T. Williams

COVID-19 is associated with a dysregulated immune response but it is unclear how immune dysfunction contributes to the chronic morbidity persisting in many COVID-19 patients during convalescence (long COVID).We assessed phenotypical and functional changes of monocytes in COVID-19 patients during hospitalisation and up to 9 months of convalescence following COVID-19, respiratory syncytial virus or influenza A. Patients with progressive fibrosing interstitial lung disease were included as a positive control for severe, ongoing lung injury.Monocyte alterations in acute COVID-19 patients included aberrant expression of leukocyte migration molecules, continuing into convalescence (n=142) and corresponding with specific symptoms of long COVID. Long COVID patients with unresolved lung injury, indicated by sustained shortness of breath and abnormal chest radiology, were defined by high monocyte expression of C-X-C motif chemokine receptor 6 (CXCR6) (p<0.0001) and adhesion molecule P-selectin glycoprotein ligand 1 (p<0.01), alongside preferential migration of monocytes towards the CXCR6 ligand C-X-C motif chemokine ligand 16 (CXCL16) (p<0.05), which is abundantly expressed in the lung. Monocyte CXCR6 and lung CXCL16 were heightened in patients with progressive fibrosing interstitial lung disease (p<0.001), confirming a role for the CXCR6-CXCL16 axis in ongoing lung injury. Conversely, monocytes from long COVID patients with ongoing fatigue exhibited a sustained reduction of the prostaglandin-generating enzyme cyclooxygenase 2 (p<0.01) and CXCR2 expression (p<0.05). These monocyte changes were not present in respiratory syncytial virus or influenza A convalescence.Our data define unique monocyte signatures that define subgroups of long COVID patients, indicating a key role for monocyte migration in COVID-19 pathophysiology. Targeting these pathways may provide novel therapeutic opportunities in COVID-19 patients with persistent morbidity.

Journal Article Trade Negotiations in the Tokyo Round: A Quantitative Assessment Get access Trade Negotiations in the Tokyo Round: A Quantitative Assessment. By WILLIAM R. CLINE, NOBORU KAWANABE, T. O. M. KRONSJO and THOMAS WILLIAMS. (Washington: The Brookings Institution, 1978. Pp. xiv + 314.) James McGilvray James McGilvray Fraser of Allander Institute University of Strathclyde Search for other works by this author on: Oxford Academic Google Scholar The Economic Journal, Volume 89, Issue 354, 1 June 1979, Pages 428–430, https://doi.org/10.2307/2231618 Published: 01 June 1979

Time-resolved spectroscopic techniques are used to determine the primary photoprocesses of A2E in solution. Comparison of the absorption and excitation spectrum of A2E in methanol solution indicates excitation at 400 nm populates the S2 excited state. Transient absorption signals decaying with a time constant of 0.9 ps were observed probing around 800 nm. These signals are attributed to the S2→Sn transition and reveal the S2→S1 relaxation occurs on the subpicosecond time scale. Transient absorption data probing at shorter wavelengths (480 and 550 nm) are attributed to the S1→Sn absorption. These signals exhibit an exponential decay with a time constant of 11 and 13 ps, respectively. Time-resolved emission measurements of the corresponding S0←S1 decay reveal a nonexponential decay; however, >95% of the signal amplitude is described by an exponential decay with a time constant of 12.4 ps. Both time-resolved emission and absorption experiments therefore indicate repopulation of the ground electronic state occurs with a time constant of ∼12 ps. A weak transient absorption probing in the blue (400 nm) persists onto the nanosecond time scale and is attributed to the T1→Tn absorption of A2E. Photoacoustic spectroscopy establishes the quantum yield for intersystem crossing of A2E in methanol solution is at most 0.03. The emission quantum yield of A2E in ethanol is determined to be 0.01, and so, nonradiative relaxation is the dominant primary event. The quantum yield for the generation of singlet molecular oxygen following 355 nm excitation of A2E in acetonitrile was determined to be 0.02, consistent with a low production of the excited triplet state. These results establish A2E is not an efficient photogenerator of reaction oxygen species in solution.

Thomas Williams' edition offers an Introduction well suited for use in an introductory philosophy course, as well as his own preeminent translation of the text.

Abstract The Serenity-S1 is a production-optimised Advanced Telecommunications Computing Architecture (ATCA) processing blade based on the AMD Xilinx Virtex Ultrascale+ device. It incorporates many developments from the Serenity-A and Serenity-Z prototype cards and, where possible, adopts solutions being used across CERN. Due to the shortage of components during the recent semiconductor crisis, commonly used components in the prototypes had to be replaced by new ones after qualification. In this work, we discuss various improvements to simplify manufacturing, the performance of new components, some of the more difficult aspects of procurement, the performance of production-grade Samtec 25 Gb/s optical firefly parts, and concerns regarding the rack cooling infrastructure.

Abstract For the High-Luminosity LHC (HL-LHC) era, the trigger and data acquisition system of the CMS experiment will be entirely replaced. The HL-LHC CMS Level-1 Trigger system will consist of approximately 200 ATCA boards featuring Xilinx UltraScale+ FPGAs connected by 25 Gb/s optical links. These boards will process over 60 Tb/s of detector data within 9.5 μs of the collision to select up to 750 kHz of events for readout. In this paper, we summarise the current status of hardware tests, our progress on system integration tests, and the online software designed to control and monitor these boards.

