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The COVID-19 pandemic has caused strains on health systems worldwide disrupting routine hospital services for all non-COVID patients. Within this retrospective study, we analyzed inpatient hospital admissions across 18 German university hospitals during the 2020 lockdown period compared to 2018. Patients admitted to hospital between January 1 and May 31, 2020 and the corresponding periods in 2018 and 2019 were included in this study. Data derived from electronic health records were collected and analyzed using the data integration center infrastructure implemented in the university hospitals that are part of the four consortia funded by the German Medical Informatics Initiative. Admissions were grouped and counted by ICD 10 chapters and specific reasons for treatment at each site. Pooled aggregated data were centrally analyzed with descriptive statistics to compare absolute and relative differences between time periods of different years. The results illustrate how care process adoptions depended on the COVID-19 epidemiological situation and the criticality of the disease. Overall inpatient hospital admissions decreased by 35% in weeks 1 to 4 and by 30.3% in weeks 5 to 8 after the lockdown announcement compared to 2018. Even hospital admissions for critical care conditions such as malignant cancer treatments were reduced. We also noted a high reduction of emergency admissions such as myocardial infarction (38.7%), whereas the reduction in stroke admissions was smaller (19.6%). In contrast, we observed a considerable reduction in admissions for non-critical clinical situations, such as hysterectomies for benign tumors (78.8%) and hip replacements due to arthrosis (82.4%). In summary, our study shows that the university hospital admission rates in Germany were substantially reduced following the national COVID-19 lockdown. These included critical care or emergency conditions in which deferral is expected to impair clinical outcomes. Future studies are needed to delineate how appropriate medical care of critically ill patients can be maintained during a pandemic.
Genetic generalised epilepsy (GGE) is the most common form of genetic epilepsy, accounting for 20% of all epilepsies. Genomic copy number variations (CNVs) constitute important genetic risk factors of common GGE syndromes. In our present genome-wide burden analysis, large (≥ 400 kb) and rare (< 1%) autosomal microdeletions with high calling confidence (≥ 200 markers) were assessed by the Affymetrix SNP 6.0 array in European case-control cohorts of 1,366 GGE patients and 5,234 ancestry-matched controls. We aimed to: 1) assess the microdeletion burden in common GGE syndromes, 2) estimate the relative contribution of recurrent microdeletions at genomic rearrangement hotspots and non-recurrent microdeletions, and 3) identify potential candidate genes for GGE. We found a significant excess of microdeletions in 7.3% of GGE patients compared to 4.0% in controls (P = 1.8 x 10-7; OR = 1.9). Recurrent microdeletions at seven known genomic hotspots accounted for 36.9% of all microdeletions identified in the GGE cohort and showed a 7.5-fold increased burden (P = 2.6 x 10-17) relative to controls. Microdeletions affecting either a gene previously implicated in neurodevelopmental disorders (P = 8.0 x 10-18, OR = 4.6) or an evolutionarily conserved brain-expressed gene related to autism spectrum disorder (P = 1.3 x 10-12, OR = 4.1) were significantly enriched in the GGE patients. Microdeletions found only in GGE patients harboured a high proportion of genes previously associated with epilepsy and neuropsychiatric disorders (NRXN1, RBFOX1, PCDH7, KCNA2, EPM2A, RORB, PLCB1). Our results demonstrate that the significantly increased burden of large and rare microdeletions in GGE patients is largely confined to recurrent hotspot microdeletions and microdeletions affecting neurodevelopmental genes, suggesting a strong impact of fundamental neurodevelopmental processes in the pathogenesis of common GGE syndromes.
BCOR-rearranged sarcomas are rare and belong to the Ewing-like sarcomas (ELS). Their morphology and histopathological features make the diagnosis challenging. We present a case, initially diagnosed as an unusual extraskeletal myxoid chondrosarcoma (EMC). A 54-year-old male patient developed an asymptomatic swelling of the lower leg. Imaging showed a 9.5-cm large intramuscular soft tissue mass. Due to its morphological and immunohistochemical profile on biopsy, it was initially diagnosed as an EMC. The patient was treated by complete resection and adjuvant radiotherapy and remained free of tumor at 7 years follow-up. Using next-generation sequencing (NGS), we retrospectively identified RGAG1-BCOR gene fusion (confirmed by RT-PCR), which has not been described in somatic soft tissue tumors so far. This finding broadens the spectrum of partner genes in the BCOR-rearranged sarcomas in a tumor with a well-documented, long clinical follow-up.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p–Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
The Transition Radiation Detector (TRD) was designed and built to enhance the capabilities of the ALICE detector at the Large Hadron Collider (LHC). While aimed at providing electron identification and triggering, the TRD also contributes significantly to the track reconstruction and calibration in the central barrel of ALICE. In this paper the design, construction, operation, and performance of this detector are discussed. A pion rejection factor of up to 410 is achieved at a momentum of 1 GeV/c in p-Pb collisions and the resolution at high transverse momentum improves by about 40% when including the TRD information in track reconstruction. The triggering capability is demonstrated both for jet, light nuclei, and electron selection.
in den letzten 15 Jahren haben Hochschulen neben den traditionellen Lehr- und Lernformen zahlreiche neue Lerndesigns entwickelt und etabliert, die vor allem auf dem Einsatz computer- und netzwerkbasierter Technologien beruhen. Sie führen zu einer Veränderung der Angebotsstrategien in der universitären Lehre, da neue Zielgruppen ansprechbar werden. Neue Lerndesigns sind vor allem dann effektiv, wenn eine strategische didaktische Verzahnung mit klassischen Lerndesigns im Sinne eines Blended Learning stattfindet.
The crossbar-H-mode (CH) structure is the first superconducting multicell drift tube cavity for the low and medium energy range operated in the H21 mode. Because of the large energy gain per cavity, which leads to high real estate gradients, it is an excellent candidate for the efficient acceleration in high power proton and ion accelerators with fixed velocity profile. A prototype cavity has been developed and tested successfully with a gradient of 7MV/m. A few new superconducting CH cavities with improved geometries for different high power applications are under development at present. One cavity (f=325 MHz, β=0.16, seven cells) is currently under construction and studied with respect to a possible upgrade option for the GSI UNILAC. Another cavity (f=217 MHz, β=0.059, 15 cells) is designed for a cw operated energy variable heavy ion linac application. Furthermore, the EUROTRANS project (European research program for the transmutation of high level nuclear waste in an accelerator driven system, 600 MeV protons, 352 MHz) is one of many possible applications for this kind of superconducting rf cavity. In this context a layout of the 17 MeV EUROTRANS injector containing four superconducting CH cavities was proposed by the Institute for Applied Physics (IAP) Frankfurt. The status of the cavity development related to the EUROTRANS injector is presented.
