Imaging quantum oscillations and millitesla pseudomagnetic fields in graphene.

The exceptional control of the electronic energy bands in atomically thin quantum materials has led to the discovery of several emergent phenomena1. However, at present there is no versatile method for mapping the local band structure in advanced two-dimensional materials devices in which the active layer is commonly embedded in the insulating layers and metallic gates. Using a scanning superconducting quantum interference device, here we image the de Haas-van Alphen quantum oscillations in a model system, the Bernal-stacked trilayer graphene with dual gates, which shows several highly tunable bands2-4. By resolving thermodynamic quantum oscillations spanning more than 100 Landau levels in low magnetic fields, we reconstruct the band structure and its evolution with the displacement field with excellent precision and nanoscale spatial resolution. Moreover, by developing Landau-level interferometry, we show shear-strain-induced pseudomagnetic fields and map their spatial dependence. In contrast to artificially induced large strain, which leads to pseudomagnetic fields of hundreds of tesla5-7, we detect naturally occurring pseudomagnetic fields as low as 1 mT corresponding to graphene twisting by 1 millidegree, two orders of magnitude lower than the typical angle disorder in twisted bilayer graphene8-11. This ability to resolve the local band structure and strain at the nanoscale level enables the characterization and use of tunable band engineering in practical van der Waals devices.

Interior and Edge Magnetization in Thin Exfoliated CrGeTe3 Films.

CrGeTe3 (CGT) is a semiconducting vdW ferromagnet shown to possess magnetism down to a two-layer thick sample. Although CGT is one of the leading candidates for spintronics devices, a comprehensive analysis of CGT thickness dependent magnetization is currently lacking. In this work, we employ scanning SQUID-on-tip (SOT) microscopy to resolve the magnetic properties of exfoliated CGT flakes at 4.2 K. Combining transport measurements of CGT/NbSe2 samples with SOT images, we present the magnetic texture and hysteretic magnetism of CGT, thereby matching the global behavior of CGT to the domain structure extracted from local SOT magnetic imaging. Using this method, we provide a thickness dependent magnetization state diagram of bare CGT films. No zero-field magnetic memory was found for films thicker than 10 nm, and hard ferromagnetism was found below that critical thickness. Using scanning SOT microscopy, we identify a unique edge magnetism, contrasting the results attained in the CGT interior.

[Instruments of official communication by regulatory authorities on risks of drug use]. / Instrumente behördlicher Kommunikation zu Anwendungsrisiken von Arzneimitteln.

Active communication of authorities, such as the Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI), including maintenance of contacts with health care professionals, as well as press and public relations work, are essential prerequisites for ensuring that information on the risks of using medicinal products reaches both affected patients and healthcare professionals quickly and in a targeted manner. The various instruments of targeted communication describe possible risks and also contain recommendations that help to reduce the risk of using a medicinal product. The supplementary public relations work aims to make the tasks and objectives of the authority known to the public and to experts with the goal of creating and expanding trust in the actions of the authorities. To this end, appropriate communication platforms must be established and accepted so that they are used by both experts and the general public and the authority is perceived and appreciated as a reliable source of risk information. The currently available instruments of targeted risk communication, such as Dear Health Care Professional Communication (DHPC), risk management plans, and educational materials are described in this paper as well as broader communication on official websites or towards the media. Finally, PEI's risk communication is highlighted with particular reference to COVID-19 vaccines.

[Psychiatric polypharmacy and electroconvulsive therapy in treatment-resistant depression]. / Psychiatrische Polypharmazie und Elektrokonvulsionstherapie bei therapieresistenter Depression.

