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A collaborative investigation between the University of Virginia (UVA) and the Virginia Transportation Research Council was performed on the Mecklenburg Bridge (I-85 over Route 1 in Mecklenburg County). The research team aided the Virginia Department of Transportation—Richmond District in the characterization of the bridge behavior of one of the bridge beams that had been repaired due to a previous web buckling and crippling failure. The investigation focused on collecting full-field three-dimensional digital image correlation (3D-DIC) deformation measurements during the dropping sequence (removal of jacking to support beam on bearing/pier). Additionally, measurements were taken of the section prior to and after dropping using a handheld laser scanner to assess the potential of lateral deformation or out-of-plane buckling. Results from the study demonstrated that buckling of the tested beam did not occur, but did provide a series of approaches that can be used to evaluate the effectiveness of repaired steel beam ends. Specifically, the results provided an approach that could estimate the dead load distribution through back-calculation.

Background Given the expanding evidence of clinico-radiological differences between moyamoya disease (MMD) and moyamoya syndrome (MMS), we compared the clinical and radiographic features of childhood MMD and MMS to identify predictors of ischemic event recurrence. Methods We reviewed a pediatric moyamoya cohort followed between 2003 and 2019. Clinical and radiographic characteristics at diagnosis and follow-up were abstracted. Comparisons between MMD and MMS as well as between MMD and two MMS subgroups (neurofibromatosis [MMS-NF1] and sickle cell disease [MMS-SCD]) were performed. Results A total of 111 patients were identified. Patients with MMD presented commonly with transient ischemic attacks (TIAs) (35 % MMD versus 13% MMS-NF1 versus 9.5% MMS-SCD; P = 0.047). Symptomatic stroke presentation (MMD 37% versus MMS-NF1 4% versus 33%; P = 0.0147) and bilateral disease at diagnosis (MMD 73% versus MMS-NF1 22 % versus MMS-SCD 67%; P = 0.0002) were uncommon in MMS-NF1. TIA recurrence was common in MMD (hazard ratio 2.86; P = 0.001). The ivy sign was absent on neuroimaging in a majority of patients with MMS-SCD (MMD 67% versus MMS-NF1 52% versus MMS-SCD 9.5%; P = 0.0002). Predictors of poor motor outcome included early age at diagnosis (odds ratio [OR] 8.45; P = 0.0014), symptomatic stroke presentation (OR 6.6; P = 0.019), and advanced Suzuki stage (OR 3.59; P = 0.019). Conclusions Moyamoya exhibits different phenotypes based on underlying etiologies. Frequent TIAs is a common phenotype of MMD and symptomatic stroke presentation a common feature of MMD and MMS-SCD, whereas unilateral disease and low infarct burden are common in MMS-NF1. In addition, absence of ivy sign is a common phenotype in MMS-SCD.

Statine zahlen zu den am haufigsten verordneten Medikamenten deutschlandweit. Ihr Nutzen in der Senkung des kardiovaskularen Risikos ist unbestritten. Dennoch klagen viele Patienten uber Nebenwirkungen unter Statintherapie, wozu insbesondere statinassoziierte Muskelsymptome (SAMS) zahlen. Diese sind trotz ihrer relativen Haufigkeit schwer zu erfassen und objektiv zu diagnostizieren, da der Zeitraum bis zum ersten Auftreten von Symptomen, die Art der Beschwerden und der Schweregrad der Muskelprobleme sehr stark variieren. In diesem narrativen Review werden die Ursachen der SAMS sowie neue Moglichkeiten zur Diagnostik und Therapie zusammengefasst.

PURPOSE The study was performed to evaluate the refractive and visual outcome of patients with misaligned toric intraocular lenses (IOLs) after operative realignment, with and without back-calculation of the toric axis after implantation of the IOL. DESIGN Institutional, retrospective case-control study. METHODS This is a retrospective case series of 39 patients who underwent a second operation to realign a misaligned toric IOL from August 2013 to December 2019 at the Department of Ophthalmology, Goethe University, Frankfurt, Germany. Ideal toric axis was calculated using the back-calculator astigmatismfix.com. RESULTS The study consists of 39 treated eyes (20 [51%] right eyes). The toric IOLs showed a postoperative misalignment of 25.69 ± 26.06°. Postrotational, uncorrected distance visual acuity (UDVA) improved from 0.39 ± 0.29 logMAR to 0.27 ± 0.18 logMAR. Refractive outcome showed a reduction of residual sphere and cylinder. The postoperative UDVA when performing alignment to the preoperative calculated axis (51%) was 0.24 ± 0.16 logMAR with a cylinder of 0.90 ± 0.90 diopter (D). In the group with alignment to a back-calculated axis (49%), the UDVA was 0.32 ± 0.20 logMAR with a cylinder of 0.76 ± 0.72 D. High cylinder power IOLs (≥2 D) showed a higher decrease in residual cylinder when back-calculation was performed than low cylinder power IOLs (