As the successor of the EUROTRANS project, the MAX project is aiming to continue the R&D effects for a European Accelerator-Driven System and to bring the conceptual design to reality. The layout of the driver linac for MAX will follow the reference design made for the XT-ADS phase of the EUROTRANS project. For the injector part, new design strategies and approaches, e.g. half resonant frequency, half transition-energy between the RFQ and the CH-DTL, and using the 4-rod RFQ structure instead of the originally proposed 4-vane RFQ, have been conceived and studied to reach a more reliable CW operation at reduced costs. In this paper, the design and simulation results of the MAX injector are presented.
The MYRRHA Project (Multi Purpose Hybrid Reactor for High Tech Applications) at Mol/belgium will be a user facility with emphasis on research with neutron generated by a spallation source. One main aspect is the demonstration of nuclear waste technology using an accelerator driven system. A superconducting linac delivers a 4 mA, 600 MeV proton beam. The first accelerating section is covered by the 17 MeV injector. It consists of a proton source, an RFQ, two room temperature CH cavities and 4 superconducting CH-cavities. The initial design has used an RF frequency of 352 MHz. Recently the frequency of the injector has been set to 176 MHz. The main reason is the possible use of a 4-rod-RFQ with reduced power dissipation and energy, respectively. The status of the overall injector layout including cavity design is presented.
Im Rahmen des Bund-Länder-Programms "Qualitätspakt Lehre" hat die Goethe-Universität Frankfurt erfolgreich das Programm "Starker Start ins Studium" eingeworben. Dadurch verfügt das Institut für Psychologie nun über die personellen Möglichkeiten, die fachliche und soziale Integration neuer Psychologiestudierender im sechssemestrigen Bachelorstudiengang Psychologie zu verbessern. Hierzu wurden zwei obligate je zweisemestrige Lehrmodule entwickelt. In dem vorliegenden Beitrag wird das übergeordnete Lehrkonzept beschrieben und dessen Implementierung im Fach Psychologie als Praxisbeispiel illustriert.
Although chest radiograph (CXR) is commonly used in diagnosing pediatric community acquired pneumonia (pCAP), limited data on interobserver agreement among radiologists exist. PedCAPNETZ is a prospective, observational, and multicenter study on pCAP. N = 233 CXR from patients with clinical diagnosis of pCAP were retrieved and n = 12 CXR without pathological findings were added. All CXR were interpreted by a radiologist at the site of recruitment and by two external, blinded pediatric radiologists. To evaluate interobserver agreement, the reporting of presence or absence of pCAP in CXR was analyzed, and prevalence and bias-adjusted kappa (PABAK) statistical testing was applied. Overall, n = 190 (82%) of CXR were confirmed as pCAP by two external pediatric radiologists. Compared with patients with pCAP negative CXR, patients with CXR-confirmed pCAP displayed higher C-reactive protein levels and a longer duration of symptoms before enrollment (p < .007). Further parameters, that is, age, respiratory rate, and oxygen saturation showed no significant difference. The interobserver agreement between the onsite radiologists and each of the two independent pediatric radiologists for the presence of pCAP was poor to fair (69%; PABAK = 0.39% and 76%; PABAK = 0.53, respectively). The concordance between the external radiologists was fair (81%; PABAK = 0.62). With regard to typical CXR findings for pCAP, chance corrected interrater agreement was highest for pleural effusions, infiltrates, and consolidations and lowest for interstitial patterns and peribronchial thickening. Our data show a poor interobserver agreement in the CXR-based diagnosis of pCAP and emphasized the need for harmonized interpretation standards.
Background: Rare Diseases (RDs) are difficult to diagnose. Clinical Decision Support Systems (CDSS) could support the diagnosis for RDs. The Medical Informatics in Research and Medicine (MIRACUM) consortium developed a CDSS for RDs based on distributed clinical data from eight German university hospitals. To support the diagnosis for difficult patient cases, the CDSS uses data from the different hospitals to perform a patient similarity analysis to obtain an indication of a diagnosis. To optimize our CDSS, we conducted a qualitative study to investigate usability and functionality of our designed CDSS. Methods: We performed a Thinking Aloud Test (TA-Test) with RDs experts working in Rare Diseases Centers (RDCs) at MIRACUM locations which are specialized in diagnosis and treatment of RDs. An instruction sheet with tasks was prepared that the participants should perform with the CDSS during the study. The TA-Test was recorded on audio and video, whereas the resulting transcripts were analysed with a qualitative content analysis, as a ruled-guided fixed procedure to analyse text-based data. Furthermore, a questionnaire was handed out at the end of the study including the System Usability Scale (SUS). Results: A total of eight experts from eight MIRACUM locations with an established RDC were included in the study. Results indicate that more detailed information about patients, such as descriptive attributes or findings, can help the system perform better. The system was rated positively in terms of functionality, such as functions that enable the user to obtain an overview of similar patients or medical history of a patient. However, there is a lack of transparency in the results of the CDSS patient similarity analysis. The study participants often stated that the system should present the user with an overview of exact symptoms, diagnosis, and other characteristics that define two patients as similar. In the usability section, the CDSS received a score of 73.21 points, which is ranked as good usability. Conclusions: This qualitative study investigated the usability and functionality of a CDSS of RDs. Despite positive feedback about functionality of system, the CDSS still requires some revisions and improvement in transparency of the patient similarity analysis.
Background Osseointegration is crucial for the long-term success of dental implants and depends on the tissue reaction at the tissue-implant interface. Mechanical properties and biocompatibility make zirconia a suitable material for dental implants, although surface processings are still problematic. The aim of the present study was to compare osteoblast behavior on structured zirconia and titanium surfaces under standardized conditions. Methods The surface characteristics were determined by scanning electron microscopy (SEM). In primary bovine osteoblasts attachment kinetics, proliferation rate and synthesis of bone-associated proteins were tested on different surfaces. Results The results demonstrated that the proliferation rate of cells was significantly higher on zirconia surfaces than on titanium surfaces (p < 0.05; Student's t-test). In contrast, attachment and adhesion strength of the primary cells was significant higher on titanium surfaces (p < 0.05; U test). No significant differences were found in the synthesis of bone-specific proteins. Ultrastructural analysis revealed phenotypic features of osteoblast-like cells on both zirconia and titanium surfaces. Conclusion The study demonstrates distinct effects of the surface composition on osteoblasts in culture. Zirconia improves cell proliferation significantly during the first days of culture, but it does not improve attachment and adhesion strength. Both materials do not differ with respect to protein synthesis or ultrastructural appearance of osteoblasts. Zirconium oxide may therefore be a suitable material for dental implants.