BACKGROUND: Despite its relevant medical risks, polypharmacy is common particularly among difficult to treat conditions, e.g. treatment refractory depression (TRD). According to numerous guidelines, electroconvulsive therapy (ECT) is the treatment of choice in severe and treatment-resistant major depression due to the high effectiveness; however, to date limited data are available concerning the effects of ECT on the concomitant prescription of psychiatric medication. METHODS: For a retrospective explorative analysis of psychiatric polypharmacy (MED) in TRD, data from 58 inpatient treatments were collected. Due to depressive episodes, all patients received psychopharmacological treatment and cognitive behavioral therapy (MED group). Of the patients 29 also underwent ECT (ECT group). Using a modified drug burden index (mod-DBI), the psychiatric medication was quantified at admission (TP0), start (TP1) and termination of ECT (TP2) and discharge in the ECT group or in comparable periods in the MED group (TP3). Differences in distribution were tested with the t-test and alterations in measurements were tested by means of variance analysis (F-test). RESULTS: Patients treated with ECT showed higher mod-DBI values at TP0, mainly due to more frequent prescription of benzodiazepines (BZD), mood stabilizers (MS) and antipsychotic drugs (AP). At the beginning of the inpatient treatment (TP0-TP1) there was an increase in BZD use (in both groups); in the ECT group MS were reduced and AP increased. In the time interval TP1-TP3, BZD (in both groups) and AP (ECT group) were again less frequently prescribed and MS (ECT and MED group) were increased again. Excluding BZD, there was a significant increase in mod-DBI in both groups, whereas the mod-DBI no longer showed significant differences at TP2 and TP3. CONCLUSION: The data possibly indicate that patients with TRD who receive ECT during inpatient treatment already have a more extensive psychiatric medication at admission. Also, psychiatric medication appears to be increased less prominently when ECT is performed. These findings and the possibly associated long-term benefits should be addressed in future research.

[Educational material as part of risk minimisation]. / Schulungsmaterial zur Minimierung von Arzneimittelrisiken.

Educational material, for example in the form of information booklets, checklists, patient alert cards, therapeutic passports, emergency ID cards, or videos, is an important aid for the safe use of a medicinal product or drug and supplements the summary of product characteristics and package information. It is ordered, tested and approved by the competent national authorities, the Federal Institute for Drugs and Medical Devices (BfArM) and the Paul Ehrlich Institute (PEI), and made available by the respective marketing authorization holder and published on the websites of BfArM and PEI. Educational material is part of the marketing authorization of a medicinal product. Since 1 December 2016, officially approved educational material can be recognized by the blue-hand logo in Germany. There is currently specific educational material for 202 active substances with further recommendations on how to avoid or reduce risks for patients. Although educational material is one of the most common additional risk minimisation measures, little is known about its effectiveness, including related process and outcome indicators. Key elements as well as an overview of educational material are described.

Inhibition of dermatophytes by photodynamic treatment with curcumin.

Treatment of dermatophytoses with currently available antimycotic agents is often tedious and sometimes unsatisfactory. A search for better therapeutic methods-ideally with an immediate fungicidal effect-has, among others, lead to photodynamic procedures as a promising alternative, and recently curcumin was found to be a suitable agent for this application. In this study the effect of photodynamic treatment with curcumin on dermatophytes was tested in vitro. Wells of microtiter plates were filled with conidia of Trichophyton rubrum, Trichophyton interdigitale, Trichophyton terrestre, Microsporum canis, Microsporum gypseum and Epidermophyton floccosum in buffer. Then curcumin was added to the conidia and after 20 min the assays were irradiated one time only with visible light (peak wave length 367 nm, 5 J/cm2). Thereafter the wells were filled up with Sabouraud's glucose broth and in the following fungal growth was measured photometrically. The results showed that all dermatophytes were markedly inhibited depending on the concentration of curcumin. With 5.4 mg/l curcumin plus irradiation fungal growth was significantly suppressed over a period of 96 h (P < .001). Even after 96 h inhibition of T. rubrum was still complete and marked for all other species as well. M. gypseum was least susceptible. Our results are very encouraging to pursue the development of a photodynamic therapy of tinea with curcumin. The outstanding tolerance of curcumin and the innocuousness of the required light are favorable preconditions for this task.

An integrated semiconductor device enabling non-optical genome sequencing.