Background The European Atherosclerosis Society Familial Hypercholesterolaemia Studies Collaboration (FHSC) global registry provides a platform for the global surveillance of familial hypercholesterolaemia through harmonisation and pooling of multinational data. In this study, we aimed to characterise the adult population with heterozygous familial hypercholesterolaemia and described how it is detected and managed globally. Methods Using FHSC global registry data, we did a cross-sectional assessment of adults (aged 18 years or older) with a clinical or genetic diagnosis of probable or definite heterozygous familial hypercholesterolaemia at the time they were entered into the registries. Data were assessed overall and by WHO regions, sex, and index versus non-index cases. Findings Of the 61 612 individuals in the registry, 42 167 adults (21 999 [53.6%] women) from 56 countries were included in the study. Of these, 31 798 (75.4%) were diagnosed with the Dutch Lipid Clinic Network criteria, and 35 490 (84.2%) were from the WHO region of Europe. Median age of participants at entry in the registry was 46.2 years (IQR 34.3-58.0); median age at diagnosis of familial hypercholesterolaemia was 44.4 years (32.5-56.5), with 40.2% of participants younger than 40 years when diagnosed. Prevalence of cardiovascular risk factors increased progressively with age and varied by WHO region. Prevalence of coronary disease was 17.4% (2.1% for stroke and 5.2% for peripheral artery disease), increasing with concentrations of untreated LDL cholesterol, and was about two times lower in women than in men. Among patients receiving lipid-lowering medications, 16 803 (81.1%) were receiving statins and 3691 (21.2%) were on combination therapy, with greater use of more potent lipid-lowering medication in men than in women. Median LDL cholesterol was 5.43 mmol/L (IQR 4.32-6.72) among patients not taking lipid-lowering medications and 4.23 mmol/L (3.20-5.66) among those taking them. Among patients taking lipid-lowering medications, 2.7% had LDL cholesterol lower than 1.8 mmol/L; the use of combination therapy, particularly with three drugs and with proprotein convertase subtilisin-kexin type 9 inhibitors, was associated with a higher proportion and greater odds of having LDL cholesterol lower than 1.8 mmol/L. Compared with index cases, patients who were non-index cases were younger, with lower LDL cholesterol and lower prevalence of cardiovascular risk factors and cardiovascular diseases (all p, Pfizer Independent Grant for Learning Change [16157823]; Amgen; Merck Sharp Dohme; Sanofi-Aventis; Daiichi Sankyo; Regeneron; National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK; NIHR; Czech Ministry of Health [NU20-02-00261]; Canadian Institutes of Health Research; Austrian Heart Foundation; Tyrolean Regional Government; Gulf Heart Association, The EAS FHSC is an academic initiative that has received funding from a Pfizer Independent Grant for Learning & Change 2014 (16157823) and from investigator-initiated research grants to the European Atherosclerosis Society-Imperial College London from Amgen, Merck Sharp & Dohme, Sanofi-Aventis, Daiichi Sankyo, and Regeneron. KKR acknowledges support from the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre, UK. KID acknowledges support from a PhD Studentship from NIHR under the Applied Health Research programme for Northwest London, UK (the views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health). TF was supported by a grant from the Czech Ministry of Health (NU20-02-00261). JG receives support from the Canadian Institutes of Health Research. The Austrian Familial Hypercholesterolaemia registry has been supported by funds from the Austrian Heart Foundation and the Tyrolean Regional Government. The Gulf Familial Hypercholesterolaemia registry was done under the auspices of the Gulf Heart Association.

Autosomal-dominant familial hypercholesterolemia (FH) is characterized by increased plasma concentrations of low-density lipoprotein cholesterol (LDL-C) and a substantial risk to develop cardiovascular disease. Causative mutations in three major genes are known: the LDL receptor gene (LDLR), the apolipoprotein B gene (APOB) and the proprotein convertase subtilisin/kexin 9 gene (PCSK9). We clinically characterized 336 patients suspected to have FH and screened them for disease causing mutations in LDLR, APOB and PCSK9. We genotyped six single nucleotide polymorphisms (SNPs) to calculate a polygenic risk score for the patients and 1,985 controls. 117 patients had a causative variant in one of the analyzed genes. Most variants were found in the LDLR gene (84.9%) with 11 novel mutations. The mean polygenic risk score was significantly higher in FH mutation negative subjects than in FH mutation positive patients (p

STUDY OBJECTIVES: Positional obstructive sleep apnea (POSA) is a phenotype of obstructive sleep apnea (OSA) where sleep-related obstructive events occur predominantly in the supine position. Limited knowledge exists regarding the presence of POSA in children with obesity. The study objective was to determine the prevalence of POSA while identifying factors associated with POSA in children with obesity. METHODS: This was a cross-sectional study of children with obesity, aged 8 to 18 years, with a diagnostic polysomnogram (PSG) between 2012 to 2019, who were referred for the evaluation of sleep-related breathing. POSA was defined as an overall obstructive apnea-hypopnea index (OAHI) ≥5 events/h and a supine OAHI to nonsupine OAHI ratio of ≥2. Patient demographics, anthropometrics, and PSG data were recorded. RESULTS: Of the 112 children with obesity with a diagnostic PSG, 43 (38%) had OSA. Among those with OSA, 25 of 43 (58%) had POSA (mean age: 14.6 ± 2.3 years; mean body mass index: 37.7 ± 7.6 kg/m(2); 68% male) and 18 of 43 (42%) had non-POSA (mean age: 13.9 ± 2.8 years; mean body mass index: 37.9 ± 7.2 kg/m(2); 78% male). Among those with POSA, 13 of 25 (52%) had mild OSA, 7 of 25 (28%) had moderate OSA, and 5 of 25 (20%) had severe OSA. No significant differences were found in age, sex, and anthropometric measures between POSA and non-POSA groups. Time spent in supine and nonsupine sleep did not differ significantly between groups. CONCLUSIONS: In children with obesity and OSA, POSA occurs frequently. Identifying POSA allows for potential targeted positional therapy for children with obesity. CITATION: Selvadurai S, Voutsas G, Massicotte C, et al. Positional obstructive sleep apnea in an obese pediatric population. J Clin Sleep Med. 2020;16(8):1295–1301.

Aims Several the use of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) for patients at high/very high cardiovascular risk who are inadequately treated with maximally tolerated lipid-lowering therapies (LLTs). Objectives We assessed the effectiveness and safety of the PCSK9i alirocumab and evolocumab in a single-center clinical practice for up to 68 weeks. Methods In this prospective, open-label study conducted in Germany, 635 enrolled patients were treated with alirocumab [75 or 150 mg every 2 weeks (Q2W)] or evolocumab (140 mg Q2W) according to European Society of Cardiology/European Atherosclerosis Society guidelines (low-density lipoprotein cholesterol [LDL-C] > 1.81/2.59 mmol/L (70/100 mg/dL), depending on cardiovascular risk]. Investigators were able to adjust LLTs, including PCSK9i, according to their own clinical judgment. The primary effectiveness endpoint was LDL-C reduction from baseline to week 68. Results At baseline, approximately 50% of patients were statin intolerant, and approximately 90% reported a history of cardiovascular disease. LDL-C reductions remained generally unchanged from weeks 4 to 68 in each treatment group. At week 68, LDL-C mean percentage changes from baseline were − 41.7% (alirocumab 75 mg Q2W), − 53.7% (alirocumab 150 mg Q2W), and − 54.1% (evolocumab 140 mg Q2W). LDL-C reduction was 7.1% greater in patients receiving statins than in those not receiving statins because of statin intolerance (P