Background Titanium and titanium alloys are widely used for fabrication of dental implants. Since the material composition and the surface topography of a biomaterial play a fundamental role in osseointegration, various chemical and physical surface modifications have been developed to improve osseous healing. Zirconia-based implants were introduced into dental implantology as an altenative to titanium implants. Zirconia seems to be a suitable implant material because of its tooth-like colour, its mechanical properties and its biocompatibility. As the osseointegration of zirconia implants has not been extensively investigated, the aim of this study was to compare the osseous healing of zirconia implants with titanium implants which have a roughened surface but otherwise similar implant geometries. Methods Forty-eight zirconia and titanium implants were introduced into the tibia of 12 minipigs. After 1, 4 or 12 weeks, animals were sacrificed and specimens containing the implants were examined in terms of histological and ultrastructural techniques. Results Histological results showed direct bone contact on the zirconia and titanium surfaces. Bone implant contact as measured by histomorphometry was slightly better on titanium than on zirconia surfaces. However, a statistically significant difference between the two groups was not observed. Conclusion The results demonstrated that zirconia implants with modified surfaces result in an osseointegration which is comparable with that of titanium implants.
Background The successful use of zirconia ceramics in orthopedic surgery led to a demand for dental zirconium-based implant systems. Because of its excellent biomechanical characteristics, biocompatibility, and bright tooth-like color, zirconia (zirconium dioxide, ZrO2) has the potential to become a substitute for titanium as dental implant material. The present study aimed at investigating the osseointegration of zirconia implants with modified ablative surface at an ultrastructural level. Methods A total of 24 zirconia implants with modified ablative surfaces and 24 titanium implants all of similar shape and surface structure were inserted into the tibia of 12 Gottinger minipigs. Block biopsies were harvested 1 week, 4 weeks or 12 weeks (four animals each) after surgery. Scanning electron microscopy (SEM) analysis was performed at the bone implant interface. Results Remarkable bone attachment was already seen after 1 week which increased further to intimate bone contact after 4 weeks, observed on both zirconia and titanium implant surfaces. After 12 weeks, osseointegration without interposition of an interfacial layer was detected. At the ultrastructural level, there was no obvious difference between the osseointegration of zirconia implants with modified ablative surfaces and titanium implants with a similar surface topography. Conclusion The results of this study indicate similar osseointegration of zirconia and titanium implants at the ultrastructural level.
EUROTRANS is a European research program for the transmutation of high level nuclear waste in an accelerator-driven system (ADS). As proposed, the driver linac needs to deliver a 2.5–4 mA, 600 MeV continuous-wave (CW) proton beam and later a 20 mA, 800 MeV one to the spallation target in the prototype-scale and industrial-scale demonstration phases, respectively. This paper is focusing on the conceptual studies performed with respect to the 17 MeV injector. First, the special beam dynamics strategies and methods, which have been developed and applied to design a current-variable injector up to 30 mA for allowing an easy upgrade without additional R&D costs, will be introduced. Then the error study made for evaluating the tolerance limits of the designed injector will be presented as well.
MYRRHA is conceived as an accelerator driven system (ADS) for transmutation of high level nuclear waste. The neutron source is created by coupling a proton accelerator of 600 MeV with a 4 mA proton beam, a spallation source and a sub-critical core. The IAP of Frankfurt University is responsible for the development of the 17 MeV injector operated at 176 MHz. The injector consists of a 1.5 MeV 4-Rod-RFQ and six CH-drifttube-structures. The first two CH-structures will be operated at room temperature and the other CH-structures are superconducting cavities assembled in one cryo-module. To achieve the extremely high reliability required by the ADS application, the design of the 17 MeV injector has been intensively studied, with respect to thermal issues, minimum peak fields and field distribution.
Co-design of a trustworthy AI system in healthcare: deep learning based skin lesion classifier
(2021)
This paper documents how an ethically aligned co-design methodology ensures trustworthiness in the early design phase of an artificial intelligence (AI) system component for healthcare. The system explains decisions made by deep learning networks analyzing images of skin lesions. The co-design of trustworthy AI developed here used a holistic approach rather than a static ethical checklist and required a multidisciplinary team of experts working with the AI designers and their managers. Ethical, legal, and technical issues potentially arising from the future use of the AI system were investigated. This paper is a first report on co-designing in the early design phase. Our results can also serve as guidance for other early-phase AI-similar tool developments.
The crossbar H-mode (CH) cavity is an accelerating structure operated in the H21(0) mode. The robustness of the crossbar geometry allows one to realize room temperature as well as superconducting linac cavities. The shunt impedance characteristics of this structure are attractive to develop proton and heavy ion linacs in the low and medium beta range. A first room temperature eight-cell prototype has proven the feasibility of the crossbar design in terms of mechanical construction, copper plating, and cooling. An innovative rf coupling concept has been developed where two CH cavities are connected by a two gap E010-mode resonator which, at the same time, provides transverse focusing by a quadrupole triplet. The concept has been applied in the design of the new FAIR proton linac and a scaled model of the second cavity of this injector has been built and tested too. The full scale prototype is now under construction at the University of Frankfurt. In this paper, the room temperature CH cavity development as well as the general layout of the FAIR proton injector (70 MeV, 325 MHz, 70 mA) is presented and discussed.
