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Background:While some risk factors for severe COVID-19 outcomes have been identified for the general population and patients with rheumatic diseases (1-3), what drives these outcomes in specific rheumatic disease remains unclear. In addition, these findings need to be assessed across various observational data sources to ensure external validity.Objectives:To describe the demographics, comorbidities, and severe COVID-19 outcomes among rheumatoid arthritis (RA) patients infected with SARS-CoV-2 in the United States.Methods:A large nationwide electronic health record database (Optum, Inc.) in the United States, with data range between February 1, 2020 and September 17, 2020, was used to describe the demographics, comorbidities, and severe COVID-19 outcomes of RA patients with confirmed COVID-19 diagnosis (diagnosis for COVID-19 or positive PCR or antigen test). Patients with a single diagnosis of RA (ICD-10 code) before the diagnosis of COVID-19 were included. Patients missing age or sex, under 18 years of age on COVID-19 diagnosis date, or having less than 15 months of activity prior to COVID-19 diagnosis in the data source were excluded. We described demographics, comorbidities, and severe COVID-19 outcomes, including death, hospitalization, ICU admission, and acute respiratory insufficiency (ARI) identified between 14 days prior to and 30 days after COVID-19 diagnosis. Mean and standard deviation (SD) was reported for continuous variables. For categorical variables, count (N) and proportion was reported.Results:We identified 2,948 patients diagnosed with RA and infected with SARS-CoV-2 (mean age± SD: 62 years ± 16, 77% female, 68% white). Of all identified patients, 38% were current or former smokers. For the 2,614 patients with BMI recorded, 78% were overweight or obese (mean BMI±SD: 31.2±8.3). The mean Charlson comorbidity index (CCI) was 3.6 (SD 3.2), with 87% of the study cohort having one or more comorbid condition, including hypertension (55%), type 2 diabetes (26%), COPD (20%), moderate to severe asthma (17%), coronary artery disease (17%), chronic kidney disease (13%), and heart failure (13%). Severe COVID-19 outcomes occurred in 618 (21%) patients. Among all RA patients with COVID-19, 137 patients (4.6%) experienced ARI, 484 patients (16.4%) were hospitalized (including 174 (5.9%) admitted to the ICU), and 155 patients (5.3%) died.Conclusion:Underlying medical conditions that are known or possible risk factors of severe illness from SARS-CoV-2 infection in the general population are common in this RA cohort from a large national EHR database. However, whether patients with RA are more vulnerable to severe COVID-19 outcome than the general population requires adjustment by age and other important confounders.References:[1]Gianfrancesco M, Hyrich KL, Al-Adely S, Carmona L, Danila MI, Gossec L, et al. Characteristics associated with hospitalisation for COVID-19 in people with rheumatic disease: data from the COVID-19 Global Rheumatology Alliance physician-reported registry. Ann Rheum Dis. 2020;79(7):859-66.[2]Williamson EJ, Walker AJ, Bhaskaran K, Bacon S, Bates C, Morton CE, et al. Factors associated with COVID-19-related death using OpenSAFELY. Nature. 2020;584(7821):430-6.[3]Gold JAW, Wong KK, Szablewski CM, Patel PR, Rossow J, da Silva J, et al. Characteristics and Clinical Outcomes of Adult Patients Hospitalized with COVID-19 - Georgia, March 2020. MMWR Morb Mortal Wkly Rep. 2020;69(18):545-50.Disclosure of Interests:Yizhou Ye Shareholder of: AbbVie Inc. and Pfizer Inc., Employee of: AbbVie Inc., Xiaomeng Yue Employee of: AbbVie Inc., Whitney Krueger Shareholder of: AbbVie Inc., Employee of: AbbVie Inc., Lani Wegrzyn Shareholder of: AbbVie Inc., Employee of: AbbVie Inc.