Background: Hospital referral regions (HRRs) are often used to characterize inpatient referral patterns, but it is unknown how well these geographic regions are aligned with variation in Medicare-financed hospice care, which is largely provided at home. Objective: Our objective was to characterize the variability in hospice use rates among elderly Medicare decedents by HRR and county. Methods: Using 2014 Master Beneficiary File for decedents 65 and older from North and South Carolina, we applied Bayesian mixed models to quantify variation in hospice use rates explained by HRR fixed effects, county random effects, and residual error among Medicare decedents. Results: We found HRRs and county indicators are significant predictors of hospice use in NC and SC; however, the relative variation within HRRs and associated residual variation is substantial. On average, HRR fixed effects explained more variation in hospice use rates than county indicators with a standard deviation (SD) of 10.0 versus 5.1 percentage points. The SD of the residual error is 5.7 percentage points. On average, variation within HRRs is about half the variation between regions (52%). Conclusions: The magnitude of unexplained residual variation in hospice use for NC and SC suggests that novel, end-of-life-specific service areas should be developed and tested to better capture geographic differences and inform research, health systems, and policy.

Conventional communications satellites operate with fixed frequency, polarisation and coverage plans that are drawn up years before their launch during the payload definition phase. The satellite will typically be designed for a lifetime of more than fifteen years. During this operating period, changes in bandwidth requirements and the distribution of the service across its geographic coverage are more than likely. A new generation of communication satellites is expected to respond flexibly to these regional and temporal fluctuations in demand. The concept of cellular division of the coverage area and the coverage of these cells with spot beams in connection with the reuse of frequency bands enables this flexibility. The satellite's frequency plan has to be redefined throughout the mission lifetime via commands from the ground. The Flexible Down-Converter DOCON is one of the new components that allow satellite signals to be redistributed between service areas to flexibly reallocate the most critical spectrum resources as needed. DOCON is a flexible Ka-band down-converter from RF = 27.5 ... 30.0 GHz to IF = 17.7 ... 20.2 GHz designed for GEO communication satellites. The device includes the housing, DC-, RF-, and telemetry / tele-command interfaces. An Engineering Model (EM) in form, fit and function was successfully built and tested. The next stage, the Engineering Qualification Model (EQM), is currently in fabrication and will be qualified until end of 2019. The modular concept comprises hermetically sealed LTCC microwave modules as key building blocks. There are three of these LTCC-modules: the Local Oscillator Module (LOM), the Mixer Module (MXM), and the Variable Gain Module (VGM). Their function and realization shall be discussed in this paper.

Network management protocols often require timely and meaningful insight about per flow network traffic. This paper introduces Randomized Admission Policy (RAP) –a novel algorithm for the frequency , top-k , and byte volume estimation problems, which are fundamental in network monitoring. We demonstrate space reductions compared to the alternatives, for the frequency estimation problem, by a factor of up to 32 on real packet traces and up to 128 on heavy-tailed workloads. For top- $k$ identification, RAP exhibits memory savings by a factor of between 4 and 64 depending on the workloads’ skewness. These empirical results are backed by formal analysis, indicating the asymptotic space improvement of our probabilistic admission approach. In Addition, we present d-way RAP , a hardware friendly variant of RAP that empirically maintains its space and accuracy benefits.

Employing quantum sensors in field or in space implies demanding requirements on the used components and integration technologies. Within our work on compact atomic sensors, we develop miniaturized, ultra-stable optical setups for optical cooling and trapping of cold atomic gases on atom chips. Besides challenging demands on alignment precision and thermo-mechanical durability, we specifically address ultra-high vacuum (UHV) compatibility of our adhesive integration technology and the assembled optical components. A prototype of an UHV-compatible, crossed beam optical dipole trap at 1064 nm for application within a cold rubidium atomic quantum sensor currently in development at the Joint Lab Integrated Quantum Sensors at Ferdinand-Braun-Institut, Leibniz-Institut fur Hochstfrequenztechnik is described. We describe the design and first qualification efforts on adhesive micro-integration technologies. These tests are conducted in application-relevant geometries and material combinations common for micro-integrated optical setups. Adhesive aging will be investigated by thermal cycling and radiation exposure. For vacuum compatibility testing, a versatile UHV testing system for samples up to $$65\times 65\,\text{mm}^2$$ footprint is currently being set up, enabling residual gas analysis, temperature cycling up to $$200\,^{\circ }\text{C}$$ and measurement of total gas rates down to expected $$5\times 10^{-10}\,\text{mbar}\,\text{l/s}$$ at a base pressure of $$10^{-11}\,\text{mbar}$$, exceeding the common ASTM E595 test.

The purpose of this study was to compare the Infinite Cylinder and Forward Field methods of quantifying global venous oxygen saturation (Yv) in the superior sagittal sinus (SSS) from MRI phase data, and assess their applicability in systemic cerebrovascular disease.15 children with sickle cell disease (SCD) and 10 healthy age-matched controls were imaged on a 3.0 T MRI system. Anatomical and phase data around the superior sagittal sinus were acquired from a clinically available susceptibility weighted imaging sequence and converted to Yv using the Infinite Cylinder and Forward Field methods. Yv was significantly higher when calculated using the Infinite Cylinder method compared to the Forward Field method in both patients (p = 0.003) and controls (p