Artificial Intelligence (AI) has the potential to greatly improve the delivery of healthcare and other services that advance population health and wellbeing. However, the use of AI in healthcare also brings potential risks that may cause unintended harm. To guide future developments in AI, the High-Level Expert Group on AI set up by the European Commission (EC), recently published ethics guidelines for what it terms “trustworthy” AI. These guidelines are aimed at a variety of stakeholders, especially guiding practitioners toward more ethical and more robust applications of AI. In line with efforts of the EC, AI ethics scholarship focuses increasingly on converting abstract principles into actionable recommendations. However, the interpretation, relevance, and implementation of trustworthy AI depend on the domain and the context in which the AI system is used. The main contribution of this paper is to demonstrate how to use the general AI HLEG trustworthy AI guidelines in practice in the healthcare domain. To this end, we present a best practice of assessing the use of machine learning as a supportive tool to recognize cardiac arrest in emergency calls. The AI system under assessment is currently in use in the city of Copenhagen in Denmark. The assessment is accomplished by an independent team composed of philosophers, policy makers, social scientists, technical, legal, and medical experts. By leveraging an interdisciplinary team, we aim to expose the complex trade-offs and the necessity for such thorough human review when tackling socio-technical applications of AI in healthcare. For the assessment, we use a process to assess trustworthy AI, called 1Z-Inspection® to identify specific challenges and potential ethical trade-offs when we consider AI in practice.
At the Institute for Applied Physics (IAP), University of Frankfurt, a s.c. 325 MHz CH-Cavity is under development for future beam tests at GSI UNILAC, Darmstadt. The cavity with 7 accelerating cells has a geometrical beta of 0.15 corresponding to 11.4 AMeV. The design gradient is 5 MV/m. The geometry of this resonator was optimized with respect to a compact design, low peak fields, surface processing, power coupling and tuning. Furthermore a new tuning system based on bellow tuners inside the resonator will control the frequency during operation. After rf tests in Frankfurt the cavity will be tested with a 10 mA, 11.4 AMeV beam delivered by the GSI UNILAC. In this paper rf simulations, multipacting analysis as well as thermal calculations will be presented.
At GSI a new, superconducting (sc) continuous wave (cw) LINAC is under design in cooperation with the Institute for Applied Physics (IAP) of Frankfurt University and the Helmholtz Institut Mainz (HIM). This proposed LINAC is highly requested by a broad community of future users to fulfill the requirements of nuclear chemistry, nuclear physics, and especially in the research field of Super Heavy Elements (SHE). In this context the preliminary layout of the LINAC has been carried out by IAP. The main acceleration of up to 7.3 AMeV will be provided by nine sc Crossbar-H-mode (CH) cavities operated at 217 MHz. Currently, a prototype of the cw LINAC as a demonstrator is under development. The demonstrator comprises a sc CH-cavity embedded between two sc solenoids mounted in a horizontal cryomodule. A full performance test of the demonstrator in 2013/14 by injecting and accelerating a beam from the GSI High Charge Injector (HLI) is one important milestone of the project. The status of the demonstrator is presented.
The superconducting CH-structure (Crossbar-H-mode) is a multi-cell drift tube cavity for the low and medium energy range operated in the H21-mode, which has been developed at the Institute for Applied Physics (IAP) of Frankfurt University. With respect to different high power applications two types of superconducting CH-structures (f = 325 MHz, β = 0.16, seven cells and f = 217 MHz, β = 0.059, 15 cells) are presently under construction and accordingly under development. The structural mechanical simulation is a very important aspect of the cavity design. Furthermore, several simulations with ANSYS Workbench have been performed to predict the deformation of the cavity walls due to the cavity cool-down, pressure effects and mechanical vibrations. To readjust the fast frequency changes in consequence of the cavity shape deformation, a new concept for the dynamic frequency tuning has been investigated, including a novel type of bellow-tuner.
The ARMADILLO bunch compressor currently being designed at IAP is capable of reaching a longitudinal pulse compression ratio of 45 for proton beams of 150 mA at 2 MeV. It will provide one nanosecond proton pulses with a peak current of 7.7 A. The system guides nine linacμbunches deflected by a 5 MHz rf kicker and uses four dipole magnets - two homogeneous and two with field gradients - to merge them on the target. For longitudinal focusing and an energy variation of ±200 keV two multitrack rf cavities are included. ARMADILLO will be installed at the end of the Frankfurt Neutron Source FRANZ making use of the unique 250 kHz time structure. This contribution will provide an overview of the layout of the system as well as recent advances in component design and beam dynamics of the compressor.
This novel kind of neutron beam facility will provide 1 ns short neutron pulses with an approximately thermal energy distribution around 30 keV. The pulse repetition rate will be up to 250 kHz, the total proton number per pulse will be up to 6×1010 in the final stage, starting with a p – source current of 200 mA. A second target station will allow n – activation experiments by cw beam operation. An intense 2 MeV proton beam will drive a neutron source by the 7 Li (p,n) 7 Be reaction. The facility is under construction at the physics experimental hall of the J.W. Goethe – University. The 1m thick concrete tunnel was installed in 2009. In 2011 all rf amplifiers will be delivered and installed. Successful 200 mA proton source experiments in 2010 at a test stand will be followed by experiments on the 120 kV FRANZ terminal in 2011. The 250 kHz, 100 ns chopper in front of the rf linac is under construction, while the 2 MeV bunch compressor design was finished and the technical design of all components has started. The main accelerator cavity is under construction. First 2 MeV beam tests are expected for end of 2012.
For the research program with cooled antiprotons at FAIR a dedicated 70 MeV, 70 mA proton injector is required. The main acceleration of this room temperature linac will be provided by six CH cavities operated at 325 MHz. Each cavity will be powered by a 2.5 MW Klystron. For the second acceleration unit from 11.5 MeV to 24.2 MeV a 1:2 scaled model has been built. Low level RF measurements have been performed to determine the main parameters and to prove the concept of coupled CH cavities. For this second tank technical and mechanical investigations have been performed in 2010 to develop a complete technical concept for the manufacturing. In Spring 2011, the construction of the first power prototype has started. The main components of this cavity will be ready for measurements in summer 2011. At that time, the cavity will be tested with a preliminary aluminum drift tube structure, which will allow precise frequency and field tuning. This paper will report on the recent technical development and achievements. It will outline the main fabrication steps towards that novel type of proton DTL. Also first low level RF measurements are expected.
Background: Body dysmorphic disorder (BDD) is characterized by an excessive preoccupation with one or more perceived flaws in one’s own appearance. Previous studies provided evidence for deficits in configural and holistic processing in BDD. Preliminary evidence suggests abnormalities at an early stage of visual processing. The present study is the first examining early neurocognitive perception of the own face in BDD by using electroencephalography (EEG). We investigated the face inversion effect, in which inverted (upside-down) faces are disproportionately poorly processed compared to upright faces. This effect reflects a disruption of configural and holistic processing, and in consequence a preponderance of featural face processing.