Background:While some risk factors for severe COVID have been identified for patients with rheumatic diseases,1 few studies have investigated whether outcomes differ based on the type of rheumatoid arthritis (RA) treatment. Most existing reports have been limited to individual centers or voluntary reporting registries.2,3Objectives:To compare the occurrence of hospitalizations following COVID-19 diagnosis among patients with RA treated with various classes of DMARDs.Methods:A cohort of patients with confirmed COVID-19 (ICD10 diagnosis code or positive PCR or antigen test result) were identified within a large US electronic health record (EHR) dataset (Optum, Inc.) during the time period Feb 1, 2020 through Oct 14, 2020. From these, we identified RA patients (ICD10 RA diagnosis code) with treatment (most recent of JAK inhibitor [JAKi], biologic [bDMARD] or conventional synthetic [csDMARD] only) within the 12 months prior to COVID-19 diagnosis (i.e., index). The primary outcome was any hospitalization on or within 30 days after COVID-19 diagnosis. Multivariable logistic regression models compared users of JAKi’s to non-TNFi bDMARDs and csDMARDs (separately), as well as users of TNFi’s to non-TNFi bDMARDS and csDMARDs (separately), and were adjusted for age, gender, index month and baseline corticosteroid use. Sensitivity analyses included restriction of prevalent treatment use to within 180 days prior to COVID-19 diagnosis and restriction of csDMARDs to a group without hydroxychloroquine or chloroquine.Results:The study included 910 RA patients on DMARD treatment who were diagnosed with COVID-19 (mean age ± SD: 61±15, 80% female, 62% white. Of those, 26% (n=240) were hospitalized on or within 30 days after COVID-19 diagnosis. The proportion of patients hospitalized was highest in non-TNFi bDMARD users (37/87; 43%), followed by csDMARDs users (161/581; 28%) and lowest in JAKi (13/68; 19%) and TNFi users (29/174; 17%). In multivariable-adjusted models, no differences in risk of hospitalization were found comparing JAKi users to csDMARD users (aOR=0.71; 95% CI 0.37-1.36) or TNFi users to csDMARD users (aOR=0.67; 95%CI 0.43-1.06). Compared to non-TNFi bDMARD users, JAKi use and TNFi use was associated with reduced risk of hospitalization (JAKi aOR=0.32; 95%CI 0.14-0.71; TNFi aOR=0.34; 95%CI 0.18-0.62). Age and corticosteroid use were positively associated with 30-day hospitalization in all models. Results of sensitivity analyses were consistent with the main findings.Conclusion:In this study, roughly a quarter of RA patients with recent DMARD treatment were hospitalized within 30 days after COVID diagnosis. Patients treated with JAKi and TNFi therapies experienced the lowest risk of hospitalization, with risk of hospitalization significantly lower than non-TNFi bDMARDs. However, recent therapy recorded in the EHR may not reflect exposure at time of COVID-19 diagnosis and small sample size per treatment may limit interpretation.References:[1]Hyrich KL, Machado PM. Nat Rev Rheumatol 2020;1-2. doi:10.1038/s41584-020-00562-2[2]Gianfrancesco MA, et al. Lancet Rheumatol 2020;2(5):e250-e253. doi:10.1016/S2665-9913(20)30095-3[3]Veenstra J, et al. J Am Acad Dermatol 2020;83(6):1696-1703.Acknowledgements:Jonathan Johnson of Optum, Inc. provided dataset guidance and conducted data analyses. AbbVie funded this study, contributed to its design, participated in data collection, analysis, and interpretation of the data, and in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship.Disclosure of Interests:Lani Wegrzyn Shareholder of: AbbVie, Employee of: AbbVie, Kevin Winthrop Consultant of: Pfizer, AbbVie, UCB, Eli Lilly & Company, Galapagos, GSK, Roche, Gilead, BMS, Regeneron, Sanofi, AstraZeneca, Novartis, Grant/research support from: BMS, Pfizer, Seoyoung Kim Grant/research support from: institutional research grants from Pfizer, AbbVie, Roche, BMS for unrelated studies, Yizhou Ye Shareholder of: AbbVie, Employee of: AbbVie, Carrie Huisingh Shareholder of: AbbVie, Employee of: AbbVie, Whitney Krueger Shareholder of: AbbVie, Employee of: AbbVie, anna maniccia Shareholder of: AbbVie, Employee of: AbbVie, Ryan Kilpatrick Shareholder of: AbbVie, Employee of: AbbVie.

