% confidence interval (CI) 0.05 to 0.85) and 0.95 (95% CI 0.90 to 0.98), respectively, and the other a sensitivity and specificity of 0.36 (95% CI 0.24 to 0.50) and 0.92 (95% CI 0.88 to 0.95), respectively.Eight of the 11 studies which used SPECT to differentiate FTD from Alzheimer's disease used multiple-headed camera SPECT. Of these studies, five used a case-control design and reported sensitivities of between 0.52 and 1.00, and specificities of between 0.41 and 0.86. The remaining three studies used a cohort design and reported sensitivities of between 0.73 and 1.00, and specificities of between 0.94 and 1.00. The three studies that used single-headed camera SPECT reported sensitivities of between 0.40 and 0.80, and specificities of between 0.61 and 0.97. AUTHORS' CONCLUSIONS: At present, we would not recommend the routine use of rCBF SPECT in clinical practice because there is insufficient evidence from the available literature to support this.Further research into the use of rCBF SPECT for differentiating FTD from other dementias is required. In particular, protocols should be standardised, study populations should be well described, the threshold for 'abnormal' scans predefined and clear details given on how scans are analysed. More prospective cohort studies that verify the presence or absence of FTD during a period of follow up should be undertaken

Technical note: development of a 3D printed subresolution sandwich phantom for validation of brain SPECT analysis

Purpose: To make an adaptable, head shaped radionuclide phantom to simulate molecular imaging of the brain using clinical acquisition and reconstruction protocols. This will allow the characterization and correction of scanner characteristics, and improve the accuracy of clinical image analysis, including the application of databases of normal subjects. Methods: A fused deposition modeling 3D printer was used to create a head shaped phantom made up of transaxial slabs, derived from a simulated MRI dataset. The attenuation of the printed polylactide (PLA), measured by means of the Hounsfield unit on CT scanning, was set to match that of the brain by adjusting the proportion of plastic filament and air (fill ratio). Transmission measurements were made to verify the attenuation of the printed slabs. The radionuclide distribution within the phantom was created by adding 99mTc pertechnetate to the ink cartridge of a paper printer and printing images of gray and white matter anatomy, segmented from the same MRI data. The complete subresolution sandwich phantom was assembled from alternate 3D printed slabs and radioactive paper sheets, and then imaged on a dual headed gamma camera to simulate an HMPAO SPECT scan. Results: Reconstructions of phantom scans successfully used automated ellipse fitting to apply attenuation correction. This removed the variability inherent in manual application of attenuation correction and registration inherent in existing cylindrical phantom designs. The resulting images were assessed visually and by count profiles and found to be similar to those from an existing elliptical PMMA phantom. Conclusions: The authors have demonstrated the ability to create physically realistic HMPAO SPECT simulations using a novel head-shaped 3D printed subresolution sandwich method phantom. The phantom can be used to validate all neurological SPECT imaging applications. A simple modification of the phantom design to use thinner slabs would make it suitable for use in PET

Efficient pairwise RNA structure prediction and alignment using sequence alignment constraints

BACKGROUND: We are interested in the problem of predicting secondary structure for small sets of homologous RNAs, by incorporating limited comparative sequence information into an RNA folding model. The Sankoff algorithm for simultaneous RNA folding and alignment is a basis for approaches to this problem. There are two open problems in applying a Sankoff algorithm: development of a good unified scoring system for alignment and folding and development of practical heuristics for dealing with the computational complexity of the algorithm. RESULTS: We use probabilistic models (pair stochastic context-free grammars, pairSCFGs) as a unifying framework for scoring pairwise alignment and folding. A constrained version of the pairSCFG structural alignment algorithm was developed which assumes knowledge of a few confidently aligned positions (pins). These pins are selected based on the posterior probabilities of a probabilistic pairwise sequence alignment. CONCLUSION: Pairwise RNA structural alignment improves on structure prediction accuracy relative to single sequence folding. Constraining on alignment is a straightforward method of reducing the runtime and memory requirements of the algorithm. Five practical implementations of the pairwise Sankoff algorithm – this work (Consan), David Mathews' Dynalign, Ian Holmes' Stemloc, Ivo Hofacker's PMcomp, and Jan Gorodkin's FOLDALIGN – have comparable overall performance with different strengths and weaknesses

Sphingolipid Modulation Activates Proteostasis Programs to Govern Human Hematopoietic Stem Cell Self-Renewal.