Methods: We recorded face-sensitive event-related potentials (ERPs) in 16 BDD patients and 16 healthy controls, all unmedicated. Participants viewed upright and inverted (upside-down) images of their own face and an unfamiliar other face, each in two facial emotional expressions (neutral vs. smiling). We calculated the early ERP components P100, N170, P200, N250, and the late positive component (LPC), and compared amplitudes among both groups.
Results: In the early P100, no face inversion effects were found in both groups. In the N170, both groups exhibited the common face inversion effects, with significantly larger N170 amplitudes for inverted than upright faces. In the P200, both groups exhibited larger inversion effects to other (relative to own) faces, with larger P200 amplitudes for other upright than inverted faces. In the N250, no significant group differences were found in face processing. In the LPC, both groups exhibited larger inversion effects to other (relative to own) faces, with larger LPC amplitudes for other inverted than upright faces. These overall patterns appeared to be comparable for both groups. Smaller inversion effects to own (relative to other) faces were observed in none of these components in BDD, relative to controls.
Conclusions: The findings suggest no evidence for abnormalities at all levels of early face processing in our observed sample of BDD patients. Further research should investigate the neural substrates underlying BDD symptomatology.
Superconducting, energy variable heavy ion linac with constant
β, multicell cavities of CH-type
(2009)
An energy variable ion linac consisting of multigap, constant-β cavities was developed. The effect of phase sliding, unavoidable in any constant-β section, is leading to a coherent rf phase motion, which fits well to the H-type structures with their long π-mode sections and separated lenses. The exact periodicity of the cell lengths within each cavity results in technical advantages, such as higher calculation accuracy when only one single period can be simulated, simpler manufacturing, and tuning. This is most important in the case of superconducting cavities. By using this concept, an improved design for a 217 MHz cw superconducting heavy ion linac with energy variation has been worked out. The small output energy spread of ± 3 AkeV is provided over the whole range of energy variation from 3.5 to 7.3 AMeV. These capabilities would allow for a competitive research in the field of radiochemistry and for a production of super heavy elements (SHE), especially. A first 19-cell cavity of that type was designed, built, and rf tested successfully at the Institute for Applied Physics (IAP) Frankfurt. A 325.224 MHz, seven-cell cavity with constant β = 0.16 is under development and will be operated in a frequency controlled mode. It will be equipped with a power coupler and beam tests with Unilac beams at GSI are foreseen.
Objective: Acute kidney injury (AKI) after cardiac surgery procedures is associated with poor patient outcomes. Cystatin C as a marker for renal failure has been shown to be of prognostic value; however, a wide range of its predictive accuracy has been reported. The aim of the study was to evaluate whether the measurement of pre- and postoperative serum cystatin C improves the prediction of AKI.
Methods: In a single-centre, prospective study of 70 patients (74 ± 9ys; range 47-85ys; 77% male), cystatin C was measured six times: (T1 = preoperative, T2 = start cardiopulmonary bypass (CPB), T3 = 20 min after CPB, T4 = end of operation; T5 = 24 h postoperatively; T6 = 7d postoperatively). Predictive property, in terms of the need for renal replacement therapy (RRT), was analysed by receiver operating characteristics (ROC) statistics and described by the area under the curve (AUC).
Results: With respect to RRT (n = 8), serum cystatin C was significantly higher at the end of the operation (T4), 24 h postoperatively at T5 and at T6. The AUCs for preoperative T1 and intraoperative T2/3 cystatin C were <0.7 (95% CI, 0.47-0.85). The earliest significant predictive AUCs were found at the end of the operation (T4: p = 0.03 95% CI 0.58-0.88 AUC 0.73) and 24 h postoperatively (T5: p = 0.003 95% CI 0.74-0.96 AUC 0.85).
Conclusions: Early postoperative serum cystatin C increase appears to be a moderate biomarker in the prediction of AKI, whereas a preoperative and intraoperative cystatin C increase has only a limited diagnostic and predictive value.
Background: Pediatric community acquired pneumonia (pedCAP) is one of the leading causes for childhood morbidity accounting for up to 20% of pediatric hospital admissions in high income countries. In spite of its high morbidity, updated epidemiological and pathogen data after introduction of preventive vaccination and novel pathogen screening strategies are limited. Moreover, there is a need for validated recommendations on diagnostic and treatment regimens in pedCAP. Through collection of patient data and analysis of pathogen and host factors in a large sample of unselected pedCAP patients in Germany, we aim to address and substantially improve this situation.
Methods: pedCAPNETZ is an observational, multi-center study on pedCAP. Thus far, nine study centers in hospitals, outpatient clinics and practices have been initiated and more than 400 patients with radiologically confirmed pneumonia have been enrolled, aiming at a total of 1000 study participants. Employing an online data base, information on disease course, treatment as well as demographical and socioeconomical data is recorded. Patients are followed up until day 90 after enrollment; Comprehensive biosample collection and a central pedCAPNETZ biobank allow for in-depth analyses of pathogen and host factors. Standardized workflows to assure sample logistics and data management in more than fifteen future study centers have been established.
Discussion: Through comprehensive epidemiological, clinical and biological analyses, pedCAPNETZ fills an important gap in pediatric and infection research. To secure dissemination of the registry, we will raise clinical and scientific awareness at all levels. We aim at participating in decision making processes for guidelines and prevention strategies. Ultimately, we hope the results of the pedCAPNETZ registry will help to improve care and quality of life in pedCAP patients in the future.
Oncogenic rearrangements leading to targetable gene fusions are well-established cancer driver events in lung adenocarcinoma. Accurate and reliable detection of these gene fusions is crucial to select the appropriate targeted therapy for each patient. We compared the targeted next-generation-sequencing Oncomine Focus Assay (OFA; Thermo Fisher Scientific) with conventional ALK FISH and anti-Alk immunohistochemistry in a cohort of 52 lung adenocarcinomas (10 ALK rearranged, 18 non-ALK rearranged, and 24 untested cases). We found a sensitivity and specificity of 100% for detection of ALK rearrangements using the OFA panel. In addition, targeted next generation sequencing allowed us to analyze a set of 23 driver genes in a single assay. Besides EML4-ALK (11/52 cases), we detected EZR-ROS1 (1/52 cases), KIF5B-RET (1/52 cases) and MET-MET (4/52 cases) fusions. All EML4-ALK, EZR-ROS1 and KIF5B-RET fusions were confirmed by multiplexed targeted next generation sequencing assay (Oncomine Solid Tumor Fusion Transcript Kit, Thermo Fisher Scientific). All cases with EML4-ALK rearrangement were confirmed by Alk immunohistochemistry and all but one by ALK FISH. In our experience, targeted next-generation sequencing is a reliable and timesaving tool for multiplexed detection of targetable rearrangements. Therefore, targeted next-generation sequencing represents an efficient alternative to time-consuming single target assays currently used in molecular pathology.
