Breaking tolerance to the natural human liver autoantigen cytochrome P450 2D6 by virus infection

Autoimmune liver diseases, such as autoimmune hepatitis (AIH) and primary biliary cirrhosis, often have severe consequences for the patient. Because of a lack of appropriate animal models, not much is known about their potential viral etiology. Infection by liver-tropic viruses is one possibility for the breakdown of self-tolerance. Therefore, we infected mice with adenovirus Ad5 expressing human cytochrome P450 2D6 (Ad-2D6). Ad-2D6–infected mice developed persistent autoimmune liver disease, apparent by cellular infiltration, hepatic fibrosis, “fused” liver lobules, and necrosis. Similar to type 2 AIH patients, Ad-2D6–infected mice generated type 1 liver kidney microsomal–like antibodies recognizing the immunodominant epitope WDPAQPPRD of cytochrome P450 2D6 (CYP2D6). Interestingly, Ad-2D6–infected wild-type FVB/N mice displayed exacerbated liver damage when compared with transgenic mice expressing the identical human CYP2D6 protein in the liver, indicating the presence of a stronger immunological tolerance in CYP2D6 mice. We demonstrate for the first time that infection with a virus expressing a natural human autoantigen breaks tolerance, resulting in a chronic form of severe, autoimmune liver damage. Our novel model system should be instrumental for studying mechanisms involved in the initiation, propagation, and precipitation of virus-induced autoimmune liver diseases

Analysis of shared heritability in common disorders of the brain

ience, this issue p. eaap8757 Structured Abstract INTRODUCTION Brain disorders may exhibit shared symptoms and substantial epidemiological comorbidity, inciting debate about their etiologic overlap. However, detailed study of phenotypes with different ages of onset, severity, and presentation poses a considerable challenge. Recently developed heritability methods allow us to accurately measure correlation of genome-wide common variant risk between two phenotypes from pools of different individuals and assess how connected they, or at least their genetic risks, are on the genomic level. We used genome-wide association data for 265,218 patients and 784,643 control participants, as well as 17 phenotypes from a total of 1,191,588 individuals, to quantify the degree of overlap for genetic risk factors of 25 common brain disorders. RATIONALE Over the past century, the classification of brain disorders has evolved to reflect the medical and scientific communities' assessments of the presumed root causes of clinical phenomena such as behavioral change, loss of motor function, or alterations of consciousness. Directly observable phenomena (such as the presence of emboli, protein tangles, or unusual electrical activity patterns) generally define and separate neurological disorders from psychiatric disorders. Understanding the genetic underpinnings and categorical distinctions for brain disorders and related phenotypes may inform the search for their biological mechanisms. RESULTS Common variant risk for psychiatric disorders was shown to correlate significantly, especially among attention deficit hyperactivity disorder (ADHD), bipolar disorder, major depressive disorder (MDD), and schizophrenia. By contrast, neurological disorders appear more distinct from one another and from the psychiatric disorders, except for migraine, which was significantly correlated to ADHD, MDD, and Tourette syndrome. We demonstrate that, in the general population, the personality trait neuroticism is significantly correlated with almost every psychiatric disorder and migraine. We also identify significant genetic sharing between disorders and early life cognitive measures (e.g., years of education and college attainment) in the general population, demonstrating positive correlation with several psychiatric disorders (e.g., anorexia nervosa and bipolar disorder) and negative correlation with several neurological phenotypes (e.g., Alzheimer's disease and ischemic stroke), even though the latter are considered to result from specific processes that occur later in life. Extensive simulations were also performed to inform how statistical power, diagnostic misclassification, and phenotypic heterogeneity influence genetic correlations. CONCLUSION The high degree of genetic correlation among many of the psychiatric disorders adds further evidence that their current clinical boundaries do not reflect distinct underlying pathogenic processes, at least on the genetic level. This suggests a deeply interconnected nature for psychiatric disorders, in contrast to neurological disorders, and underscores the need to refine psychiatric diagnostics. Genetically informed analyses may provide important "scaffolding" to support such restructuring of psychiatric nosology, which likely requires incorporating many levels of information. By contrast, we find limited evidence for widespread common genetic risk sharing among neurological disorders or across neurological and psychiatric disorders. We show that both psychiatric and neurological disorders have robust correlations with cognitive and personality measures. Further study is needed to evaluate whether overlapping genetic contributions to psychiatric pathology may influence treatment choices. Ultimately, such developments may pave the way toward reduced heterogeneity and improved diagnosis and treatment of psychiatric disorders

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

Vergleich von drei unterschiedlichen Telepathologiesystemen zur primären histologischen Schnellschnittdiagnostik auf der Grundlage einer retrospektiven Studie