Abstract Background p53 is the most commonly mutated gene in human cancer, prevalent in nearly all tumor types. Despite its significant medical relevance and the knowledge that human T cells recognize these mutations[1,2], immunotherapies designed to promote responses against mutated p53 (mp53) have not had the hoped-for clinical impact[3]. The Amphiphile (AMP) platform improves the potency of vaccine immunotherapy by programming the delivery of vaccine components to the lymph nodes where efficient uptake by immune cells initiates tumor-targeted immune responses. AMP-modification of vaccine components (peptide antigens, molecular adjuvants) results in covalent conjugation to albumin-binding lipids. Upon injection, AMP-vaccines associate with tissue-resident albumin which efficiently distributes to draining lymph nodes. This approach was shown to promote activation of polyfunctional, cytotoxic T cells with promising safety and improved clinical outcomes in a Phase 1 trial of ELI-002, an mKRAS AMP therapeutic vaccine (AMPLIFY-201 NCT05726864). Application of this strategy to p53 mutations with ELI-008 offers the potential for improved immunotherapeutic activity in a setting of significant unmet need. Methods Following immunization of C57BL/6J mice with AMP-modified or soluble comparator vaccines consisting of mp53 peptides and CpG adjuvant, analyses were performed 7 days after the third bi-weekly dose. To assess antigen-specific T cell responses, ELISpot (IFNγ, GzmB), multiplexed proteomic, and flowcytometric analysis of effector cytokines (IFNγ, TNFα, IL-2) were performed following antigenic stimulation. Responses were determined in secondary lymphoid tissues and lung. Cytolytic capabilities of antigen-specific T cells were evaluated by monitoring specific killing of IV-transferred antigen-pulsed target cells. Results AMP-immunization generated robust immune responses yielding strong T cell activation against common p53 hot spot mutations (R248W, R248Q, R175H, G245S, R273H, Y220C, C135Y, R158H, H214R). Responses to AMP-vaccination were characterized by the generation of increased frequency of polyfunctional T cells (IFNγ, TNFα, IL2) specific to mp53 epitopes. Induced T cells demonstrated significant levels of cytolytic activity including GzmB production and elimination of target cells in vivo. Non-lymph targeted vaccines using soluble comparators were inactive. Conclusions AMP-conjugation permits efficient delivery directly to the lymph nodes and thus improves the immunogenicity of peptide vaccination. These substantially improved immune responses induced by ELI-008 represent a promising therapeutic opportunity for targeting cancer in a large fraction of human tumors. The AMP-platform technology is simple, rapid and scalable, promising broad clinical, off-the-shelf application for treating p53 mutated tumors. Citation Format: Martin P. Steinbuck, Xavier Cabana-Puig, Erica Palmer, Mimi M. Jung, Thomas Williams, Kristen Osaer, Jeff Zhang, Christopher M. Haqq, Peter C. DeMuth. AMP-peptide vaccination against multiple p53 mutant epitopes promotes lymph node delivery to generate potent, functional T cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4099.

Abstract Background Mutations in BRAF cause ~8% of human cancers[1]. Nonetheless, therapies designed to promote immune responses against mutated BRAF (mBRAF) have led to limited clinical success[2], despite evidence confirming T cell recognition of these mutations[3,4]. The Amphiphile (AMP) platform improves the potency of vaccine immunotherapy by programming the delivery of vaccine components to the lymph nodes where efficient uptake by resident immune cells initiates tumor-targeted immune responses. AMP-modification of vaccine components including peptide antigens and molecular adjuvants results in covalent conjugation to albumin-binding lipids. Upon injection, AMP-vaccines associate with tissue resident albumin which efficiently distributes to draining lymph nodes. This approach was shown to promote activation of polyfunctional, cytotoxic T cells with promising safety, and improved clinical outcomes in a Phase 1 trial of ELI-002, an mKRAS AMP therapeutic vaccine (AMPLIFY-201 NCT04853017). Application of this strategy to prevalent BRAF mutations with ELI-007 offers the potential for improved therapeutic activity in a setting of significant unmet need, as BRAF inhibitors benefit only a fraction of patients, with near universal progression. Methods Following multi-dose immunization of C57BL/6J mice with AMP-modified or soluble comparator vaccines consisting of mBRAF V600E/K peptides and CpG adjuvant, immunological readouts were performed 7 days after dosing. Antigen-specific T cell responses were assessed after ex vivo re-stimulation of cells with mBRAF overlapping peptides. Assays included analysis of antigen-specific T cell frequencies, multiplexed proteomics determining polyfunctionality, and effector function and cytotoxic potential evaluation. Responses were determined in secondary lymphoid tissues (spleen), as well as lung, to which many BRAF driven cancers metastasize. Results AMP-immunization generated robust in vivo immune responses yielding strong T cell activation against mBRAF epitopes. Non-lymph node targeted vaccination using soluble comparators were inactive with no response above mock treated mice. Responses to AMP-vaccination were characterized by the generation of significantly increased frequency of Th1-skewed, polyfunctional T cells (IFNγ, TNFα, IL2) specific to mBRAF V600E and V600K. Induced T cells further exhibited mBRAF-specific cytotoxic function. Conclusions AMP-conjugation enhances efficient delivery directly to the lymph nodes and thus improves the immunogenicity of peptide vaccination. These enhanced immune responses provide an encouraging therapeutic opportunity to treat &amp;gt;90% of BRAF-mutated cancers[5] with the AMP-mBRAF vaccine, ELI-007. Moreover, the AMP-platform technology is simple, rapidly executable, and scalable, promising broad clinical off-the-shelf application for BRAF. Citation Format: Martin P. Steinbuck, Xavier Cabana-Puig, Erica Palmer, Mimi M. Jung, Thomas Williams, Kristen Osaer, Jeff Zhang, Christopher M. Haqq, Peter C. DeMuth. AMP-peptide vaccination against mutant BRAF epitopes promotes lymph node delivery to generate potent, functional T cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4100.

ABSTRACT Sudlow Site I of human serum albumin (HSA) is located in subdomain IIA of the protein and serves as a binding cavity for a variety of ligands. In this study, the binding of warfarin (W) is examined using computational techniques and isothermal titration calorimetry (ITC). The structure of the docked warfarin anion (W − ) to Site I is similar to that revealed by X‐ray crystallography, with a calculated binding constant of 5.8 × 10 5 M −1 . ITC experiments (pH 7.13 and I = 0.1) carried out in three different buffers (MOPs, phosphate and Tris) reveal binding of W − is accompanied by uptake of 0.30 ± 0.02 protons from the solvent. This measurement suggests that the binding of W − is stabilized by an ion‐pair interaction between protonated H242 and the phenoxide group of W − .

Simulations using 3D and 2D full-wave codes have shown that edge filaments in tokamak plasmas can significantly affect the propagation of microwaves across a broad frequency spectrum, resulting in scattering angles of up to 46°. Parameter scans were carried out for density perturbations comparable in width and amplitude to MAST filaments and the effect on the measured emission was calculated. 3D effects were discovered in the case of an obliquely incident beam.

Abstract In early human development, gastrulation is tightly associated with lineage specification. The interplay between mechanical forces and biochemical signals during these processes is poorly understood. Here, we dissect the effects of biochemical cues and physical confinement on a 3D in vitro model of gastrulation that uses spheroids formed from human induced pluripotent stem cells (hiPSCs). First, we compare self-renewing versus differentiating media conditions in free-floating cultures, and observe the emergence of organised tri-germ layers. In these unconfined cultures, BMP4 exposure induces polarised expression of SOX17 in conjunction with spheroid elongation. We then physically confine spheroids using PEG-peptide hydrogels and observe dramatically reduced SOX17 expression, albeit rescued if gels that soften over time are used instead. Our study combines high-content imaging, synthetic hydrogels and hiPSCs-derived models of early development to define the drivers causing changes in shape and emergence of germ layers.