Previous studies in developing Xenopus and zebrafish reported that the phosphate transporter slc20a1a is expressed in pronephric kidneys. The recent identification of SLC20A1 as a monoallelic candidate gene for cloacal exstrophy further suggests its involvement in the urinary tract and urorectal development. However, little is known of the functional role of SLC20A1 in urinary tract development. Here, we investigated this using morpholino oligonucleotide knockdown of the zebrafish ortholog slc20a1a. This caused kidney cysts and malformations of the cloaca. Moreover, in morphants we demonstrated dysfunctional voiding and hindgut opening defects mimicking imperforate anus in human cloacal exstrophy. Furthermore, we performed immunohistochemistry of an unaffected 6-week-old human embryo and detected SLC20A1 in the urinary tract and the abdominal midline, structures implicated in the pathogenesis of cloacal exstrophy. Additionally, we resequenced SLC20A1 in 690 individuals with bladder exstrophy-epispadias complex (BEEC) including 84 individuals with cloacal exstrophy. We identified two additional monoallelic de novo variants. One was identified in a case-parent trio with classic bladder exstrophy, and one additional novel de novo variant was detected in an affected mother who transmitted this variant to her affected son. To study the potential cellular impact of SLC20A1 variants, we expressed them in HEK293 cells. Here, phosphate transport was not compromised, suggesting that it is not a disease mechanism. However, there was a tendency for lower levels of cleaved caspase-3, perhaps implicating apoptosis pathways in the disease. Our results suggest SLC20A1 is involved in urinary tract and urorectal development and implicate SLC20A1 as a disease-gene for BEEC.
Objectives: The SAVI-TF (Symetis ACURATE neo Valve Implantation Using Transfemoral Access) registry was initiated to study the ACURATE neo transcatheter heart valve in a large patient population treated under real-world conditions.
Background: The self-expanding, supra-annular ACURATE neo prosthesis is a transcatheter heart valve that gained the Conformité Européene mark in 2014, but only limited clinical data are available so far.
Methods: This prospective, multicenter registry enrolled 1,000 patients at 25 European centers who were followed for 1 year post-procedure.
Results: Mean patient age was 81.1 ± 5.2 years; mean logistic European System for Cardiac Operative Risk Evaluation I score, European System for Cardiac Operative Risk Evaluation II score, and Society of Thoracic Surgeons score were 18.1 ± 12.5%, 6.6 ± 7.5%, and 6.0 ± 5.6%, respectively. At 1 year, 8.0% (95% confidence interval [CI]: 6.3% to 9.7%) of patients had died, 2.3% (95% CI: 1.3% to 3.2%) had disabling strokes, and 9.9% (95% CI: 8.1% to 11.8%) had permanent pacemaker implantations. Through 1 year, 5 reinterventions (0.5%; 95% CI: 0.1% to 1.0%) were performed: 3 valve-in-valve and 2 surgical aortic valve replacements. Mean effective orifice area was 1.84 ± 0.43 cm2, mean gradient was 7.3 ± 3.7 mm Hg, and greater than mild paravalvular leakage was observed in 3.6% of patients.
Conclusions: Transfemoral implantation of the ACURATE neo prosthesis resulted in favorable 1-year clinical and echocardiographic outcomes with very low mortality and new pacemaker rates.
In order to quantitatively analyse the chemical and dynamical evolution of the polar vortex it has proven extremely useful to work with coordinate systems that follow the vortex flow. We propose here a two-dimensional quasi-Lagrangian coordinate system {X i, delta X i}, based on the mixing ratio of a long-lived stratospheric trace gas i, and its systematic use with i = N2O, in order to describe the structure of a well-developed Antarctic polar vortex. In the coordinate system {X i, delta X i} the mixing ratio X i is the vertical coordinate and delta X i = X i(theta) - X i vort(theta) is the meridional coordinate (X i vort(theta) being a vertical reference profile in the vortex core). The quasi-Lagrangian coordinates {X i, delta X i} persist for much longer time than standard isentropic coordinates, potential temperature theta and equivalent latitude Phi e, do not require explicit reference to geographic space, and can be derived directly from high-resolution in situ measurements. They are therefore well-suited for studying the evolution of the Antarctic polar vortex throughout the polar winter with respect to the relevant chemical and microphysical processes. By using the introduced coordinate system {X N2O, delta X N2O} we analyze the well-developed Antarctic vortex investigated during the APE-GAIA (Airborne Polar Experiment – Geophysica Aircraft in Antarctica – 1999) campaign (Carli et al., 2000). A criterion, which uses the local in-situ measurements of X i=X i(theta) and attributes the inner vortex edge to a rapid change (delta-step) in the meridional profile of the mixing ratio X i, is developed to determine the (Antarctic) inner vortex edge. In turn, we suggest that the outer vortex edge of a well-developed Antarctic vortex can be attributed to the position of a local minimum of the X H2O gradient in the polar vortex area. For a well-developed Antarctic vortex, the delta X N2O-parametrization of tracer-tracer relationships allows to distinguish the tracer inter-relationships in the vortex core, vortex boundary region and surf zone and to examine their meridional variation throughout these regions. This is illustrated by analyzing the tracer-tracer relationships X i : X N2O obtained from the in-situ data of the APE-GAIA campaign for i = CFC-11, CFC-12, H-1211 and SF6. A number of solitary anomalous points in the CFC-11 : N2O correlation, observed in the Antarctic vortex core, are interpreted in terms of small-scale cross-isentropic dispersion.
Studies on land use in Africa have usually been carried out by ethnologists or human geographers and were rarely concerned with data on the physical conditions of soil. There is hardly any issue, however, where interdependencies between natural and cultural factors are as evident as in the topic of land use. For this project the approach of three ethnologists, Braukämper, Kirscht and Platte, was therefore combined with the analysis of Thiemeyer as physical geographer. The area of research is the Local Government Area of Marte in the Nigerian State of Borno. As part of the Chad Basin this region is mainly characterised by clay sediments which are commonly labelled firgi by its inhabitants. Beside this general term, however, the local peasants clearly distinguish five types of soil (Kanuri: katti), to which different physical conditions and qualities with respect to their cultivation are attributed. The question arose how far can this popular knowledge, accumulated by agricultural experiences over generations, be correlated with scientific data. That is why samples of the mentioned types of soil were collected by the members of our team and analysed in the laboratory of the Frankfurt Institute of Physical Geography. The detailed presentation of this analysis has to be preceded by the classification of the respective soil types in the terminology of the indigenous farmers.