The seminal importance of DNA sequencing to the life sciences, biotechnology and medicine has driven the search for more scalable and lower-cost solutions. Here we describe a DNA sequencing technology in which scalable, low-cost semiconductor manufacturing techniques are used to make an integrated circuit able to directly perform non-optical DNA sequencing of genomes. Sequence data are obtained by directly sensing the ions produced by template-directed DNA polymerase synthesis using all-natural nucleotides on this massively parallel semiconductor-sensing device or ion chip. The ion chip contains ion-sensitive, field-effect transistor-based sensors in perfect register with 1.2 million wells, which provide confinement and allow parallel, simultaneous detection of independent sequencing reactions. Use of the most widely used technology for constructing integrated circuits, the complementary metal-oxide semiconductor (CMOS) process, allows for low-cost, large-scale production and scaling of the device to higher densities and larger array sizes. We show the performance of the system by sequencing three bacterial genomes, its robustness and scalability by producing ion chips with up to 10 times as many sensors and sequencing a human genome.

Electrically Tunable Multiterminal SQUID-on-Tip.

We present a new nanoscale superconducting quantum interference device (SQUID) whose interference pattern can be shifted electrically in situ. The device consists of a nanoscale four-terminal-four-junction SQUID fabricated at the apex of a sharp pipet using a self-aligned three-step deposition of Pb. In contrast to conventional two-terminal-two-junction SQUIDs that display optimal sensitivity when flux biased to about a quarter of the flux quantum, the additional terminals and junctions allow optimal sensitivity at arbitrary applied flux, thus eliminating the magnetic field "blind spots". We demonstrate spin sensitivity of 5 to 8 µB/Hz1/2 over a continuous field range of 0 to 0.5 T with promising applications for nanoscale scanning magnetic imaging.

Survival of the Scandinavian total ankle replacement (STAR): results of ten to nineteen years follow-up.

PURPOSE: The purpose of this study was to evaluate survival and clinical outcome of the Scandinavian total ankle replacement (STAR) prosthesis after a minimum of ten years up to a maximum of 19 years. METHODS: Fifty STAR prostheses in 46 patients with end stage ankle osteoarthritis operated between 1996 and 2006 by the same surgeon (MH) were included. Minimal follow-up was ten years (median 14.6 years, 95% confidence interval [CI] 12.9-16.4). Clinical (Kofoed score) and radiological assessments were taken before the operation and at one, ten (+2), and 16 (±3) years after implantation. The primary endpoint was defined as exchange of the whole prosthesis or conversion to arthrodesis (def. 1), exchange of at least one metallic component (def. 2), or exchange of any component including the inlay (due to breakage or wear) (def. 3). Survival was estimated according to Kaplan-Meier. Further reoperations related to STAR were also recorded. RESULTS: The ten year survival rate was (def. 1) 94% (CI 82-98%), (def. 2) 90% (CI, 77-96%), and (def. 3) 78% (CI 64-87%). The 19-year survival rate was (def. 1) 91% (CI 78-97%), (def. 2) 75% (CI 53-88%), and (def. 3) 55% (CI 34-71%). Considering any re-operations related to STAR, 52% (26/50) of prostheses were affected by re-operations. Mean pre-operative Kofoed score was 49, which improved to 84 after one year (n = 50), to 90 after ten years (n = 46), and to 89 after 16 years (n = 28). CONCLUSIONS: The survival rate for def. 1 and 2 was high. However, re-operations occurred in 52% of all STAR prosthesis. STUDY DESIGN: Retrospective cohort study, evidence Level 4.

Three-junction SQUID-on-tip with tunable in-plane and out-of-plane magnetic field sensitivity.

Nanoscale superconducting quantum interference devices (SQUIDs) demonstrate record sensitivities to small magnetic moments but are typically sensitive only to the field component that is normal to the plane of the SQUID and out-of-plane with respect to the scanned surface. We report on a nanoscale three-junction Pb SQUID, which is fabricated on the apex of a sharp tip. Because of its three-dimensional structure, it exhibits a unique tunable sensitivity to both in-plane and out-of-plane fields. We analyze the two-dimensional interference pattern from both numerical and experimental points of view. This device is integrated into a scanning microscope, and its ability to independently measure the different components of the magnetic field with outstanding spin sensitivity better than 5 µB/Hz(1/2) is demonstrated. This highlights its potential as a local probe of nanoscale magnetic structures.

Spasticity treatment with onabotulinumtoxin A: data from a prospective German real-life patient registry.