AIMS Lipoprotein (a) [Lp(a)] is a lipoprotein species causatively associated with atherosclerosis. Unlike statins, PCSK9 inhibitors (PCSK9i) reduce Lp(a), but this reduction is highly variable. Levels of Lp(a) are chiefly governed by the size of its signature protein, apolipoprotein (a) [apo(a)]. Whether this parameter determines some of the reduction in Lp(a) induced by PCSK9i remains unknown. We aimed to investigate if the Lp(a) lowering efficacy of PCSK9i is modulated by the size of apo(a), which is genetically determined by the variable number of KIV domains present on that protein. METHODS AND RESULTS The levels of Lp(a) and the size of apo(a) were assessed in plasma samples from 268 patients before and after treatment with PCSK9i. Patients were recruited at the Outpatient Lipid Clinic of the Charite Hospital (Berlin) between 2015 and 2020. They were hypercholesterolemic at very high CVD risk with LDL-cholesterol levels above therapeutic targets despite maximally tolerated lipid-lowering therapy. Patients received either Alirocumab (75 or 150 mg) or Evolocumab (140 mg) every 2 weeks. Apo(a), apoB100, and apoE concentrations as well as apoE major isoforms were determined by liquid chromatography high-resolution mass spectrometry. Apo(a) isoforms sizes were determined by Western Blot. PCSK9i sharply reduced LDL-cholesterol (-57%), apoB100 (-47%) and Lp(a) (-36%). There was a positive correlation between the size of apo(a) and the relative reduction in Lp(a) induced by PCSK9i (r = 0.363, p = 0.0001). The strength of this association remained unaltered after adjustment for baseline Lp(a) levels and all other potential confounding factors. In patients with two detectable apo(a) isoforms, there was also a positive correlation between the size of apo(a) and the reduction in Lp(a), separately for the smaller (r = 0.350, p = 0.0001) and larger (r = 0.324, p = 0.0003) isoforms. The relative contribution of the larger isoform to the total concentration of apo(a) was reduced from 29% to 15% (p

Large geostationary high-power satellites for broad- cast application still form an important market segment for satellite industry. They require, however, new technical features that enable cost reductions, in-orbit flexibility and efficient use of available resources. This paper addresses an active Ku-band feed chain as core element for future direct radiating arrays or array-fed reflector antennas on broadcast satellites.

We investigate the representations learned by vision and language models in tasks that require relational reasoning. Focusing on the problem of assessing the relative size of objects in abstract visual contexts, we analyse both one-step and two-step reasoning. For the latter, we construct a new dataset of three-image scenes and define a task that requires reasoning at the level of the individual images and across images in a scene. We probe the learned model representations using diagnostic classifiers. Our experiments show that pretrained multimodal transformer-based architectures can perform higher-level relational reasoning, and are able to learn representations for novel tasks and data that are very different from what was seen in pretraining.

Consistency of a model -- that is, the invariance of its behavior under meaning-preserving alternations in its input -- is a highly desirable property in natural language processing. In this paper we study the question: Are Pretrained Language Models (PLMs) consistent with respect to factual knowledge? To this end, we create ParaRel, a high-quality resource of cloze-style query English paraphrases. It contains a total of 328 paraphrases for 38 relations. Using ParaRel, we show that the consistency of all PLMs we experiment with is poor -- though with high variance between relations. Our analysis of the representational spaces of PLMs suggests that they have a poor structure and are currently not suitable for representing knowledge robustly. Finally, we propose a method for improving model consistency and experimentally demonstrate its effectiveness., Comment: Accepted to the TACL journal, pre-MIT Press publication version

Recently, it has been found that monolingual English language models can be used as knowledge bases. Instead of structural knowledge base queries, masked sentences such as "Paris is the capital of [MASK]" are used as probes. We translate the established benchmarks TREx and GoogleRE into 53 languages. Working with mBERT, we investigate three questions. (i) Can mBERT be used as a multilingual knowledge base? Most prior work only considers English. Extending research to multiple languages is important for diversity and accessibility. (ii) Is mBERT's performance as knowledge base language-independent or does it vary from language to language? (iii) A multilingual model is trained on more text, e.g., mBERT is trained on 104 Wikipedias. Can mBERT leverage this for better performance? We find that using mBERT as a knowledge base yields varying performance across languages and pooling predictions across languages improves performance. Conversely, mBERT exhibits a language bias; e.g., when queried in Italian, it tends to predict Italy as the country of origin., Comment: Accepted to EACL 2021

International audience; Background: Proprotein Convertase Subtilisin/Kexin type 9 inhibitors (PCSK9-I) have been reported to cause a moderate increase in high-density lipoprotein (HDL) cholesterol in human studies. We thus evaluated the effect of two approved PCSK9-I on the concentration and lipid composition of HDL particle subclasses.Subjects and methods: 95 patients (62.8 ± 10.3 years old, 58% men), with or without statin and/or ezetimibe treatment and eligible for PCSK9-I therapy, received either evolocumab (140 mg) or alirocumab (75 or 150 mg). Their HDL particle profiles were measured by NMR spectroscopy at baseline and after 4 weeks of PCSK9-I treatment.Results: PCSK9-I treatment increased the level of HDL-C by 7%. The level of medium-sized HDL particles (M-HDL-P) increased (+8%) while the level of XL-HDL-P decreased (-19%). The lipid core composition was altered in the smaller S- and M-HDL-P, with a reduction in triglycerides (TG) and an enrichment in cholesterol esters (CE), whereas the for the larger XL- and L-HDL-P the relative CE content decreased and the TG content increased. Ezetimibe therapy differentially impacted the HDL particle distribution, independently of statin use, with an increase in S-HDL-P in patients not receiving ezetimibe.Conclusions: As S- and M-HDL-P levels are inversely related to cardiovascular risk, PCSK9-I treatment may result in a more atheroprotective HDL particle profile, particularly in patients not concomitantly treated with ezetimibe.