Early experiences of childhood sexual or physical abuse are often associated with functional impairments, reduced well-being and interpersonal problems in adulthood. Prior studies have addressed whether the traumatic experience itself or adult psychopathology is linked to these limitations. To approach this question, individuals with posttraumatic stress disorder (PTSD) and healthy individuals with and without a history of child abuse were investigated. We used global positioning system (GPS) tracking to study temporal and spatial limitations in the participants’ real-life activity space over the course of one week. The sample consisted of 228 female participants: 150 women with PTSD and emotional instability with a history of child abuse, 35 mentally healthy women with a history of child abuse (healthy trauma controls, HTC) and 43 mentally healthy women without any traumatic experiences in their past (healthy controls, HC). Both traumatized groups—i.e. the PTSD and the HTC group—had smaller movement radii than the HC group on the weekends, but neither spent significantly less time away from home than HC. Some differences between PTSD and HC in movement radius seem to be related to correlates of PTSD psychopathology, like depression and physical health. Yet group differences between HTC and HC in movement radius remained even when contextual and individual health variables were included in the model, indicating specific effects of traumatic experiences on activity space. Experiences of child abuse could limit activity space later in life, regardless of whether PTSD develops.
Background: Patients with rare diseases (RDs) are often diagnosed too late or not at all. Clinical decision support systems (CDSSs) could support the diagnosis in RDs. The MIRACUM (Medical Informatics in Research and Medicine) consortium, which is one of four funded consortia in the German Medical Informatics Initiative, will develop a CDSS for RDs based on distributed clinical data from ten university hospitals. This qualitative study aims to investigate (1) the relevant organizational conditions for the operation of a CDSS for RDs when diagnose patients (e.g. the diagnosis workflow), (2) which data is necessary for decision support, and (3) the appropriate user group for such a CDSS.
Methods: Interviews were carried out with RDs experts. Participants were recruited from staff physicians at the Rare Disease Centers (RDCs) at the MIRACUM locations, which offer diagnosis and treatment of RDs.
An interview guide was developed with a category-guided deductive approach. The interviews were recorded on an audio device and then transcribed into written form. We continued data collection until all interviews were completed. Afterwards, data analysis was performed using Mayring’s qualitative content analysis approach.
Results: A total of seven experts were included in the study. The results show that medical center guides and physicians from RDC B-centers (with a focus on different RDs) are involved in the diagnostic process. Furthermore, interdisciplinary case discussions between physicians are conducted.
The experts explained that RDs exist which cannot be fully differentiated, but rather described only by their overall symptoms or findings: diagnosis is dependent on the disease or disease group. At the end of the diagnostic process, most centers prepare a summary of the patient case. Furthermore, the experts considered both physicians and experts from the B-centers to be potential users of a CDSS. The experts also have different experiences with CDSS for RDs.
Conclusions: This qualitative study is a first step towards establishing the requirements for the development of a CDSS for RDs. Further research is necessary to create solutions by also including the experts on RDs.
The RFQ direct injection project (RFQ-DIP) for the neutrino physics experiment IsoDAR aims at an efficient injection of a high-current H²⁺ beam into the dedicated 60 MeV driver cyclotron. Therefore, it is intended to use a compact 32.8 MHz RFQ structure of the split-coaxial type as a pre-buncher. To determine the thermal elongation of the 1.4 m long electrode rods as well as the thermal frequency detuning of the RF structure at a maximum nominal power load of 3.6 kW, an extensive thermal and structural mechanical analysis using COMSOL Multiphysics was conducted. The water heating along the cooling channels as well as the properties of heat transfer from the copper structure to the cooling water were taken into account, which required CFD simulations of the cooling water flow in the turbulent regime. Here we present the methods and results of the sophisticated thermal and structural mechanical simulations using COMSOL and provide a comparison to more simplistic simulations conducted with CST Studio Suite.
Explosive volcanism affects weather and climate. Primary volcanic ash particles which act as ice nuclei (IN) can modify the phase and properties of cold tropospheric clouds. During the Eyjafjallajökull volcanic eruption we have measured the highest ice nucleus number concentrations (>600 L) in our record of 2 years of daily IN measurements in central Germany. Even in Israel, located about 5000 km away from Iceland, IN were as high as otherwise only during desert dust storms. These measurements are the only ones available on the properties of IN in the Eyjafjallajökull plume. The measured high concentrations and high activation temperature (−8 °C) point to an important impact of volcanic ash on microphysical and radiative properties of clouds through enhanced glaciation.
We have sampled atmospheric ice nuclei (IN) and aerosol in Germany and in Israel during spring 2010. IN were analyzed by the static vapor diffusion chamber FRIDGE, as well as by electron microscopy. During the Eyjafjallajökull volcanic eruption of April 2010 we have measured the highest ice nucleus number concentrations (>600 l−1) in our record of 2 yr of daily IN measurements in central Germany. Even in Israel, located about 5000 km away from Iceland, IN were as high as otherwise only during desert dust storms. The fraction of aerosol activated as ice nuclei at −18 °C and 119% rhice and the corresponding area density of ice-active sites per aerosol surface were considerably higher than what we observed during an intense outbreak of Saharan dust over Europe in May 2008.
Pure volcanic ash accounts for at least 53–68% of the 239 individual ice nucleating particles that we collected in aerosol samples from the event and analyzed by electron microscopy. Volcanic ash samples that had been collected close to the eruption site were aerosolized in the laboratory and measured by FRIDGE. Our analysis confirms the relatively poor ice nucleating efficiency (at −18 °C and 119% ice-saturation) of such "fresh" volcanic ash, as it had recently been found by other workers. We find that both the fraction of the aerosol that is active as ice nuclei as well as the density of ice-active sites on the aerosol surface are three orders of magnitude larger in the samples collected from ambient air during the volcanic peaks than in the aerosolized samples from the ash collected close to the eruption site. From this we conclude that the ice-nucleating properties of volcanic ash may be altered substantially by aging and processing during long-range transport in the atmosphere, and that global volcanism deserves further attention as a potential source of atmospheric ice nuclei.