This study aimed at providing real-life baseline, injection and outcome data for the treatment of various forms of spasticity with onabotulinumtoxin A in Germany. Prospective data were collected in an open multicenter patient registry from 2005 until 2010, encompassing the experience of ten specialized German centers in the treatment of spasticity using onabotulinumtoxin A in 508 patients with a total of 2005 treatment sessions. Disease entities comprised spasticity following stroke (both ischemic and hemorrhagic), traumatic brain injury, multiple sclerosis, cerebral palsy, and anoxia. Sustained improvement was observed in a variety of outcome parameters including goal attainment and motor performance scores for up to five repeated injection sessions. No significant differences between disease entities or between upper and lower limb treatment were observed with regard to efficacy and safety following onabotulinumtoxin A treatment. Minor to moderate side effects were reported in <1 % of the study population. We conclude that repetitive treatment of focal and multifocal spasticity with onabotulinumtoxin A provides a safe and efficacious therapeutic strategy for patients with different disease entities of the central nervous system.

Frequency and correlates of maladaptive responses to paranoid thoughts in patients with psychosis compared to a population sample.

INTRODUCTION: The aims of this study were to identify whether responses to paranoid thoughts distinguish patients with psychotic disorders from people in the population who have paranoid thoughts occasionally and to identify factors that are associated with and might explain the different ways of responding. METHODS: Paranoid thoughts were assessed in patients diagnosed with a psychotic disorder (n = 32) and a population control sample (n = 34) with the Paranoia Checklist. Responses to paranoid thoughts were assessed with the Reactions to Paranoid Thoughts Scale (RePT) and social support, self-efficacy and cognitive insight were assessed as potential correlates of the responses to paranoid thoughts. RESULTS: The patients showed significantly more depressed, physical and devaluating responses to paranoid thoughts and employed less normalising responses than the controls. The differences in normalising responses were explained by perceived social integration, whereas the differences in depressive responses were explained by the overall levels of depression and partly explained by externality and social integration. CONCLUSIONS: Maladaptive responses to paranoid thoughts could be relevant to the pathogenesis and maintenance of persecutory delusions. Interventions aimed at reducing paranoia could benefit from targeting dysfunctional responses to paranoid thoughts and by placing a stronger emphasis on treating depression and improving social integration.

Technical report: precisely fitting bars on implants in five steps-a CAD/CAM concept for the edentulous mandible.

Various treatment concepts have been presented for the edentulous mandible. Manufacturing tension-free and precisely fitting bars on dental implants was previously a great challenge in prosthetic dentistry and required great effort. Modern computer aided design/computer aided manufacturing technology in combination with some clinical modifications of the established workflow enables the clinician to achieve precise results in a very efficient way. The innovative five-step concept is presented in a clinical case.

The STAR Compass to Guide Future Pharmacovigilance Based on a 10-Year Review of the Strengthened EU System.

This article reflects on the 2010 pharmacovigilance legislation of the European Union (EU). Its legislative aim of better patient and public health protection through new responsibilities for pharmaceutical companies and regulatory bodies is considered to have been achieved and is well supported by the good pharmacovigilance practices 'EU-GVP'. For future progress, we set out a vision for high-quality pharmacovigilance in a world of ongoing medical, technological and social changes. To deliver this vision, four principles are proposed to guide actions for further progressing the EU pharmacovigilance system: synergistic interactions with healthcare systems; trustworthy evidence for regulatory decisions; adaptive process efficiency; and readiness for emergency situations (the 'STAR principles'). Like a compass, these principles should guide actions for building capacity, technology and methods; improving regulatory processes; and expanding policies, frameworks and research agendas. Fit for the future, the EU system should achieve further improved outputs in terms of safe, effective and trusted use of medicines and positive health outcomes within patient-centred healthcare.

De Haas-van Alphen spectroscopy and magnetic breakdown in moiré graphene.

Quantum oscillations originating from the quantization of electron cyclotron orbits provide sensitive diagnostics of electron bands and interactions. We report on nanoscale imaging of the thermodynamic magnetization oscillations caused by the de Haas-van Alphen effect in moiré graphene. Scanning by means of superconducting quantum interference device (SQUID)-on-tip in Bernal bilayer graphene crystal axis-aligned to hexagonal boron nitride reveals large magnetization oscillations with amplitudes reaching 500 Bohr magneton per electron in weak magnetic fields, unexpectedly low frequencies, and high sensitivity to superlattice filling fraction. The oscillations allow us to reconstruct the complex band structure, revealing narrow moiré bands with multiple overlapping Fermi surfaces separated by unusually small momentum gaps. We identified sets of oscillations that violate the textbook Onsager Fermi surface sum rule, signaling formation of broad-band particle-hole superposition states induced by coherent magnetic breakdown.