Purpose This pilot study aimed to determine interobserver reliability and ease of use of three workflows for measuring metabolic tumor volume (MTV) and total lesion glycolysis (TLG) in diffuse large B cell lymphoma (DLBCL). Procedures Twelve baseline [18F]FDG PET/CT scans from DLBCL patients with wide variation in number and size of involved organs and lymph nodes were selected from the international PETRA consortium database. Three observers analyzed scans using three workflows. Workflow A: user-defined selection of individual lesions followed by four automated segmentations (41%SUVmax, A50%SUVpeak, SUV≥2.5, SUV≥4.0). For each lesion, observers indicated their “preferred segmentation.” Individually selected lesions were summed to yield total MTV and TLG. Workflow B: fully automated preselection of [18F]FDG-avid structures (SUV≥4.0 and volume≥3ml), followed by removing non-tumor regions with single mouse clicks. Workflow C: preselected volumes based on Workflow B modified by manually adding lesions or removing physiological uptake, subsequently checked by experienced nuclear medicine physicians. Workflow C was performed 3 months later to avoid recall bias from the initial Workflow B analysis. Interobserver reliability was expressed as intraclass correlation coefficients (ICC). Results Highest interobserver reliability in Workflow A was found for SUV≥2.5 and SUV≥4.0 methods (ICCs for MTV 0.96 and 0.94, respectively). SUV≥4.0 and A50%Peak were most and SUV≥2.5 was the least preferred segmentation method. Workflow B had an excellent interobserver reliability (ICC = 1.00) for MTV and TLG. Workflow C reduced the ICC for MTV and TLG to 0.92 and 0.97, respectively. Mean workflow analysis time per scan was 29, 7, and 22 min for A, B, and C, respectively. Conclusions Improved interobserver reliability and ease of use occurred using fully automated preselection (using SUV≥4.0 and volume≥3ml, Workflow B) compared with individual lesion selection by observers (Workflow A). Subsequent manual modification was necessary for some patients but reduced interobserver reliability which may need to be balanced against potential improvement on prognostic accuracy.

BackgroundCheckpoint inhibitors (CPIs) such as anti-PD(L)-1 and anti-CTLA-4 antibodies have resulted in unprecedented rates of antitumor responses and extension of survival of patients with a variety of cancers. But some patients fail to respond or initially respond but later relapse as they develop resistance to immune therapy. One of the tumor-extrinsic mechanisms for resistance to immune therapy is the accumulation of regulatory T cells (Treg) in tumors. In preclinical and clinical studies, it has been suggested that tumor trafficking of Treg is mediated by CC chemokine receptor 4 (CCR4). Over 90% of human Treg express CCR4 and migrate toward CCL17 and CCL22, two major CCR4 ligands that are either high at baseline or upregulated in tumors on CPI treatment. Hence, CCR4 antagonism has the potential to be an effective antitumor treatment by reducing the accumulation of Treg into the tumor microenvironment (TME).MethodsWe developed in vitro and in vivo models to assess Treg migration and antitumor efficacy using a potent and selective CCR4 antagonist, CCR4-351. We used two separate tumor models, Pan02 and CT26 mouse tumors, that have high and low CCR4 ligand expression, respectively. Tumor growth inhibition as well as the frequency of tumor-infiltrating Treg and effector T cells was assessed following the treatment with CCR4 antagonist alone or in combination with CPI.ResultsUsing a selective and highly potent, novel small molecule inhibitor of CCR4, we demonstrate that migration of CCR4+ Treg into the tumor drives tumor progression and resistance to CPI treatment. In tumor models with high baseline levels of CCR4 ligands, blockade of CCR4 reduced the number of Treg and enhanced antitumor immune activity. Notably, in tumor models with low baseline level of CCR4 ligands, treatment with immune CPIs resulted in significant increases of CCR4 ligands and Treg numbers. Inhibition of CCR4 reduced Treg frequency and potentiated the antitumor effects of CPIs.ConclusionTaken together, we demonstrate that CCR4-dependent Treg recruitment into the tumor is an important tumor-extrinsic mechanism for immune resistance. Blockade of CCR4 led to reduced frequency of Treg and resulted in increased antitumor activity, supporting the clinical development of CCR4 inhibitors in combination with CPI for the treatment of cancer.Statement of significanceCPI upregulates CCL17 and CCL22 expression in tumors and increases Treg migration into the TME. Pharmacological antagonism of the CCR4 receptor effectively inhibits Treg recruitment and results in enhanced antitumor efficacy either as single agent in CCR4 ligandhigh tumors or in combination with CPIs in CCR4 ligandlow tumors.

How can pretrained language models (PLMs) learn factual knowledge from the training set? We investigate the two most important mechanisms: reasoning and memorization. Prior work has attempted to quantify the number of facts PLMs learn, but we present, using synthetic data, the first study that investigates the causal relation between facts present in training and facts learned by the PLM. For reasoning, we show that PLMs seem to learn to apply some symbolic reasoning rules correctly but struggle with others, including two-hop reasoning. Further analysis suggests that even the application of learned reasoning rules is flawed. For memorization, we identify schema conformity (facts systematically supported by other facts) and frequency as key factors for its success., Accepted to CoNLL 2020

Familial hypercholesterolemia (FH) is amongst the most common genetic disorders encountered in primary care. Yet, only a minority of affected patients is diagnosed and treated. This interim analysis of the CaRe High Registry aims at examining the state of treatment and attainment of lipid goals in German FH patients.The CaRe High registry includes FH patients from lipid clinics and private practices. Data have been collected using questionnaires filled in by the recruiting physicians and by interviewing the participating patients.We examined 512 F H patients diagnosed according to clinical criteria. Median age at the time of the first FH diagnosis was 39 (25th and 75th percentile: 27-50) years, median treatment naïve LDL cholesterol (LDL-C) was 239.4 mg/dl (6.19 mmol/l), 25th to 75th percentile 191.8-342.5 mg/dl (4.96-8.86 mmol/l). 27% of the participants did not receive lipid-lowering drugs. Among the patients treated with lipid-lowering drugs, 19% received a PCSK9 inhibitor (PCSK9i) in combination with a statin, 9% were treated with a PCSK9i alone and 3% were treated with a combination of PCSK9i and a non-statin drug. Patients with pre-existing CVD were more likely to be treated with lipid-lowering drugs and more likely to receive a PCSK9i, but LDL-C targets were only achieved by a minority of patients (20%). Gap to target LDL-C was lowest and the median achieved LDL-C reduction was 1.4 times higher with PCSK9i treatment than with (oral) lipid-lowering therapy without PCSK9i.The Care High registry has included patients with the typical clinical features of familial hypercholesterolemia. PCSK9i treatment in addition to standard therapy allows attainment of target values in many patients with initially very high LDL-C.