Surface measurements of aerosol and ice nuclei (IN) at a Central European mountain site during an episode of dust transport from the Sahara are presented. Ice nuclei were sampled by electrostatic precipitation on silicon wafers and were analyzed in an isothermal static vapor diffusion chamber. The transport of mineral dust is simulated by the Eulerian regional dust model DREAM. Ice nuclei and mineral dust are significantly correlated, in particular IN number concentration and aerosol surface area. The ice nucleating characteristics of the aerosol as analyzed with respect to temperature and supersaturation are similar during the dust episode than during the course of the year. This suggests that dust may be a main constituent of ice nucleating aerosols in Central Europe.
Surface measurements of aerosol and ice nuclei (IN) at a Central European mountain site during an episode of dust transport from the Sahara are presented. Transport is simulated by the Eulerian regional dust model DREAM. Ice nuclei and mineral dust are significantly correlated. The highest correlation is found between IN concentration and aerosol surface area. The ice nucleating characteristics of the aerosol with respect to temperature and supersaturation are similar during the dust episode than during the course of the year. This suggests that dust is always a dominant constituent of ice nucleating aerosols in Central Europe.
Background: Pulmonary nocardiosis (PN) is an uncommon but potentially life-threatening infection. Most of our knowledge is derived from case reports or smaller case series. Recently, increasing PN incidence rates have been reported. We aim to describe the clinical course of and risk factors for PN in four Western European countries and to estimate population-based annual hospitalization rates.
Methods: Retrospective evaluation (1995 to 2011) of the clinical course of and risk factors for PN in patients from 11 hospitals in four European countries (Germany, Austria, Switzerland and The Netherlands). Calculation of population-based estimates of hospitalization rates of PN in Germany (2005 to 2011) using official German nationwide diagnosis-related groups (DRG) hospital statistics.
Results: Forty-three patients fulfilled stringent criteria for proven (n = 8) and probable (n = 35) PN; seven with extrapulmonary dissemination. Within the 43 patients, major PN risk factors were immunocompromising (83.7%) and/or pulmonary (58.1%; in 27.9% as only comorbidity) comorbidities. Median duration of PN targeted therapy was 12 weeks. Distinguished patterns of resistance were observed (imipenem susceptibility: N. farcinica 33.3%; N. asteroides 66.7%). Overall mortality rate was 18.9%; in disseminated PN 50%. Over time, annual PN hospitalization rates remained unchanged at around 0.04/100′000 with the highest rate among men aged 75–84 years (0.24/100′000).
Conclusion: PN is rare, but potentially life-threatening, and mainly affects immunocompromised elder males. Overall annual hospitalization rates remained stable between 2005 and 2011.
A new technique developed for measuring nuclear reactions at low momentum transfer with stored beams in inverse kinematics was successfully used to study isoscalar giant resonances. The experiment was carried out at the experimental heavy-ion storage ring (ESR) at the GSI facility using a stored 58Ni beam at 100 MeV/u and an internal helium gas-jet target. In these measurements, inelastically scattered α-recoils at very forward center-of-mass angles (θcm ≤ 1.5°) were detected with a dedicated setup, including ultra-high vacuum compatible detectors. Experimental results indicate a dominant contribution of the isoscalar giant monopole resonance at this very forward angular range. It was found that the monopole contribution exhausts 79+12−11% of the energy-weighted sum rule (EWSR), which agrees with measurements performed in normal kinematics. This opens up the opportunity to investigate the giant resonances in a large domain of unstable and exotic nuclei in the near future. It is a fundamental milestone towards new nuclear reaction studies with stored ion beams.
Reliable, easy-to-handle phenotypic screening platforms are needed for the identification of anti-SARS-CoV-2 compounds. Here, we present caspase 3/7 activity as a read-out for monitoring the replication of SARS-CoV-2 isolates from different variants, including a remdesivir-resistant strain, and of other coronaviruses in a broad range of cell culture models, independently of cytopathogenic effect formation. Compared to other cell culture models, the Caco-2 subline Caco-2-F03 displayed superior performance, as it possesses a stable SARS-CoV-2 susceptible phenotype and does not produce false-positive hits due to drug-induced phospholipidosis. A proof-of-concept screen of 1796 kinase inhibitors identified known and novel antiviral drug candidates including inhibitors of PHGDH, CLK-1, and CSF1R. The activity of the PHGDH inhibitor NCT-503 was further increased in combination with the HK2 inhibitor 2-deoxy-D-glucose, which is in clinical development for COVID-19. In conclusion, caspase 3/7 activity detection in SARS-CoV-2-infected Caco-2F03 cells provides a simple phenotypic high-throughput screening platform for SARS-CoV-2 drug candidates that reduces false positive hits.
The KASCADE-Grande experiment has significantly contributed to the current knowledge about the energy spectrum and composition of cosmic rays for energies between the knee and the ankle. Meanwhile, post-LHC versions of the hadronic interaction models are available and used to interpret the entire data set of KASCADE-Grande. In addition, a new, combined analysis of both arrays, KASCADE and Grande, was developed significantly increasing the accuracy of the shower observables. First results of the new analysis with the entire data set of the KASCADE-Grande experiment will be the focus of this contribution.
Reliable, easy-to-handle phenotypic screening platforms are needed for the identification of anti-SARS-CoV-2 compounds. Here, we present caspase 3/7 activity as a readout for monitoring the replication of SARS-CoV-2 isolates from different variants, including a remdesivir-resistant strain, and of other coronaviruses in numerous cell culture models, independently of cytopathogenic effect formation. Compared to other models, the Caco-2 subline Caco-2-F03 displayed superior performance. It possesses a stable SARS-CoV-2 susceptibility phenotype and does not produce false-positive hits due to drug-induced phospholipidosis. A proof-of-concept screen of 1,796 kinase inhibitors identified known and novel antiviral drug candidates including inhibitors of phosphoglycerate dehydrogenase (PHGDH), CDC like kinase 1 (CLK-1), and colony stimulating factor 1 receptor (CSF1R). The activity of the PHGDH inhibitor NCT-503 was further increased in combination with the hexokinase II (HK2) inhibitor 2-deoxy-D-glucose, which is in clinical development for COVID-19. In conclusion, caspase 3/7 activity detection in SARS-CoV-2-infected Caco-2-F03 cells provides a simple phenotypic high-throughput screening platform for SARS-CoV-2 drug candidates that reduces false-positive hits.