The heat released from the disposal of High-Heat-Generating Waste (HHGW) in a Geological Disposal Facility (GDF) will result in an increase in temperature, and therefore thermal expansion of both the engineering materials and surrounding rocks. The changes to the stress state arising from the thermal expansion of these materials, restrained by the surrounding rock mass, could affect several of the Thermal, Hydraulic, and Mechanical (THM) processes that operate after closure of a GDF. In this paper a methodology is described which suggests how the influence of thermal stress on fracture aperture around a GDF can be evaluated. A set of calculations on an illustrative Discrete Fracture Network (DFN) are reported. These calculations estimate the responses of the fractures to changes in rock stress, considering changes in fracture aperture and the resultant changes to effective intrinsic permeability.

Full-wave simulations are performed in order to investigate the interaction of plasma density perturbations and microwaves. The perturbations are divided into two cases: A single blob-like structure and a fully turbulent density profile. The resulting scattering of a microwave beam and the effect on the O–X mode conversion are presented for both cases. Quantitative analyses are performed as a function of the average size and position of the perturbations. The usage of spatial coordinates normalized to the vacuum wavelength of the microwave allows to easily adopt the results to a specific problem.

Spiders are able to extract crucial information, such as the location prey, predators, mates, and even broken threads from propagating web vibrations. The complex structure of the web suggests that the morphology itself might provide computational support in form of a mechanical signal processing system - often referred to as morphological computation. We present preliminary results on identifying these computational aspects in naturally spun webs. A recently presented definition for physical computational systems, consisting of three main elements: (i) a mathematical part, (ii) a computational setup with a theoretical and real part, and (iii) an interpretation, is employed for the first time, to characterize these morphological computation properties. Signal transmission properties of a real spider orb web, as the real part of a morphological computation setup, is investigated in response to step transverse inputs. The parameters of a lumped system model, as the theoretical part of a morphological computation setup, are identified empirically and with the help of an earlier FEM model for the same web. As the possible elements of a computational framework, the web transverse signal filtering, attenuation, delay, memory effect, and deformation modes are briefly discussed based on experimental data and numerical simulations.

Augustine began writing commentary on scripture not long after his conversion. His first such work, meant as a counterblast to Manichaean attacks on the creation account, was De Genesi contra Manichaeos (388-390). In many ways it sets the tone for much of his later work: Augustine admits an allegorical sense but warns against overenthusiasm for allegory and denigration of the literal sense; we see also from the outset Augustine's interest in scripture as a controversialist and polemicist. After his ordination to the priesthood in 391, he seems to have gone through something of a writer's block, starting but leaving incomplete a treatise on exegetical theory (De doctrina christiana, begun 396 but not completed until 427), another commentary on Genesis (De Genesi ad litteram imperfectus liber, 393-394), and an exposition of Romans (Epistolae ad Romanos inchoata expositio, 394-395). He did manage to finish a verse-by-verse commentary on Galatians, giving the literal sense (Epistolae ad Galatas expositio, 394-395) and a commentary on the Sermon on the Mount (De sermone Domini in monte, 393-396). His Expositio quarundam propositionum ex epistola ad Romanos (394) derives from conversations with the monks at Hippo, who recorded his answers to their questions about Romans; Augustine tells us later that he missed what he eventually came to see as the main point of the epistle.

This chapter explores Anselm's account of the divine attributes in the Monologion and Proslogion. His arguments in those works reveal a being that is far removed from the objects of ordinary experience: a being without parts, without accidents, without location in space or time. Because of his eternity and immutability, God alone exists in an unqualified sense.

Sir Eustace D'aubrichecourt Get access Thomas Williams Thomas Williams Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume s8-V, Issue 118, 31 March 1894, Page 252, https://doi.org/10.1093/nq/s8-V.118.252b Published: 31 March 1894

"Salzbery" and "Sombreset" in 1502 Get access Thomas Williams Thomas Williams 1Aston Clinton Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume s8-III, Issue 63, 11 March 1893, Page 197, https://doi.org/10.1093/nq/s8-III.63.197c Published: 11 March 1893

Journal Article Maps of hundred divisions Get access Thomas Williams Thomas Williams 1Aston Clinton Rectory Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume s8-I, Issue 9, 27 February 1892, Pages 176–177, https://doi.org/10.1093/nq/s8-I.9.176d Published: 27 February 1892

Journal Article English queens of England Get access Thomas Williams Thomas Williams 1Aston Clinton Rectory Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume s8-I, Issue 16, 16 April 1892, Page 323, https://doi.org/10.1093/nq/s8-I.16.323e Published: 16 April 1892

Blethyn ap Confyn Get access Thomas Williams Thomas Williams 1ston Clinton Rectory Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume s8-II, Issue 27, 2 July 1892, Pages 18–19, https://doi.org/10.1093/nq/s8-II.27.18k Published: 02 July 1892

Journal Article John of Gaunt Get access Thomas Williams Thomas Williams 1Aston Clinton Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume s8-III, Issue 68, 15 April 1893, Page 293, https://doi.org/10.1093/nq/s8-III.68.293b Published: 15 April 1893

Journal Article Kytel Get access Thomas Williams Thomas Williams 1Aston Clinton Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume s8-IV, Issue 88, 2 September 1893, Page 189, https://doi.org/10.1093/nq/s8-IV.88.189b Published: 02 September 1893

Cecil Get access Thomas Williams Thomas Williams 1Aston Clinton Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume s9-III, Issue 61, 25 February 1899, Page 154, https://doi.org/10.1093/nq/s9-III.61.154a Published: 25 February 1899

Rastell Get access Thomas Williams Thomas Williams Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume s7-XII, Issue 293, 8 August 1891, Page 112, https://doi.org/10.1093/nq/s7-XII.293.112b Published: 08 August 1891

Journal Article English queens of England Get access Thomas Williams Thomas Williams Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume s8-I, Issue 7, 13 February 1892, Page 134, https://doi.org/10.1093/nq/s8-I.7.134a Published: 13 February 1892

Robert Auguillon Get access Thomas Williams Thomas Williams 1Aston Clinton Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume s8-IV, Issue 81, 15 July 1893, Page 53, https://doi.org/10.1093/nq/s8-IV.81.53d Published: 15 July 1893

John of Gaunt Get access Thomas Williams Thomas Williams 1Aston Clinton Search for other works by this author on: Oxford Academic Google Scholar Notes and Queries, Volume s8-III, Issue 75, 3 June 1893, Pages 431–432, https://doi.org/10.1093/nq/s8-III.75.431e Published: 03 June 1893

When dangers strike a cell, they are detected by sensors. Sensors tell messengers about the danger. Messengers tell the organiser. The organiser plans the cell defence, using responders and recyclers. Researchers in the MRC-PPU are figuring out how these different parts interact with each other.