Ziel der vorliegenden Arbeit ist es, die Frage nach Eignung der Technik, des Aufwands, der Schulung und der Vor- und Nachteile eines Einsatzes der Telepathologie in der Schnellschnitt-Diagnostik zu analysieren. Weltweit wurden verschiedene Telepathologiesysteme entwickelt, die zum Teil für den Schnellschnitt verwendet werden können. Auch an der Charité entstanden mit dem 1.ATM-System, 2.dem TPS-System und 3.dem TELEMIC-System, drei technisch völlig unterschiedliche Systeme. Diese Systeme wurden anhand einer retrospektiven Studie hinsichtlich ihrer Einsatzfähigkeit in der telepathologische Schnellschnitt-Diagnostik untersucht. Um die Systeme untereinander vergleichen zu können, wurden 124 histologische Schnellschnittpräparate aus dem Jahr 1999 herausgesucht (ausschließlich Brustgewebe), die von vier erfahrenen Pathologen mit jedem System erneut bearbeitet wurden. Qualitativ wurden mit dem ATM- und dem TPS-System gleichwertige Ergebnisse wie in der konventionellen Schnellschnitt-Diagnostik erreicht. Das TELEMIC-System war qualitativ aufgrund der hohen Rate von Rückweisungen den anderen Systemen und dem konventionellen Schnellschnitt deutlich unterlegen. Bei den Diagnosezeiten zeigte sich eine leichte Unterlegenheit des TPS-Systems gegenüber dem konventionellen Schnellschnitt. Da es jedoch insbesondere als Möglichkeit der Ferndiagnose eingesetzt wird, fallen die bei der konventionellen Schnellschnitt-Diagnostik nötigen Transportzeiten durch einen Kurier weg. Das ATM-System und das TELEMIC-System sind auch ohne Zurechnung der Transportzeiten zeitlich zum konventionellen Schnellschnitt vergleichbare Systeme.Target of the available work is it, the question about suitability of the technique, the expenditure, to analyze the training and the pro and cons of an application of the Telepathologie on fresh frozen diagnostics. World-wide different Systems for telepathology were developed, which can be used partially for the fresh frozen diagnostics. At the Charité were developed three technically completely different systems: 1.ATM-System, 2.TPS system and 3.TELEMIC system, These systems were examined on the basis a retrospective study regarding their serviceability on telepathologische fresh frozen diagnostics. In order to be able to compare the systems among themselves, 124 histological fresh frozen preparations were picked out from the year 1999 (excluding chest tissues), which were again processed by four experienced pathologists with each system. Qualitatively with ATM and TPS system equivalent results as on were achieved conventional fresh frozen diagnostics. The TELEMIC system was qualitatively inferior for the other systems and the conventional fresh frozen diagnostics due to the high rate of rejections. With the diagnostic times an easy inferiority of the TPS system showed up in relation to the conventional fresh frozen diagnostics. Since it is used however in particular as possibility of the remote diagnostics, the feed times necessary with the conventional fresh frozen diagnostics are omitted by a courier. The ATM system and the TELEMIC system are also without addition of the feed times temporally to the conventional fresh frozen diagnostics comparable systems

Online Platform as a Tool to Support Postgraduate Training in General Practice – A Case Report

Objective: Physicians in postgraduate training (PPT) in General Practice (GP) typically have very little interaction with their peers, as there is usually only one resident physician working in their respective department or GP office at a given time. Therefore, the online platform KOLEGEA, presented here, aims to support postgraduate training in general practice (PT in GP) in Germany through virtual interaction.Methodology: In 2012, the interdisciplinary research project KOLEGEA set up an online platform that any physicians in PT in GP can use for free after registration with their unitary continuous education number (Einheitliche Fortbildungsnummer, EFN). It offers problem-based learning and allows to discuss self-published anonymized patient cases with the community that can be classified and discussed with experienced mentors (specialists in general practice - GPs) in small virtual groups.Results: An anonymous online survey carried out as part of the 2014 project evaluation showed a good acceptance of the platform, even though shortage of time was mentioned as a limiting factor for its use. Data analysis showed that KOLEGEA was used by PPT in GP in all federal states. Patterns of passive use were predominant (90%). This report also describes the further development of the platform (in 2015 and 2016) that integrates an activity monitor as part of a gamification concept.Conclusions: Due to a low response rate of the 2014 online survey and the preliminary evaluations of usage patterns we could identify only initial trends regarding the role of KOLEGEA in supporting PPT. The platform was perceived as a helpful supplement to better structure PT in GP

Heterogeneous integration of vertical GaN power transistor on Si capacitor for DC-DC converters: Presentation held at ESTC 2018, IEEE 7th Electronics System-Integration Technology Conference, September 18th-21st, 2018, Dresden, Germany

Point of load (PoL) converters are emerging as common solution for industrial applications, telecommunications, server, and aerospace. In this work, a topology is designed for a single stage 48 V to 1 V PoL converter by using new gallium nitride (GaN) devices and integrated silicon capacitors. Various wafer-level packaging concepts such as die-to-wafer bonding, wafer-level thinning, and through-silicon via (TSV) will be presented and discussed based on this topology. Furthermore, two novel devices will be developed and used for the packaging concepts. One is a GaN transistor with vertical channel, which will exhibit significantly lower power losses when switching and converting power. The other is an integrated silicon capacitor with lateral geometry, in which positive and negative electro des are insulated from the substrate and formed on the same side. Simulation is performed to compare the parasitic inductance from the different concepts. A direct bonding process is shown to provide flexibility in engineering new device geometries and can be exploited to mitigate the electrical parasitics