Cellular stress responses serve as crucial decision points balancing persistence or culling of hematopoietic stem cells (HSCs) for lifelong blood production. Although strong stressors cull HSCs, the linkage between stress programs and self-renewal properties that underlie human HSC maintenance remains unknown, particularly at quiescence exit when HSCs must also dynamically shift metabolic state. Here, we demonstrate distinct wiring of the sphingolipidome across the human hematopoietic hierarchy and find that genetic or pharmacologic modulation of the sphingolipid enzyme DEGS1 regulates lineage differentiation. Inhibition of DEGS1 in hematopoietic stem and progenitor cells during the transition from quiescence to cellular activation with N-(4-hydroxyphenyl) retinamide activates coordinated stress pathways that coalesce on endoplasmic reticulum stress and autophagy programs to maintain immunophenotypic and functional HSCs. Thus, our work identifies a linkage between sphingolipid metabolism, proteostatic quality control systems, and HSC self-renewal and provides therapeutic targets for improving HSC-based cellular therapeutics.E.L. is supported by Wellcome grant 107630/Z/15/Z and a core support grant from the Wellcome and MRC to the Wellcome-Medical Research Council Cambridge Stem Cell Institute. C.L. is supported by U.S. NIH, NCI Grant P01-CA097132. JED is supported by funds from the Princess Margaret Cancer Centre Foundation, Canadian Institutes for Health Research, Joint Canada-Israel Health Research Program, Terry Fox Foundation, and a Canada Research Chair

Ernst Freund as Precursor of the Rational Study of Corporate Law

Gindis, David, Ernst Freund as Precursor of the Rational Study of Corporate Law (October 27, 2017). Journal of Institutional Economics, Forthcoming. Available at SSRN: https://ssrn.com/abstract=2905547, doi: https://dx.doi.org/10.2139/ssrn.2905547The rise of large business corporations in the late 19th century compelled many American observers to admit that the nature of the corporation had yet to be understood. Published in this context, Ernst Freund's little-known The Legal Nature of Corporations (1897) was an original attempt to come to terms with a new legal and economic reality. But it can also be described, to paraphrase Oliver Wendell Holmes, as the earliest example of the rational study of corporate law. The paper shows that Freund had the intuitions of an institutional economist, and engaged in what today would be called comparative institutional analysis. Remarkably, his argument that the corporate form secures property against insider defection and against outsiders anticipated recent work on entity shielding and capital lock-in, and can be read as an early contribution to what today would be called the theory of the firm.Peer reviewe

Fear filter: Visualising the UK terror threat level

Fear Filter is a digital artwork comprising of a mobile phone photo filters application for Android / iOS platforms and a digital photo stream. The photo filters are created by gathering current and historical information about the UK Threat Level from a live feed from MI5, the UK security service. Photographs taken with the mobile application are transformed by the photo filters, each of which correspond to a different moment in time and the related Threat Level from that period. The filters cover the period 1 August 2006 until the present moment. Photos shared from the mobile application are automatically posted to a public photo stream.Fear Filter exploits the confluence of mobile digital photography, platforms, networks and the online security theatre of the UK Threat Level to reformulate the relationship between photography and terrorism

Measurement of the cross-section and charge asymmetry of WW bosons produced in proton-proton collisions at s=8\sqrt{s}=8 TeV with the ATLAS detector

This paper presents measurements of the $W^+ \rightarrow \mu^+\nu$ and $W^- \rightarrow \mu^-\nu$ cross-sections and the associated charge asymmetry as a function of the absolute pseudorapidity of the decay muon. The data were collected in proton--proton collisions at a centre-of-mass energy of 8 TeV with the ATLAS experiment at the LHC and correspond to a total integrated luminosity of 20.2~\mbox{fb^{-1}}. The precision of the cross-section measurements varies between 0.8% to 1.5% as a function of the pseudorapidity, excluding the 1.9% uncertainty on the integrated luminosity. The charge asymmetry is measured with an uncertainty between 0.002 and 0.003. The results are compared with predictions based on next-to-next-to-leading-order calculations with various parton distribution functions and have the sensitivity to discriminate between them.Comment: 38 pages in total, author list starting page 22, 5 figures, 4 tables, submitted to EPJC. All figures including auxiliary figures are available at https://atlas.web.cern.ch/Atlas/GROUPS/PHYSICS/PAPERS/STDM-2017-13

Search for chargino-neutralino production with mass splittings near the electroweak scale in three-lepton final states in √s=13 TeV pp collisions with the ATLAS detector

A search for supersymmetry through the pair production of electroweakinos with mass splittings near the electroweak scale and decaying via on-shell W and Z bosons is presented for a three-lepton final state. The analyzed proton-proton collision data taken at a center-of-mass energy of √s=13  TeV were collected between 2015 and 2018 by the ATLAS experiment at the Large Hadron Collider, corresponding to an integrated luminosity of 139  fb−1. A search, emulating the recursive jigsaw reconstruction technique with easily reproducible laboratory-frame variables, is performed. The two excesses observed in the 2015–2016 data recursive jigsaw analysis in the low-mass three-lepton phase space are reproduced. Results with the full data set are in agreement with the Standard Model expectations. They are interpreted to set exclusion limits at the 95% confidence level on simplified models of chargino-neutralino pair production for masses up to 345 GeV