A long-standing problem when deriving the physical properties of stellar populations is the degeneracy between age, reddening, and metallicity. When a single metallicity is used for all star clusters in a galaxy, this degeneracy can result in $`$catastrophic$'$ errors for old globular clusters. Typically, approximately 10 - 20 % of all clusters detected in spiral galaxies can have ages that are incorrect by a factor of ten or more. In this paper we present a pilot study for four galaxies (NGC 628, NGC 1433, NGC 1365, and NGC 3351) from the PHANGS-HST survey. We describe methods to correct the age-dating for old globular clusters, by first identifying candidates using their colors, and then reassigning ages and reddening based on a lower metallicity solution. We find that young $`$interlopers$'$ can be identified from their Halpha flux. CO (2-1) intensity or the presence of dust can also be used, but our tests show that they do not work as well. Improvements in the success fraction are possible at the $\sim$ 15 % level (reducing the fraction of catastrophic age-estimates from between 13 - 21 % to 3 - 8 %). A large fraction of the incorrectly age-dated globular clusters are systematically given ages around 100 Myr, polluting the younger populations as well. Incorrectly age-dated globular clusters significantly impact the observed cluster age distribution in NGC 628, which affects the physical interpretation of cluster disruption in this galaxy. For NGC 1365, we also demonstrate how to fix a second major age-dating problem, where very dusty young clusters with E(B-V) $&gt;$ 1.5 mag are assigned old, globular-cluster like ages. Finally, we note the discovery of a dense population of $\sim$ 300 Myr clusters around the central region of NGC 1365. and discuss how this results naturally from the dynamics in a barred galaxy.

All living things from whole people to single cells and even viruses have life cycles. Explore the weird and wonderful world of life cycles at the level of the cell in this top trumps inspired game. Print and cut out the cards, then play anywhere you want!

The Space Weather Empirical Ensemble Package (SWEEP) is a 3-year project that, very recently, delivered a suite of software tools to the UK Met Office to improve their space weather forecasting capabilities. Part of this package was Automated CME Characterisation (ACMEC) software to automatically detect, and characterise, CMEs in near real-time (NRT) coronagraph data. ACMEC ingests STEREO COR2 beacon data, and SOHO LASCO C2/C3 NRT data, and given the availability of clean data, provides estimates of the CME&amp;#8217;s 3D trajectory, angular extent, and speed. It also provides estimates of uncertainties in these values, enabling an ensemble forecast at Earth. We present example case studies to show the efficiacy of ACMEC, and reflect on the challenges faced, and lessons learned during the development stages. Future perspectives are given, including new missions, and the realisation that the development of machine learning methods are required for such complicated tasks in the next 10 years.&amp;#160;

<h3>Objective:</h3> A retrospective review of the 302 patients discussed in the Queen Square Adult Leukodystrophy Group (QSALG); a tertiary-centre, multidisciplinary team (MDT) of neurologists, neuroradiologists and metabolic physicians who review the clinical presentations, investigations, and neuroimaging of adults with suspected inherited white matter disorders referred from throughout the UK and abroad. <h3>Background:</h3> When extensive white matter abnormalities are detected on MRI scans it represents the start of a common and occasionally complex diagnostic challenge for even the most experienced neurologist. While straightforward investigations can reveal an acquired cause, many cases have a genetic aetiology (a leukodystrophy) and regardless, specialist input is often needed to advance diagnosis. Here, we describe the experience of our UK-wide MDT; our recommended approach including when to suspect a genetic disorder, and outcomes following MDT discussion. <h3>Design/Methods:</h3> A review of all patients with white matter abnormalities discussed in the QSALG MDT from February 2012 to October 2022. <h3>Results:</h3> Following MDT discussion and follow-up investigation, a definitive diagnosis was made in 179 cases (59.3%) and 37 cases (12.3%) were thought of as unsolvable. 86 patients (28.5%) have ongoing, open investigations. Of those receiving a diagnosis, a genetic diagnosis was made 42.46% of the time and the most common leukodystrophies diagnosed were CSF1R-related ALSP, adrenoleukodystrophy and vanishing white matter disease. Acquired causes were common, in particular small-vessel disease (aSVD) and multiple sclerosis (MS). <h3>Conclusions:</h3> Here we report our experience and lessons learned in diagnosing difficult white matter disorders in the largest European cohort of such patients, with a doubling of the cohort since last reporting (ABN, 2019). Less than half of those referred as suspected leukodystrophy are then genetically confirmed. We describe a high instance of diagnosing acquired causes, emphasising that though most neurologists are of course familiar with these diagnoses, difficulties still arise with atypical presentations, or in end-stage disease. <b>Disclosure:</b> Dr. Wade has nothing to disclose. Dr. Williams has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Merck. Dr. Williams has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis. Dr. Williams has received research support from UK MS Society. The institution of Dr. Merwick has received research support from Irish Institute of Clinical Neuroscience. Dr. Ahmed has nothing to disclose. Dr. Kinsella has nothing to disclose. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Merck. Frederik Barkhof has received personal compensation in the range of $0-$499 for serving as a Consultant for Biogen. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Combinostics. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for IXICO. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Frederik Barkhof has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EISAI. Dr. John has nothing to disclose. The institution of Jason Warren has received research support from Alzheimer’s Society. Catherine Mummery has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Catherine Mummery has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for roche. Catherine Mummery has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for biogen. Dr. Schott has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for Alzheimer’s Research UK. Dr. Schott has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for UK Dementia Research Institute. Dr. Schott has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Dr. Schott has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for GE. Dr. Schott has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Oxford University Press. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Biogen. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for EMD Serono. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Sanofi. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Novartis. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Brownlee has received personal compensation in the range of $500-$4,999 for serving as an Editor, Associate Editor, or Editorial Advisory Board Member for Sage. Matthew Adams has nothing to disclose. Indran Davagnanam has nothing to disclose. Henry Houlden has nothing to disclose. Dr. Murphy has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Recordati Rare Diseases Fondation d’Enterprise. Dr. Lynch has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Vigil Neuroscience. Dr. Chataway has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Janseen. Dr. Chataway has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Chataway has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Merck. Dr. Chataway has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for NerveGen. Dr. Chataway has received personal compensation in the range of $500-$4,999 for serving on a Speakers Bureau for Novartis.