China's economy, the second largest in the world, is undergoing a fundamental transition. Its transition from a strong focus on investment and exports towards a larger share of consumption could have important ramifications for China's trading partners. Using China as a case study, this paper deploys a sectoral input-output (IO) analysis to take into account higher-round spillovers from a reduction in import demand or a shift in the composition of the Chinese economy. This approach demonstrates strong indirect effects that exceed by far the initial shock from direct trade links, reflecting China's integration into a closely knit global value chain. The result suggests that the ongoing transition in China will have important effects on the global economy.

BACKGROUND The associations between mechanical circulatory support (MCS), acquired von Willebrand syndrome (AvWS), and clinical outcome are incompletely understood. METHODS In 128 heart failure patients with pulsatile MCS implants (65 total artificial heart or biventricular assist device implants, 63 left ventricular assist device [LVAD] implants) and 76 patients with continuous flow LVAD implants, we analyzed the von Willebrand factor (vWF) profile before (≤24 h) and 17.5 (standard deviation: 5.1) days after device implant. We determined vWF concentrations, vWF activity, and vWF collagen binding capacity and calculated ratios of vWF activity/binding capacity with vWF concentration. The relation of the vWF profile with clinical outcomes such as stroke, gastrointestinal bleeding, and survival was also evaluated. Events were assessed up to 1 year of device implant. RESULTS All entities of vWF were already significantly elevated preoperatively and remained high after MCS implantation. The ratios of vWF activity/concentration (vWF:RCo/Ag) and collagen binding capacity/concentration (vWF:CBA/Ag) were significantly reduced preoperatively and remained low postoperatively, indicating AvWS. The preoperative alterations in the vWF profile were already present in patients without intra-aortic balloon pump and/or extracorporeal circulatory membrane oxygenation implants. The vWF profile was unrelated to postoperative stroke. However, a higher postoperative ratio of vWF:CBA/Ag was independently associated with increased gastrointestinal bleeding. In addition, a postoperative increase in vWF concentrations and activity were independent predictors of increased 1-year mortality. CONCLUSIONS Our data indicate that AvWS is present in heart failure patients before device implantation, and is independently associated with clinical outcomes, especially with 1-year mortality.

Use of the Medicare hospice benefit has been associated with high-quality care at the end of life, and hospice length of use in particular has been used as a proxy for appropriate timing of hospice enrollment. Quantile regression has been underutilized as an alternative tool to model distributional changes in hospice length of use and hospice payments outside of the mean.To test for heterogeneity in the relationship between patient characteristics and hospice outcomes across the distribution of hospice days.Medicare Beneficiary Summary File and survey data (2014) for hospice beneficiaries in North and South Carolina with common terminal diagnoses.Distributional shifts associated with patient characteristics were evaluated at the 25th and 75th percentiles of hospice days and hospice payments using quantile regressions and compared to the mean shift estimated by ordinary least squares (OLS) regression.Significant (p 0.001) heterogeneity in the marginal effects on hospice days and costs was observed, with patient characteristics associated with generally larger shifts in the 75th percentile than the 25th percentile. Mean effects estimated by OLS regression overestimate the magnitude of the median marginal effects for all patient characteristics except for race. Results for hospice payments in 2014 were similar.Methodological decisions can have a meaningful impact in the evaluation of factors influencing hospice length of use or cost.

On January 1, 2016, Medicare implemented a new "two-tiered" model for hospice services, with per diem rates increased for days 1 through 60, decreased for days 61 and greater, and service intensity add-on payments made retrospectively for the last seven days of life.To estimate whether the Medicare hospice benefit's potential for cost savings will change as a result of the January 2016 change in payment structure.Analysis of decedents' claims records using propensity score matching, logistic regression, and sensitivity analysis.All age-eligible Medicare decedents who received care and died in North Carolina in calendar years 2009 and 2010.Costs to Medicare for hospice and other healthcare services.Medicare costs were reduced from hospice election until death using both 2009-2010 and new 2016 payment structures and rates. Mean cost savings were $1,527 with actual payment rates, and would have been $2,105 with the new payment rates (p 0.001). Cost savings were confirmed by reducing the number of days used for cost comparison by three days for those with hospice stays of at least four days ($4,318 using 2009-2010 rates, $3,138 for 2016 rates: p 0.001). Cost savings were greater for males ($3,393) versus females ($1,051) and greatest in cancer ($6,706) followed by debility and failure to thrive ($5,636) and congestive heart failure ($1,309); dementia patients had higher costs (+$1,880) (p 0.001). When adding 3 days to the comparison period, hospice increased costs to Medicare.Medicare savings could continue with the 2016 payment rate change. Cost savings were found for all primary diagnoses analyzed except dementia.

Little is known about the characteristics and treatments of patients with severe asthma across Europe, but both are likely to vary. This is the first study in the European Respiratory Society Severe Heterogeneous Asthma Research collaboration, Patient-centred (SHARP) Clinical Research Collaboration and it is designed to explore these variations. Therefore, we aimed to compare characteristics of patients in European severe asthma registries and treatments before starting biologicals.This was a cross-sectional retrospective analysis of aggregated data from 11 national severe asthma registries that joined SHARP with established patient databases.Analysis of data from 3236 patients showed many differences in characteristics and lifestyle factors. Current smokers ranged from 0% (Poland and Sweden) to 9.5% (Belgium), mean body mass index ranged from 26.2 (Italy) to 30.6 kg·m−2 (the UK) and the largest difference in mean pre-bronchodilator forced expiratory volume in 1 s % predicted was 20.9% (the Netherlands versus Hungary). Before starting biologicals patients were treated differently between countries: mean inhaled corticosteroid dose ranged from 700 to 1335 µg·day−1 between those from Slovenia versus Poland when starting anti-interleukin (IL)-5 antibody and from 772 to 1344 µg·day−1 in those starting anti-IgE (Slovenia versus Spain). Maintenance oral corticosteroid use ranged from 21.0% (Belgium) to 63.0% (Sweden) and from 9.1% (Denmark) to 56.1% (the UK) in patients starting anti-IL-5 and anti-IgE, respectively.The severe asthmatic population in Europe is heterogeneous and differs in both clinical characteristics and treatment, often appearing not to comply with the current European Respiratory Society/American Thoracic Society guidelines definition of severe asthma. Treatment regimens before starting biologicals were different from inclusion criteria in clinical trials and varied between countries.