Efficient control is often the most cost-effective option to improve on the running cost of a ThreePipe Water Pumping System. However, the effect of changing the control strategy (i.e. on energy consumption) is usually difficult to predict. A new simulation tool, QUICKcontrol, was used to investigate the energy cost savings potential in a Three-Pipe Water Pumping System. The influence of pump scheduling, dam level set points, control parameters and different combinations thereof were investigated. The simulation models were firstly verified with measurements obtained from the existing system to confirm their accuracy for realistic control retrofit simulations. With the aid of the integrated simulation tool, it was possible to predict savings of R195 000 per year with an average 3.8 MW of load shifted out of peak times. These control strategies can be implemented in the pumping system with a direct payback period of less than 6 months.

Primary sclerosing cholangitis (PSC) is an incurable, fibroinflammatory biliary disease for which there is no effective pharmacotherapy. We recently reported cholangiocyte senescence as an important phenotype in PSC while others showed that portal macrophages accumulate in PSC. Unfortunately, our ability to explore cholangiocyte senescence and macrophage accumulation has been hampered by limited in vitro models. Thus, our aim was to develop and characterize a three dimensional model (3D) of normal and diseased bile ducts (cholangioids) starting with normal human cholangiocytes (NHC), senescent NHC (NHC-sen), and cholangiocytes from PSC patients. In 3D culture, NHCs formed spheroids of ~5000 cells with a central lumen of ~150 μm. By confocal microscopy and western blot, cholangioids retained expression of cholangiocyte proteins (cytokeratin 7/19) and markers of epithelial polarity (secretin receptor and GM130). Cholangioids are functionally active, and upon secretin stimulation, luminal size increased by ~ 80%. Cholangioids exposed to hydrogen peroxide exhibited cellular senescence (SA-βGal and γH2A.x expression) and the senescence associated secretory phenotype (SASP; increased IL-6, p21, β;-Gal and p16 expression). Furthermore, cholangioids derived from NHC-sen or PSC patients were smaller and had slower growth than the controls. When co-cultured with THP-1 macrophages, the number of macrophages associated with NHC-sen or PSC cholangioids was 5 to7-fold greater compared to co-culture with non-senescent NHC. We observed that NHC-sen and PSC cholangioids release greater numbers of extracellular vesicles (ECVs) compared to controls. Moreover, conditioned media from NHC-sen cholangioids resulted in an ~2-fold increase in macrophage migration. In summary, we developed a method to normal and diseased cholangioids, characterized them morphologically and functionally, showed that they can be induced to senescence and SASP, and demonstrated both ECV release and macrophage attraction. This novel model mimics several features of PSC and thus will be useful for studying the pathogenesis of PSC and potentially identifying new therapeutic targets.

Background and aims Hepatocytes play a central role in storage and utilization of fat by the liver. Selective breakdown of lipid droplets (LDs) by autophagy (also called lipophagy) is a key process utilized to catabolize these lipids as an energy source. How the autophagic machinery is selectively targeted to LDs, where it mediates membrane engulfment and subsequent degradation, is unclear. Recently, we have reported that two distinct GTPases, the mechanoenzyme, dynamin2 (Dyn2), and the small regulatory Rab GTPase, Rab10, work independently at distinct steps of lipophagy in hepatocytes. Approach and results In an attempt to understand how these proteins are regulated and recruited to autophagic organelles, we performed a nonbiased biochemical screen for Dyn2-binding partners and found that Dyn2 actually binds Rab10 directly through a defined effector domain of Rab10 and the middle domain of Dyn2. These two GTPases can be observed to interact transiently on membrane tubules in hepatoma cells and along LD-centric autophagic membranes. Most important, we found that a targeted disruption of this interaction leads to an inability of cells to trim tubulated cytoplasmic membranes, some of which extend from lipophagic organelles, resulting in LD accumulation. Conclusions This study identifies a functional, and direct, interaction between Dyn2 and a regulatory Rab GTPase that may play an important role in hepatocellular metabolism.