Multimorbidity is one of the greatest challenges facing health and social care systems globally. It is associated with high rates of health service use, adverse healthcare events, and premature death. Despite its importance, little is known about the effects of contextual determinants such as household and area characteristics on health and care outcomes for people with multimorbidity. This study protocol presents a plan for the examination of associations between individual, household, and area characteristics with important health and social care outcomes.The study will use a cross-section of data from the SAIL Databank on 01 January 2019 and include all people alive and registered with a Welsh GP. The cohort will be stratified according to the presence or absence of multimorbidity, defined as two or more long-term conditions. Multilevel models will be used to examine covariates measured for individuals, households, and areas to account for social processes operating at different levels. The intra-class correlation coefficient will be calculated to determine the strength of association at each level of the hierarchy. Model outcomes will be any emergency department attendance, emergency hospital or care home admission, or mortality, within the study follow-up period.Household and area characteristics might act as protective or risk factors for health and care outcomes for people with multimorbidity, in which case results of the analyses can be used to guide clinical and policy responses for effective targeting of limited resources.

<h3>Background</h3> p53 and BRAF are frequently mutated proteins that together contribute to a significant proportion of human solid cancers. While mutations in both proteins are known to be recognized by T cells in humans,^1–4 therapies designed to promote these responses have led to limited clinical success.^{5 6} To improve the efficacy of anti-tumor immunotherapies, the Amphiphile (AMP) platform promotes the delivery of vaccine components to lymph nodes (LN) where immune responses are orchestrated. Here, conjugation to an albumin-binding lipid enables AMP-modified antigens and adjuvants to ‘hitch-hike’ on albumin into LNs where they elicit strong tumor-directed T cell responses. Application of this approach for cancer vaccine immunotherapy is known to improve LN delivery and promote activation of polyfunctional, cytotoxic T cells relative to unmodified comparators. Promising clinical safety, T cell activation, and anti-tumor biomarker responses have recently been observed for ELI-002, an mKRAS-targeting AMP therapeutic vaccine (AMPLIFY-201 NCT05726864). Application of this approach to mutant BRAF and p53 (mBRAF/mp53) offers the potential for improved immunotherapeutic activity in a setting of significant unmet need. <h3>Methods</h3> C57BL/6J mice were immunized with three doses of AMP-modified or soluble comparator vaccines, comprised of mBRAF/mp53 peptides and CpG-adjuvant, which were subcutaneously injected in two-week intervals. Immunological readouts were performed 7 days post dosing. To assess antigen-specific T cell responses, ELISpot (IFNγ, Granzyme B), multiplexed proteomic, and flowcytometric analysis of effector cytokines (IFNγ, TNFα, IL-2) were performed following antigenic stimulation. Cytolytic capabilities of antigen-specific T cells were evaluated via <i>in vivo</i> killing assays, in which antigen-pulsed target cells were intravenously transferred to immunized recipient mice, recovered after 24 hours from spleens, and analyzed by flow cytometry. <h3>Results</h3> AMP-immunization generated robust immune responses yielding strong T cell activation against both mp53 and mBRAF in vivo. Soluble comparators were inactive with no response above mock immunized animals. Responses were characterized by the generation of significantly increased frequency of polyfunctional T cells specific to mp53 (IFNγ: 122-fold) and mBRAF (IFNγ: 69-fold). T cells demonstrated significant levels of cytolytic activity including Granzyme B production and specific elimination of target cells <i>in vivo</i>. <h3>Conclusions</h3> By providing efficient delivery of immunogens directly to the LNs, the AMP-platform is capable of enhancing the potency of peptide vaccines. For mp53 and mBRAF, substantially improved immune response represents a promising therapeutic opportunity for targeting these cancers in a large fraction of human tumors. Furthermore, this platform technology is simple, rapid and scalable for broad clinical application. <h3>References</h3> Sharkey MS, Lizée G, Gonzales MI, Patel S, Topalian SL. CD4(+) T-cell recognition of mutated B-RAF in melanoma patients harboring the V599E mutation. <i>Cancer Res</i>. 2004 Mar 1;<b>64</b>(5):1595–9. doi: 10.1158/0008–5472.can-03–3231. PMID: 14996715. Somasundaram R, Swoboda R, Caputo L, Otvos L, Weber B, Volpe P, van Belle P, Hotz S, Elder DE, Marincola FM, Schuchter L, Guerry D, Czerniecki BJ, Herlyn D. Human leukocyte antigen-A2-restricted CTL responses to mutated BRAF peptides in melanoma patients. <i>Cancer Res</i>. 2006 Mar 15;<b>66</b>(6):3287–93. doi: 10.1158/0008–5472.CAN-05–1932. PMID: 16540682. Malekzadeh P, Yossef R, Cafri G, Paria BC, Lowery FJ, Jafferji M, Good ML, Sachs A, Copeland AR, Kim SP, Kivitz S, Parkhurst MR, Robbins PF, Ray S, Xi L, Raffeld M, Yu Z, Restifo NP, Somerville RPT, Rosenberg SA, Deniger DC. Antigen Experienced T Cells from Peripheral Blood Recognize p53 Neoantigens. <i>Clin Cancer Res</i>. 2020 Mar 15;<b>26</b>(6):1267–1276. doi: 10.1158/1078–0432.CCR-19–1874. Epub 2020 Jan 29. PMID: 31996390; PMCID: PMC7424598. Yu Y, Zhang J, Ni L, Zhu Y, Yu H, Teng Y, Lin L, Xue Z, Xue X, Shen X, Song H, Su X, Sun W, Cai Z. Neoantigen-reactive T cells exhibit effective anti-tumor activity against colorectal cancer. <i>Hum Vaccin Immunother</i>. 2022 Dec 31;<b>18</b>(1):1–11. doi: 10.1080/21645515.2021.1891814. Epub 2021 Mar 9. PMID: 33689574; PMCID: PMC8920255. Veatch JR, Lee SM, Fitzgibbon M, Chow IT, Jesernig B, Schmitt T, Kong YY, Kargl J, Houghton AM, Thompson JA, McIntosh M, Kwok WW, Riddell SR. Tumor-infiltrating BRAFV600E-specific CD4+ T cells correlated with complete clinical response in melanoma. <i>J Clin Invest</i>. 2018 Apr 2;<b>128</b>(4):1563–1568. doi: 10.1172/JCI98689. Epub 2018 Mar 12. PMID: 29360643; PMCID: PMC5873881. Zhou S, Fan C, Zeng Z, Young KH, Li Y. Clinical and Immunological Effects of p53-Targeting Vaccines. <i>Front Cell Dev Biol</i>. 2021 Nov 3;<b>9</b>:762796. doi: 10.3389/fcell.2021.762796. PMID: 34805170; PMCID: PMC8595300.