Molecular fingerprinting reflects different histotypes and brain region in low grade gliomas.

BACKGROUND: Paediatric low-grade gliomas (LGGs) encompass a heterogeneous set of tumours of different histologies, site of lesion, age and gender distribution, growth potential, morphological features, tendency to progression and clinical course. Among LGGs, Pilocytic astrocytomas (PAs) are the most common central nervous system (CNS) tumours in children. They are typically well-circumscribed, classified as grade I by the World Health Organization (WHO), but recurrence or progressive disease occurs in about 10-20% of cases. Despite radiological and neuropathological features deemed as classic are acknowledged, PA may present a bewildering variety of microscopic features. Indeed, tumours containing both neoplastic ganglion and astrocytic cells occur at a lower frequency. METHODS: Gene expression profiling on 40 primary LGGs including PAs and mixed glial-neuronal tumours comprising gangliogliomas (GG) and desmoplastic infantile gangliogliomas (DIG) using Affymetrix array platform was performed. A biologically validated machine learning workflow for the identification of microarray-based gene signatures was devised. The method is based on a sparsity inducing regularization algorithm l1l2 that selects relevant variables and takes into account their correlation. The most significant genetic signatures emerging from gene-chip analysis were confirmed and validated by qPCR. RESULTS: We identified an expression signature composed by a biologically validated list of 15 genes, able to distinguish infratentorial from supratentorial LGGs. In addition, a specific molecular fingerprinting distinguishes the supratentorial PAs from those originating in the posterior fossa. Lastly, within supratentorial tumours, we also identified a gene expression pattern composed by neurogenesis, cell motility and cell growth genes which dichotomize mixed glial-neuronal tumours versus PAs. Our results reinforce previous observations about aberrant activation of the mitogen-activated protein kinase (MAPK) pathway in LGGs, but still point to an active involvement of TGF-beta signaling pathway in the PA development and pick out some hitherto unreported genes worthy of further investigation for the mixed glial-neuronal tumours. CONCLUSIONS: The identification of a brain region-specific gene signature suggests that LGGs, with similar pathological features but located at different sites, may be distinguishable on the basis of cancer genetics. Molecular fingerprinting seems to be able to better sub-classify such morphologically heterogeneous tumours and it is remarkable that mixed glial-neuronal tumours are strikingly separated from PAs.

Patient satisfaction and clinical parameters in psychiatric inpatients--the prevailing role of symptom severity and pharmacologic disturbances.

OBJECTIVE: A high degree of satisfaction is probably one of the most important aims for each patient during medical treatment. However, database on the influencing variables in a general psychiatric inpatient sample is still small. Therefore, the objective of this study is to identify clinical variables related to patients' treatment satisfaction. METHODS: In 113 patients (59 females; mean age, 48.3 ± 16.6 years; mean treatment duration, 1.4 ± 1.2 months) admitted to a psychiatric hospital, data were assessed on treatment satisfaction using the ZUF-8 questionnaire ("Fragebogen zur Patientenzufriedenheit"; questionnaire of patient satisfaction) at discharge and on general treatment variables as well as the psychosocial functioning using the "Basisdokumentation" (basic documentation) questionnaire including Clinical Global Impression scale (CGI) and Global Assessment of Functioning scale (GAF) at admission and discharge. Student t tests, univariate variance analyses, and Pearson correlations were performed. RESULTS: ZUF-8 sum score correlated significantly negatively with CGI score at discharge (part 1: P = .036), positively with GAF at discharge (P = .011), and as a trend with the reduction of CGI during the treatment (CGI change; P = .050). Patients with pharmacologic disturbances (P = .003) and with a schizophrenia spectrum disorder or a personality disorder were less content (trend; P = .071). Satisfaction did not differ in dependency of the variables age, sex, native language, number of inpatient treatments, therapeutic setting of the ward, duration of disorder or treatment, level of school education, bodily impairment, number of somatic diagnoses, psychopharmacologic treatment (vs none), antidepressants, body weight, or body weight change. CONCLUSION: The results of the study suggest that patient satisfaction is dependent on symptom severity and global functioning at discharge, on pharmacologic disturbances during treatment, and on the diagnostic group. Therefore, symptom relief and reduction of adverse side effects as far as possible should be the primary aim of an inpatient treatment.