Single-phase monoclinic aluminum–gallium oxide powders, β−(AlxGa1−x)2O3, have been produced by solution combustion synthesis for Al fraction 0 ≤ x

The next generation enterprise Xeon server processor maximum configuration supports 18 dual-threaded 64 bit Haswell cores, 45 MB L3 cache, 4 DDR4–2133 MHz memory channels, 40 8 GT/s PCIe lanes, and 40 9.6 GT/s QPI lanes. The processor has 5.56 B transistors on a 31.9 mm $\,\times\,$ 20.8 mm die in Intel's Hi-K metal-gate tri-gate 22 nm CMOS technology with 11 metal layers and achieves up to 33% performance boost. The design supports a wide range of configurations including thermal design power ranging from 55 to 160 W and frequencies ranging from 1.6 to 3.7 GHz. Key architectural innovations include the addition of AVX2 technology, DDR4, and fully integrated voltage regulators (FIVR) that enable per core p-states and uncore frequency scaling.

Thin-film photovoltaic (PV) devices can be fabricated using a solution-based synthesis procedure in which metal-chalcogenide nanocrystals with aliphatic coordinating ligands are suspended in a solvent to produce a printable ink (NC-ink). However, the aliphatic ligands that are used to solubilize and stabilize the nanocrystals operate as a significant source of carbon impurities that are incorporated into the final device absorber layer. Despite the ubiquity of this technique and the fact that carbon defects have been reported to be found across a spectrum of devices, the structure, properties, and influence of the carbon on PV device performance remain relatively unexplored. Our findings indicate that these organic ligands undergo a pyrolysis reaction during annealing, producing an electrically conductive, graphitic carbon that also reacts with chalcogens (S or Se) to produce heterocyclic moieties. In this work, we used oleylamine (OLA) and dodecylamine (DDA) to fabricate Cu2ZnSn(SxSe1–x)4 (CZTSSe) photov...

The animals and other content of children's stories may relate primarily to a child's internal emotional life, to experiences otherwise ethereal and incomprehensible. Animal stories appeal to the unconscious and the conscious at the same time, so that contradictions coexist, unlike in the "real" world where the child has to be only good, only loving. The stage theories of development, most notably the psychoanalytic perspective of Sigmund Freud, and the cognitive developmental scheme of J. Piaget, both serve as backdrop to the literature of children. Children respond consciously and unconsciously to the symbolic meanings of animals presented in stories; these symbolic themes encapsulate unresolved issues for which there is no immediate mastery. The illustrations prevent that, keeping us to a predetermined story line with the containment of illustrations. The illustration of the animal groom is usually as a disgusting or ferocious animal such as Beauty and the Beast, Snow-White and Rose-Red, The Frog King, and The Princess and the Frog.

Tumor cells utilize invadopodia to remodel the surrounding stroma during metastatic invasion. Qiang et al. demonstrate that MTCBP-1 significantly attenuates invadopodia formation and function by binding MT1-MMP and preventing the interaction of MT1-MMP with the actin cytoskeleton., The process by which tumor cells mechanically invade through surrounding stroma into peripheral tissues is an essential component of metastatic dissemination. The directed recruitment of the metalloproteinase MT1-MMP to invadopodia plays a critical role in this invasive process. Here, we provide mechanistic insight into MT1-MMP cytoplasmic tail binding protein 1 (MTCBP-1) with respect to invadopodia formation, matrix remodeling, and invasion by pancreatic tumor cells. MTCBP-1 localizes to invadopodia and interacts with MT1-MMP. We find that this interaction displaces MT1-MMP from invadopodia, thereby attenuating their number and function and reducing the capacity of tumor cells to degrade matrix. Further, we observe an inverse correlation between MTCBP-1 and MT1-MMP expression both in cultured cell lines and human pancreatic tumors. Consistently, MTCBP-1–expressing cells show decreased ability to invade in vitro and metastasize in vivo. These findings implicate MTCBP-1 as an inhibitor of the metastatic process.