There is growing interest in U.S. cities to shift resources towards community-led solutions to crime and disorder. However, there is a simultaneous need to provide community organizations with access to real-time data to facilitate decision making, to which only the police normally have access. In this work we present a low-cost gunshot detection system with localization that has been developed for community-based violence interruption. The distributed real-time gunshot detection sensor network is linked to a mobile phone-based alert and tasking system for exclusive use by civilian gang interventionists. Here we present details on the system architecture and gunshot detection model, which consists of an Audio Spectrogram Transformer (AST) neural network. We then combine gradient maps of the input to the AST for time of arrival identification with a Bayesian maximum a posteriori estimation procedure to identify the location of gunshots. We conduct several experiments using simulated data, open data from the commercial ShotSpotter detection system in Pittsburgh, and data collected using our devices during live-fire experiments at the Indianapolis Metropolitan Police Department (IMPD) gun firing range. We then discuss potential applications of the system and directions for future research.

"Crossing Disciplinary Boundaries in Studies of the Viking Age." Medieval Archaeology, 67(2), pp. 510–511

As the cases of severe COVID-19 decline, long COVID is emerging as the major complication of SARS CoV2 infection. We have reasoned that the dysregulated immune response characterising acute COVID-19 is unlikely to resolve in an orderly fashion and that persistence of some features may be present in patients with long COVID. We have extended our landmark acute COVID-19 studies [1, 2], following up 53 patients one year into convalescence. This unique cohort includes 30 people who are fully recovered and 23 with long COVID. All have been evaluated by multi-parameter flow cytometry and a subset have had B cell receptor repertoire sequencing. The main perturbations of B/T cell phenotypes in acute COVID-19 resolve, however, there was an unexpected peak in the complementarity determining region of the B cell receptor repertoire in long COVID patients. Interestingly, the consensus sequence is an 82% match to spike protein monoclonal antibody sequences (Figure 1) and only present in IgM and IgD receptors. This implies that patients with long COVID have a different humoral response to those with a full recovery from acute COVID-19. <b>References:</b> [1] Mann ER, Menon M, Knight SB, et al. Longitudinal immune profiling reveals key myeloid signatures associated with COVID-19. Sci Immunol. 2020;5(51). [2] Shuwa HA, Shaw TN, Knight SB, et al. Alterations in T and B cell function persist in convalescent COVID-19 patients. Med (N Y). 2021;2(6):720-35 e4.

This chapter presents an outline of Anselm's life and career, emphasizing those aspects of his history that are helpful for interpreting Anselm's works. Anselm was born in 1033 in Aosta, a Burgundian town on the frontier with Lombardy. Anselm was a bright and likeable boy. He left home in 1056. In 1059, he arrived at the Abbey of Bec in Normandy. In 1060, Anselm decided to become a monk at Bec. His work, the Monologion, was written to prove a wide range of conclusions about God. The Proslogion was a direct outgrowth of the Monologion In 1080–86, he composed three dialogues: On Truth, On Freedom of Choice, and On the Fall of the Devil. After becoming archbishop, he began work on Cur Deus Homo. On the Tuesday of Holy Week, April 21, 1109, Anselm died peacefully, surrounded by the monks of Canterbury.

In previous work, researchers in Human-Robot Interaction (HRI) have demonstrated that user trust in robots depends on effective and transparent communication. This may be particularly true for robots used for transportation, due to user reliance on such robots for physical movement and safety. In this paper, we present the design of an experiment examining the importance of proactive communication by robotic wheelchairs, as compared to non-vehicular mobile robots, within a Virtual Reality (VR) environment. Furthermore, we describe the specific advantages -- and limitations -- of conducting this type of HRI experiment in VR.

The MS-STAT2 study is a Phase III, 3 year multi-centre, randomised, placebo-controlled trial assessing the efficacy of 80mg simvastatin vs. placebo in secondary progressive multiple sclerosis (SPMS). Building upon the promising results of the MS-STAT1 study, it is an academically led study funded through a collaboration of the NIHR HTA, MS Society (UK), National MS Society (US), and the Rosetrees Trust. Here we will provide an update on the trial design and progress, including: The agreed trial extension period Adaptations to recruitment targets and trial design An update on trial sites where patients can be referred An update on current trial progress thomas.williams@nhs.net

The propagation of EM radiation past wavelength-sized inhomogeneities is not well understood, yet is of importance for both microwave heating and diagnostic applications in tokamaks. The work presented in this thesis improves this understanding; for this purpose, EMIT-3D, a new finite-difference time-domain (FDTD) code implementing a cold-plasma model has been written to extend full-wave simulations of propagation in magnetized plasmas to 3D. The numerical development of the algorithm is presented and supported with a new stability analysis. Studies of propagation past density filaments (`blobs') are presented and compared with 2D simulations. The synergistic effects of blob density and width on scattering angle are investigated, resulting in the conclusion that even filaments of densities below beam critical density can cause significant deviation in beam paths over a wide frequency range. Further to this, the case of oblique incidence is an explicitly 3D interaction, and its effects have been calculated. The broadening and defocusing effect on microwave beams caused by realistic edge turbulence, observed in all magnetic fusion devices, is also investigated. A fluid model for edge turbulence is used to produce realistic turbulent profiles, which in turn are used to initialise a set of microwave propagation simulations. The effect of propagation through a turbulent layer is observed even at low fluctuation amplitude, and observed to have a peak when eddy sizes approach beam wavelength. This work supports MAST experiments using the SAMI diagnostic to image microwave emission from the plasma edge due to mode conversion from electron Bernstein waves; however, it has relevance for numerous microwave diagnostic, heating and current drive applications in plasmas.

As the LHC increases luminosity and energy, it will become increasingly difficult to select interesting physics events and remain within the readout bandwidth limitations. An upgrade to the CMS Calorimeter Trigger implementing more complex algorithms is proposed. It utilizes AMC cards with Xilinx FPGAs running in microTCA crate with card interconnections via crate backplanes and optical links operating at up to 10 Gbps. Prototype cards with Virtex-6 and Virtex-7 FPGAs have been built and software frameworks for operation and monitoring developed. The physics goals, hardware architectures, and software will be described in this talk. More details can be found in a separate poster at this conference.