Over the past few years, the demands on satellite communication have undergone significant changes, and, as a consequence, its technologies and system designs are also changing in important ways. Since the introduction of high-definition television, classical geostationary (GEO) satellites in orbit at 36,800 km must transmit higher data rates. Also, GEO satellites are increasingly used for global data transfer, e.g., for Internet applications and business communication. As a consequence, higher-frequency bandwidth, higher transmitting frequencies in the millimeter-wave range, and efficient frequency reuse are needed [1].

Blood-brain barrier breakdown (BBBB) occurs in relapsing remitting multiple sclerosis (RRMS). Relative recirculation (rR), a BBBB surrogate, may show inflammation undetectable by gadolinium. We compared normal appearing white matter (NAWM) rR in patients with and without disability measured with Symbol Digit Modalities Test and the Expanded Disability Status Scale (EDSS). Thirty-nine RRMS patients were prospectively recruited and classified as impaired or non-impaired based on the SDMT and EDSS threshold ≥3. Significant demographic, MRI structural and regional rR characteristics were advanced into multivariate analysis to assess the association with impairment of cognition and EDSS. Bonferroni corrected p

Background This article was written to provide clinicians and researchers with an overview of a number of advanced neuroimaging techniques in an effort to promote increased utility and the design of future studies using advanced neuroimaging in childhood stroke. The current capabilities of advanced magnetic resonance imaging techniques provide the opportunity to build on our knowledge of the consequences of stroke on the developing brain. These capabilities include providing information about the physiology, metabolism, structure, and function of the brain that are not routinely evaluated in the clinical setting. Methods During the Proceedings of the Stroke Imaging Laboratory for Children Workshop in Toronto in June 2015, a subgroup of clinicians and imaging researchers discussed how the application of advanced neuroimaging techniques could further our understanding of the mechanisms of stroke injury and repair in the pediatric population. This subgroup was established based on their interest and commitment to design collaborative, advanced neuroimaging studies in the pediatric stroke population. Results In working toward this goal, we first sought to describe here the magnetic resonance imaging techniques that are currently available for use, and how they have been applied in other stroke populations (e.g., adult and perinatal stroke). Conclusions With the continued improvement in advanced neuroimaging techniques, including shorter acquisition times, there is an opportunity to apply these techniques to their full potential in the research setting and learn more about the effects of stroke in the developing brain.

Background and aim Hepatic encephalopathy (HE) is a frequent complication of cirrhosis, characterized by cognitive deficits that negatively impact patients' quality of life. The mild, minimal hepatic encephalopathy (mHE) can only be detected by psychometric tests and early mHE detection can prevent more severe complications or even survival times. Here, we aimed to investigate the feasibility and validity of the novel-developed electronic number connection test (eNCT), which is designed as a fast and easy-to-perform mHE patient self-test. Methods The eNCT design was inspired by the paper-pencil number connection test version A, showing 25 numbers on the screen (1-25), in a random order. The time required to tap on all digits in the correct order was measured. A total of 238 individuals (112 patients with liver cirrhosis) were enrolled in this study and eNCT times were compared with well-established paper-pencil tests. The Psychometric Hepatic Encephalopathy Score test battery was used to detect mHE and cut-off values for mHE detection by the eNCT were defined. Results Overall, cirrhotic patients showed significantly slower test completion times compared with control participants. The eNCT performance was inversely correlated with Psychometric Hepatic Encephalopathy Score test performance in cirrhotic patients, independent of the HE status. Thirty cirrhotic patients fulfilled the mHE criteria and receiver operating characteristic curve analysis showed high sensitivity (>82%) and specificity (>85%) for mHE detection. Finally, the eNCT showed excellent test-retest reliability (intraclass correlation coefficient=0.94). Conclusion The novel eNCT is a reliable HE self-test to monitor cognitive function and detect cognitive impairment in cirrhotic patients.

Khandelwal et al. (2020) use a k-nearest-neighbor (kNN) component to improve language model performance. We show that this idea is beneficial for open-domain question answering (QA). To improve the recall of facts encountered during training, we combine BERT (Devlin et al., 2019) with a traditional information retrieval step (IR) and a kNN search over a large datastore of an embedded text collection. Our contributions are as follows: i) BERT-kNN outperforms BERT on cloze-style QA by large margins without any further training. ii) We show that BERT often identifies the correct response category (e.g., US city), but only kNN recovers the factually correct answer (e.g., "Miami"). iii) Compared to BERT, BERT-kNN excels for rare facts. iv) BERT-kNN can easily handle facts not covered by BERT's training set, e.g., recent events., Comment: to appear in EMNLP Findings

Sickle cell disease (SCD) is associated with a high risk of stroke, and affected individuals often have focal brain lesions termed silent cerebral infarcts. The mechanisms leading to these types of injuries are at present poorly understood. Our group has recently demonstrated a non-invasive measurement of cerebrovascular impedance and wave reflection in mice using high-frequency ultrasound in the common carotid artery. To better understand the pathophysiology in SCD, we used this approach in combination with micro-computed tomography to investigate changes in cerebrovascular morphology in the Townes mouse model of SCD. Relative to controls, the SCD mice demonstrated the following: (i) increased carotid artery diameter, blood flow and vessel wall thickness; (ii) elevated pulse wave velocity; (iii) increased reflection coefficient; and (iv) an increase in the total number of vessel segments in the brain. This study highlights the potential for wave reflection to aid the non-invasive clinical assessment of vascular pathology in SCD.