The fiber orientation in the atria has a significant contribution to the electrophysiologic behavior of the heart and to the genesis of arrhythmia. Atrial fiber orientation has a direct effect on excitation propagation, activation patterns and the P-wave. We present a rule-based algorithm that works robustly on different volumetric meshes composed of either isotropic hexahedra or arbitrary tetrahedra as well as on 3-dimensional triangular surface meshes in patient-specific geometric models. This method fosters the understanding of general proarrhythmic mechanisms and enhances patient-specific modeling approaches.

Metastatic invasion of tumors into peripheral tissues is known to rely upon protease-mediated degradation of the surrounding stroma. This remodeling process utilizes complex, actin-based, specializations of the plasma membrane termed invadopodia that act both to sequester and release matrix metalloproteinases. Here we report that cells of mesenchymal origin, including tumor-associated fibroblasts, degrade substantial amounts of surrounding matrix by a mechanism independent of conventional invadopodia. These degradative sites lack the punctate shape of conventional invadopodia to spread along the cell base and are reticular and/or fibrous in character. In marked contrast to invadopodia, this degradation does not require the action of Src kinase, Cdc42, or Dyn2. Rather, inhibition of Dyn2 causes a dramatic upregulation of stromal matrix degradation. Further, expression and activity of matrix metalloproteinases are differentially regulated between tumor cells and stromal fibroblasts. This matrix remodeling by fibroblasts increases the invasive capacity of tumor cells, thereby illustrating how the tumor microenvironment can contribute to metastasis. These findings provide evidence for a novel matrix remodeling process conducted by stromal fibroblasts that is substantially more effective than conventional invadopodia, distinct in structural organization, and regulated by disparate molecular mechanisms.

This paper describes a tutorial to introduce a product line engineering solution, including tools and methods, that is the subject of an upcoming ISO standard and known as "Feature-Based Systems and Software Product Line Engineering." This tutorial will explain the approach, give its history and a brief summary of some of its many successes, and discuss its application to systems and software engineering. Moreover, the tutorial will cover how its usage is spreading beyond the traditional engineering realm, across the entire enterprise in areas such as product marketing, portfolio planning, manufacturing, supply chain management, product service and maintenance, and much more.

ECG imaging is an emerging technology for the reconstruction of cardiac electric activity from non-invasively measured body surface potential maps. In this case report, we present the first evaluation of transmurally imaged activation times against endocardially reconstructed isochrones for a case of sustained monomorphic ventricular tachycardia (VT). Computer models of the thorax and whole heart were produced from MR images. A recently published approach was applied to facilitate electrode localization in the catheter laboratory, which allows for the acquisition of body surface potential maps while performing non-contact mapping for the reconstruction of local activation times. ECG imaging was then realized using Tikhonov regularization with spatio-temporal smoothing as proposed by Huiskamp and Greensite and further with the spline-based approach by Erem et al. Activation times were computed from transmurally reconstructed transmembrane voltages. The results showed good qualitative agreement between the non-invasively and invasively reconstructed activation times. Also, low amplitudes in the imaged transmembrane voltages were found to correlate with volumes of scar and grey zone in delayed gadolinium enhancement cardiac MR. The study underlines the ability of ECG imaging to produce activation times of ventricular electric activity-and to represent effects of scar tissue in the imaged transmembrane voltages.