How causal machine learning can leverage marketing strategies: Assessing and improving the performance of a coupon campaign.

We apply causal machine learning algorithms to assess the causal effect of a marketing intervention, namely a coupon campaign, on the sales of a retailer. Besides assessing the average impacts of different types of coupons, we also investigate the heterogeneity of causal effects across different subgroups of customers, e.g., between clients with relatively high vs. low prior purchases. Finally, we use optimal policy learning to determine (in a data-driven way) which customer groups should be targeted by the coupon campaign in order to maximize the marketing intervention's effectiveness in terms of sales. We find that only two out of the five coupon categories examined, namely coupons applicable to the product categories of drugstore items and other food, have a statistically significant positive effect on retailer sales. The assessment of group average treatment effects reveals substantial differences in the impact of coupon provision across customer groups, particularly across customer groups as defined by prior purchases at the store, with drugstore coupons being particularly effective among customers with high prior purchases and other food coupons among customers with low prior purchases. Our study provides a use case for the application of causal machine learning in business analytics to evaluate the causal impact of specific firm policies (like marketing campaigns) for decision support.

DICOM® integrated EEG data: A first clinical implementation of the new DICOM standard for neurophysiology data.

OBJECTIVE: Demonstrating a pilot implementation of the Digital Imaging and Communication in Medicine (DICOM) neurophysiology standard published in 2020. METHODS: An automated workflow for converting EEG data from a proprietary vendor EEG format to standardized and interoperable DICOM format was developed and tested. RESULTS: Retrieval of proprietary EEG data, associated videos, annotations and metadata from the vendor EEG archive and their subsequent conversion to DICOM EEG was possible without changes to the departmental workflow. To transfer DICOM EEG data to the central radiology DICOM archive, only minor extensions in the parameterization of the archive's DICOM interfaces were necessary. Linkage with the electronic health record (EHR) and display in a DICOM EEG viewer could be demonstrated. A random sample of 88 DICOM EEG studies was compared to the original vendor files and EEG and video file sizes were comparable. CONCLUSIONS: Storing and reviewing EEG data in standardized DICOM format is feasible, facilitated by existing DICOM infrastructure, and therefore allows for vendor independent access to EEG data. SIGNIFICANCE: We report the first implementation of the DICOM neurophysiology standard, thus promoting standardization in the field of neurophysiology as well as data exchange and access to legacy recordings in an interoperable vendor independent format.

Rapid and robust endoscopic content area estimation: A lean GPU-based pipeline and curated benchmark dataset.

Endoscopic content area refers to the informative area enclosed by the dark, non-informative, border regions present in most endoscopic footage. The estimation of the content area is a common task in endoscopic image processing and computer vision pipelines. Despite the apparent simplicity of the problem, several factors make reliable real-time estimation surprisingly challenging. The lack of rigorous investigation into the topic combined with the lack of a common benchmark dataset for this task has been a long-lasting issue in the field. In this paper, we propose two variants of a lean GPU-based computational pipeline combining edge detection and circle fitting. The two variants differ by relying on handcrafted features, and learned features respectively to extract content area edge point candidates. We also present a first-of-its-kind dataset of manually annotated and pseudo-labelled content areas across a range of surgical indications. To encourage further developments, the curated dataset, and an implementation of both algorithms, has been made public (https://doi.org/10.7303/syn32148000, https://github.com/charliebudd/torch-content-area). We compare our proposed algorithm with a state-of-the-art U-Net-based approach and demonstrate significant improvement in terms of both accuracy (Hausdorff distance: 6.3 px versus 118.1 px) and computational time (Average runtime per frame: 0.13 ms versus 11.2 ms).