Software switches are emerging as a vital measurement vantage point in many networked systems. Sketching algorithms or sketches, provide high-fidelity approximate measurements, and appear as a promising alternative to traditional approaches such as packet sampling. However, sketches incur significant computation overhead in software switches. Existing efforts in implementing sketches in virtual switches make sacrifices on one or more of the following dimensions: performance (handling 40 Gbps line-rate packet throughput with low CPU footprint), robustness (accuracy guarantees across diverse workloads), and generality (supporting various measurement tasks). In this work, we present the design and implementation of NitroSketch, a sketching framework that systematically addresses the performance bottlenecks of sketches without sacrificing robustness and generality. Our key contribution is the careful synthesis of rigorous, yet practical solutions to reduce the number of per-packet CPU and memory operations. We implement NitroSketch on three popular software platforms (Open vSwitch-DPDK, FD.io-VPP, and BESS) and evaluate the performance. We show that accuracy is comparable to unmodified sketches while attaining up to two orders of magnitude speedup, and up to 45% reduction in CPU usage.

By temporally integrating information about pupil contours extracted from eye images, model-based methods for glint-free gaze estimation can mitigate pupil detection noise. However, current approaches require time-consuming iterative solving of a nonlinear minimization problem to estimate key parameters, such as eyeball position. Based on the method presented by [Swirski and Dodgson 2013], we propose a novel approach to glint-free 3D eye-model fitting and gaze prediction using a single near-eye camera. By recasting model optimization as a least-squares intersection of lines, we make it amenable to a fast non-iterative solution. We further present a method for estimating deterministic refraction-correction functions from synthetic eye images and validate them on both synthetic and real eye images. We demonstrate the robustness of our method in the presence of pupil detection noise and show the benefit of temporal integration of pupil contour information on eyeball position and gaze estimation accuracy.

Background To evaluate the presence of Wallerian degeneration and its relationship with sensorimotor deficits following childhood-onset arterial ischemic stroke (AIS). Methods Children surviving unilateral AIS older than one month of age were assessed for severity of sensorimotor neurological deficit with the Pediatric Stroke Outcome Measure at least one year post stroke (mean follow-up = 2.9 years, S.D. = ±1.6). The area (mm3) of each cerebral peduncle was measured on T2-weighted magnetic resonance images to calculate an Asymmetry Index (AI). The AI between patients with childhood stroke (cases) and controls (children with normal MRI) was compared. In the stroke group, the AI between patients with good and poor motor outcome, and the correlation between the AI and motor outcome was calculated. Results Asymmetry was compared in 52 children with stroke (cases) and 20 controls (normal brain MRIs). The AI was greater in patients with stroke (mean = 6.8%, S.D. = ±5.9) compared with controls (mean = 3.4%, S.D. = ±3.5, P Conclusions Asymmetry of the cerebral peduncle is a feasible method of assessing Wallerian degeneration in children with unilateral AIS. The degree of asymmetry in the cerebral peduncles was moderately correlated with neurological outcome severity and reflects the degree of motor deficit in children following stroke.

Sickle cell anaemia (SCA) is a devastating genetic blood disorder leading to chronic anaemia, impaired cerebrovascular dilatory capacity and cerebral infarctions. Our aim was to assess the relationship between microstructural properties of the white matter (WM) and both cerebrovascular reactivity (CVR) and cerebral blood flow, as well as the effects of hydroxycarbamide on these relationships. Our results demonstrate that mean CVR was increased in hydroxycarbamide-treated patients compared to untreated patients. Moreover, untreated SCA patients had increased skew and kurtosis of mean diffusivity histograms in the WM compared to hydroxycarbamide-treated patients and healthy age-matched controls, indicating disruption of WM integrity. Regression analysis of CVR and WM mean diffusivity (MD) revealed a significant linear relationship between CVR and MD histogram skew and kurtosis in healthy controls, but not in either of the two SCA groups. These findings suggest that patients treated with hydroxycarbamide possess white matter MD histogram parameters which more closely resemble those of healthy controls.

Erratum zu: CardioVasc. 2020;21(6):31-2.In diesem Artikel war die Korrespondenzadresse falsch angegeben. Richtig muss es heisen:Dr. med. Ursula KassnerLipidambulanz, Klinik fur EndokrinologieCharite - Universitatsmedizin BerlinChariteplatz 110117 Berlinursula.kassner@charite.deDer ursprungliche Artikel wur...

To stay competitive in a global market, companies strive to adjust their IT architectures to the characteristics of Industrie 4.0. This means the adaptation of a data-driven manufacturing model, which includes the horizontal and vertical integration of the value chain and the management of data across the whole product life cycle. Currently companies face two major problems in this transformation of their IT architectures: 1) There are multiple reference architectures for Industrie 4.0, whose suitability has not been evaluated in a straightforward way. 2) There are no maturity models to objectively assess data-driven IT architectures. In this work we address these problems by providing an overview of Industrie 4.0 features in multiple reference architectures and developing a maturity model for IT architectures for data-driven manufacturing. We first give an overview of the current maturity models with aspects of data-driven manufacturing. Based on this overview we survey three reference architectures for Industrie 4.0: the Industrial Internet Reference Architecture, the Reference Architecture Model Industrie 4.0, and the Stuttgart IT Architecture for Manufacturing. We analyze and assess each approach and define maturity levels for data-driven manufacturing to guide companies in the adaption process of Industrie 4.0, as well as criteria for meeting these levels.

Objectives The aim of this study was to compare outcomes of bailout and planned rotational atherectomy (RA) in the treatment of calcified coronary lesions. Background Current guidelines recommend RA as a bailout procedure for calcified or fibrotic lesions that cannot be adequately dilated before stenting. Nonetheless, planned RA is sometimes performed in certain challenging anatomies. Methods Data of patients treated with RA between 2002 and 2014 at a single-center registry were retrospectively analyzed. The bailout RA group included patients where RA was employed after failure of balloon dilatation or stent delivery. Planned RA included patients where RA was employed electively without previous device failure. Results The study comprised 204 patients (221 lesions) and 308 patients (338 lesions) treated with bailout or planned RA, respectively. Angiographic success was achieved in the majority of cases, but was lower in the bailout RA group (93.7% vs. 97.6%, P = 0.02). Coronary dissections occurred more frequently in the bailout RA group (8.6% vs. 4.4%, P = 0.04), mean contrast amount was higher (279 ± 135 mL vs. 202 ± 92 mL, P