Automatic speech recognition is now playing an important role in volume control and adjustment of modern smart speakers. According to the recognition results by using the advanced deep neural network technology, this paper proposes an efficient processing system for automatic volume control (AVC) and limiter. The theoretical analyses, subjective and objective testing results show that the proposed processing system can offer a significant improvement for speech recognition performance during audio playback and improvement for audio playback performance in smart speakers. Driven by input data and audio contents, the proposed AVC is able to adaptively learn and track an effective signal level at the speed corresponding to the width of transient sound; the adaptation is frozen in the case of silence and noise periods. The proposed limiter measures the peaks and can guarantee that no peak will go over the predetermined peak threshold so as to avoid clipping and harmonic distortions.

With the advent of cloud computing and its model for IT services based on the Internet and big data centers, the interest of industries into XaaS ("Anything as a Service") paradigm is increasing. Business intelligence and knowledge discovery services are typical services that companies tend to externalize on the cloud, due to their data intensive nature and the algorithms complexity. What is appealing for a company is to rely on external expertise and infrastructure to compute the analytical results and models which are required by the business analysts for understanding the business phenomena under observation. Although it is advantageous to achieve sophisticated analysis there exist several serious privacy issues in this paradigm. In this paper we investigate through an industrial use-case the application of a framework for privacypreserving outsourcing of pattern mining on event-log data. Moreover, we present and discuss some ideas about possible extensions.

Near-field acoustical holography methods are used to predict sound radiation from an engine installed on a high-performance military fighter aircraft. Cylindrical holography techniques are an efficient approach to measure the large and complex sound fields produced by full-scale jets. It is shown that a ground-based, one-dimensional array of microphones can be used in conjunction with a cylindrical wave function field representation to provide a holographic reconstruction of the radiated sound field at low frequencies. In the current work, partial field decomposition methods and numerical extrapolation of data beyond the boundaries of the hologram aperture are required prior to holographic projection. Predicted jet noise source distributions and directionality are shown for four frequencies between 63 and 250 Hz. It is shown that the source distribution narrows and moves upstream, and that radiation directionality shifts toward the forward direction, with increasing frequency. A double-lobe feature of full-scale jet radiation is also demonstrated.

Recent reports have shown that self-assembled monolayers (SAMs) can induce doping effects in graphene transistors. However, a lack of understanding persists surrounding the quantitative relationship between SAM molecular design and its effects on graphene. In order to facilitate the fabrication of next-generation graphene-based devices it is important to reliably and predictably control the properties of graphene without negatively impacting its intrinsic high performance. In this study, SAMs with varying dipole magnitudes/directions are utilized and these values are directly correlated to changes in performance seen in graphene transistors. It is found that, by knowing the z-component of the SAM dipole, one can reliably predict the shift in graphene charge neutrality point after taking into account the influence of the metal electrodes (which also play a role in doping graphene). This relationship is verified through density functional theory and comprehensive device studies utilizing atomic force microscopy, X-ray photoelectron spectroscopy, Raman spectroscopy, and electrical characterization of graphene transistors. It is shown that properties of graphene transistors can be predictably controlled with SAMs when considering the total doping environment. Additionally, it is found that methylthio-terminated SAMs strongly interact with graphene allowing for a cleaner graphene transfer and enhanced charge mobility.

A novel protein complex facilitates lipid droplet autophagy., The autophagic digestion of lipid droplets (LDs) through lipophagy is an essential process by which most cells catabolize lipids as an energy source. However, the cellular machinery used for the envelopment of LDs during autophagy is poorly understood. We report a novel function for a small Rab guanosine triphosphatase (GTPase) in the recruitment of adaptors required for the engulfment of LDs by the growing autophagosome. In hepatocytes stimulated to undergo autophagy, Rab10 activity is amplified significantly, concomitant with its increased recruitment to nascent autophagic membranes at the LD surface. Disruption of Rab10 function by small interfering RNA knockdown or expression of a GTPase-defective variant leads to LD accumulation. Finally, Rab10 activation during autophagy is essential for LC3 recruitment to the autophagosome and stimulates its increased association with the adaptor protein EHBP1 (EH domain binding protein 1) and the membrane-deforming adenosine triphosphatase EHD2 (EH domain containing 2) that, together, are essential in driving the activated “engulfment” of LDs during lipophagy in hepatocytes.