In previous work, researchers in Human-Robot Interaction (HRI) have demonstrated that user trust in robots depends on effective and transparent communication. This may be particularly true forrobots used for transportation, due to user reliance on such robots for physical movement and safety. In this paper, we present the design of an experiment examining the importance of proactive communication by robotic wheelchairs, as compared to non-vehicular mobile robots, within a Virtual Reality (VR) environment. Furthermore, we describe the specific advantages – and limitations – of conducting this type of HRI experiment in VR.

Book Review| October 01 2002 The Cambridge Translations of Medieval Philosophical Texts, vol. 2: Ethics and Political Philosophy Arthur Stephen McGrade, John Kilcullen, and Matthew Kempshall, eds. The Cambridge Translations of Medieval Philosophical Texts, vol. 2: Ethics and Political Philosophy. Cambridge: Cambridge University Press, 2001. Pp. xii, 664. Thomas Williams Thomas Williams Search for other works by this author on: This Site Google The Philosophical Review (2002) 111 (4): 576–578. https://doi.org/10.1215/00318108-111-4-576 Views Icon Views Article contents Figures & tables Video Audio Supplementary Data Peer Review Share Icon Share Facebook Twitter LinkedIn Email Tools Icon Tools Permissions Cite Icon Cite Search Site Citation Thomas Williams; The Cambridge Translations of Medieval Philosophical Texts, vol. 2: Ethics and Political Philosophy. The Philosophical Review 1 October 2002; 111 (4): 576–578. doi: https://doi.org/10.1215/00318108-111-4-576 Download citation file: Zotero Reference Manager EasyBib Bookends Mendeley Papers EndNote RefWorks BibTex toolbar search Search Dropdown Menu toolbar search search input Search input auto suggest filter your search Books & JournalsAll JournalsThe Philosophical Review Search Advanced Search The text of this article is only available as a PDF. Cornell University2002 Article PDF first page preview Close Modal Issue Section: Book Reviews You do not currently have access to this content.

Natural-gas hydrates have been encountered beneath the permafrost and considered a nuisance by the oil and gas industry for years. Engineers working in Russia, Canada and the USA have documented numerous drilling problems, including kicks and uncontrolled gas releases, in arctic regions. Information has been generated in laboratory studies pertaining to the extent, volume, chemistry and phase behavior of gas hydrates. Scientists studying hydrate potential agree that the potential is great--on the North Slope of Alaska alone, it has been estimated at 590 TCF. However, little information has been obtained on physical samples taken from actual rock containing hydrates. This gas-hydrate project is in the final stages of a cost-shared partnership between Maurer Technology, Noble Corporation, Anadarko Petroleum, and the U.S. Department of Energy's Methane Hydrate R&D program. The purpose of the project is to build on previous and ongoing R&D in the area of onshore hydrate deposition to identify, quantify and predict production potential for hydrates located on the North Slope of Alaska. Hot Ice No. 1 was planned to test the Ugnu and West Sak sequences for gas hydrates and a concomitant free gas accumulation on Anadarko's 100% working interest acreage in section 30 of Township 9N, Range 8E of the Harrison Bay quadrangle of the North Slope of Alaska. The Ugnu and West Sak intervals are favorably positioned in the hydrate-stability zone over an area extending from Anadarko's acreage westward to the vicinity of the aforementioned gas-hydrate occurrences. This suggests that a large, north-to-south trending gas-hydrate accumulation may exist in that area. The presence of gas shows in the Ugnu and West Sak reservoirs in wells situated eastward and down dip of the Hot Ice location indicate that a free-gas accumulation may be trapped by gas hydrates. The Hot Ice No. 1 well was designed to core from the surface to the base of the West Sak interval using the revolutionary and new Arctic Drilling Platform in search of gas hydrate and free gas accumulations at depths of approximately 1200 to 2500 ft MD. A secondary objective was the gas-charged sands of the uppermost Campanian interval at approximately 3000 ft. Summary results of geophysical analysis of the well are presented in this report.

L’arthroplastie totale de hanche est exposée à des complications notamment l’inégalité de longueur, source important de judiciarisation. La navigation permettrait d’optimiser la procédure mais son efficacité à gérer les longueurs de membre reste controversée. Aussi, nous avons mené une étude pour mesurer : – son intérêt pour atteindre les objectifs d’allongement et de latéralisation ; – sa fiabilité en évaluant la corrélation des données radiologiques et de navigation ; – sa sécurité par l’analyse des complications spécifiques et non spécifiques à la navigation. La navigation permet de gérer les longueurs de membres avec une erreur de 5 mm ou moins dans plus de 80 % des cas. Nous avons analysé rétrospectivement une série continue de 321 prothèses totales de hanche sans ciment naviguées implantées par voie postéro-latérale. Au recul minimal de 1 an, nous avons évalué l’atteinte des objectifs d’allongement et d’offset, la concordance données de navigation, données radiologiques et les incidents liées ou non à la navigation. En considérant l’hypothèse de 80 % de patients ayant une inégalité de moins de 5 mm et en considérant l’hypothèse nulle (PA = P0) avec alpha à 0,05, il fallait 200 observations avec une puissance de 90 %. Les objectifs d’allongement et de latéralisation ont été respectés dans respectivement 83,3 et 88 % des cas. Vingt-deux patients ont nécessité une compensation afin d’équilibrer une inégalité de longueur des membres inférieurs. La corrélation entre les données radiologique et la navigation était satisfaisante avec des coefficients de Pearson respectivement de 0,79 pour la longueur et 0,74 pour la latéralisation. Quarante-sept incidents (14,6 %) per- et postopératoire spécifiques (12,1 %) ou non (2,5 %) de la navigation ont été observés. Notre étude démontre un intérêt de la navigation quant à l’obtention des objectifs préopératoires avec une bonne corrélation des données navigation radios et sans incident majeur reporté.

It is axiomatic of capitalist society that the concept of value must inevitably be reduced down to a single monetary index. In other words, we have come to expect that, in final analysis, economic value trumps all others. In the last couple of years we have seen this most clearly expressed in the government’s attitude to forestry. The historical reluctance of officaldom to recognise value of a more intangible kind also lies at the heart of the tension in cultural heritage management between the historic environment and the pressure placed on its guardians to exploit or ignore those assets in favour of economic priorities...

Trustworthy guidance spanning every aspect of adolescent health care. Unlike other adolescent medicine references, the all-new AAP Textbook of Adolescent Care is an action-oriented working tool expressly built for efficient, on-target clinical problem-solving. Broad scope - Nearly 200 chapters cover physical growth and development, examination and laboratory screening, sexual development, puberty, obesity, sleep disorders, adolescent dermatology and much more. Clear management guidelines - Provides step-by-step recommendations: What to do, How to do it; When to admit, When to treat, When to refer. Evidence-based approach - Treat patients and counsel parents with high confidence. Excellent study reference - for the pediatric or internal medicine boards. Integrated companion resources - Use with complementary AAP resources: AAP Textbook of Pediatric Care, Tools for Practice, and Pediatric Care Online.

Ce texte est l'exposé de l'équipe MATh.en.JEANS mixte entre le lycée Blaise Pascal (Orsay) et l'université Paris-Sud 11. Les jeunes auteurs développent une solution pour un problème géométrique à deux joueurs puis simulent ces résultats informatiquement.

You have accessJournal of UrologyCME1 May 2022PD14-03 ANALYSIS OF TWO INDEPENDENT RISK STRATIFICATION EVALUATION TOOLS IN A COHORT OF PATIENTS WITH MICROSCOPIC HEMATURIA Thomas Williams, Eric Macdonald, Max Kuster, Michelle Ou, Tavya Benjamin, Manish Vira, and Simon Hall Thomas WilliamsThomas Williams More articles by this author , Eric MacdonaldEric Macdonald More articles by this author , Max KusterMax Kuster More articles by this author , Michelle OuMichelle Ou More articles by this author , Tavya BenjaminTavya Benjamin More articles by this author , Manish ViraManish Vira More articles by this author , and Simon HallSimon Hall More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002546.03AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: While the prevalence of microscopic hematuria (MH) in the general population remains high, the malignancy detection rate is low. Extensive workup may create unnecessary radiation and instrumentation. Multiple guidelines and nomograms have been published to help reduce excessive evaluations. This study aimed to review our institution’s malignancy detection rate, modelled using the revised 2021 AUA/SUFU Microhematuria guideline and Kaiser-Permanente Hematuria Risk Index (HRI). METHODS: Retrospective review of our microscopic hematuria database of 3,147 patients to analyze malignancy detection rate, stratified for the 2021 AUA guidelines and HRI risk categories. Patient inclusion was RBC ≥ 3/hpf with completed fields for demographics, risk factors, and full work-up. Categorization of malignancy was further broken down into grade, stage, and type. Solid parenchymal tumors (SPT) were included if pathologically confirmed or highly suspicious on imaging. Patients who presented with MH but had a history of gross hematuria were stratified per AUA or HRI grouping. Statistical analysis was performed by area under receiver operating characteristic curves. RESULTS: 2,001 patients met inclusion criteria. Overall, 36 neoplasms were diagnosed after workup: 21 non-muscle invasive bladder cancer, 1 muscle-invasive bladder cancer, 2 upper tract urothelial cancers, 12 SPTs. AUA risk categories had a total positive detection rate of 0% (Low), 0.67% (Medium), and 2.83% (High). HRI score (0-11) showed malignancy detection rates of 0.97% (Low; 0-4), 2.65% (Moderate; 5-8), and 9.68% (High; 9-11). Looking only at urothelial malignancies (excluding SPT), the breakdown (AUA versus HRI respectively) was Low: 0 vs 0.18%, Medium/Moderate: 0.13 vs 2.28%, and High: 2.10 vs 9.68%. The HRI classified 1,139 patients as low-risk with 2 urothelial malignancies detected (0.18%), while the AUA classification only included 163 patients (0%). The HRI score stratification urothelial detection area under the curve for ROC was 0.812 compared to 0.709 (AUA). CONCLUSIONS: After stratifying our database population based on the 2021 AUA/SUFU Guideline and Kaiser-Permanente HRI, we found that both groups had linear increases in malignancy detection rates with increasing risk group. However, the HRI, which uses a more granular categorization, would have avoided unnecessary workup in a significantly higher proportion of patients. Future directions should analyze further sub-stratification to create a more specific nomogram that avoids unnecessary workup. Source of Funding: None © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e257 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Thomas Williams More articles by this author Eric Macdonald More articles by this author Max Kuster More articles by this author Michelle Ou More articles by this author Tavya Benjamin More articles by this author Manish Vira More articles by this author Simon Hall More articles by this author Expand All Advertisement PDF DownloadLoading ...

Abstract This chapter discusses Anselm's theory of free choice. Free choice, understood as “the power to preserve rectitude of will for its own sake”, requires the absence of causal necessity. But what is more important to Anselm's account of free choice is the teleological element. Because “rectitude of will preserved for its own sake” is his definition of justice, free choice is simply the power to be just.

Anselm's work is thoroughly argumentative in a way that is not burdened by elaborate technical machinery. Much of his writing was done in response to a request or as a reaction against some emergent heresy. As a result, he only wrote about what he was interested in at the time. What is important to Anselm is that God creates all things in accordance with the one divine Word that is consubstantial with the One who utters it, and that creatures in some way reflect the perfect goodness that God does not merely have but actually is. Although Anselm can be disappointingly uncurious or single-minded about his own interests and impatient with what he regards as inessentials, he is a valuable interlocutor for contemporary philosophers and theologians. Though even his most sympathetic readers, will not agree with everything he says, Anselm's arguments and views almost always command respect.

This chapter looks in detail at the Trinity. After examining the metaphysics of the Trinity as Anselm understands it, it turns to his constructive arguments for the doctrine: first for the divinity of the Word; second, for the distinctness of the Word from the Father; and third, for the procession of the Holy Spirit from both Father and Word. There are two works in which Anselm engages philosophically with Trinitarian doctrine. In the Monologion, he makes his constructive case for the doctrine, and in De incarnatione Verbi he clarifies the metaphysics of the Trinity in order to meet a challenge posed by Roscelin of Compiégne.

Abstract This chapter considers Anselm's account of truth, which not only completes his theory of signification but also introduces the notion of rectitude that is the cornerstone of Anselm's understanding of freedom, morality, sin, and redemption. He deploys the concept of rectitude to assimilate all the various manifestations of truth—in statements, opinions, wills, actions, the senses, and the being of things—to each other and, in the end, to the supreme Truth. His theory invokes two correspondences. A statement is true when it corresponds both to the way things are and to the purpose of making statements.