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Aims Clinical practice guidelines restrict rhythm control therapy to patients with symptomatic atrial fibrillation (AF). The EAST-AFNET 4 trial demonstrated that early, systematic rhythm control improves clinical outcomes compared to symptom-directed rhythm control. Methods and results This prespecified EAST-AFNET 4 analysis compared the effect of early rhythm control therapy in asymptomatic patients (EHRA score I) to symptomatic patients. Primary outcome was a composite of death from cardiovascular causes, stroke, or hospitalization with worsening of heart failure or acute coronary syndrome, analyzed in a time-to-event analysis. At baseline, 801/2633 (30.4%) patients were asymptomatic [mean age 71.3 years, 37.5% women, mean CHA2DS2-VASc score 3.4, 169/801 (21.1%) heart failure]. Asymptomatic patients randomized to early rhythm control (395/801) received similar rhythm control therapies compared to symptomatic patients [e.g. AF ablation at 24 months: 75/395 (19.0%) in asymptomatic; 176/910 (19.3%) symptomatic patients, P = 0.672]. Anticoagulation and treatment of concomitant cardiovascular conditions was not different between symptomatic and asymptomatic patients. The primary outcome occurred in 79/395 asymptomatic patients randomized to early rhythm control and in 97/406 patients randomized to usual care (hazard ratio 0.76, 95% confidence interval [0.6; 1.03]), almost identical to symptomatic patients. At 24 months follow-up, change in symptom status was not different between randomized groups (P = 0.19). Conclusion The clinical benefit of early, systematic rhythm control was not different between asymptomatic and symptomatic patients in EAST-AFNET 4. These results call for a shared decision discussing the benefits of rhythm control therapy in all patients with recently diagnosed AF and concomitant cardiovascular conditions (EAST-AFNET 4; ISRCTN04708680; NCT01288352; EudraCT2010-021258-20).

Objective This study aimed to measure health-related quality of life (HRQOL) in children and adolescents with tuberous sclerosis complex (TSC) and quality of life (QOL) and depressive symptoms among caregivers. Methods Adequate metrics were used to assess HRQOL in children and adolescents with TSC (4-18 years, KINDLR) as well as QOL (EQ-5D) and symptoms of depression (BDI-II) among caregivers. Predictors for reduced HRQOL and depressive symptoms were identified by variance analysis, ordinal regression, and bivariate correlation. Results The mean HRQOL score was 67.9 ± 12.7, and significantly lower values were associated with increasing age, attending special needs education, TSC-associated psychiatric symptoms, and drug-related adverse events. The mean QOL of caregivers was 85.4 ± 15.7, and caregiver's sex, TSC mutation locus, familial TSC clustering, special needs education, degree of disability, care dependency, presence of TSC-associated psychiatric symptoms, and TSC severity were significant predictors of lower QOL. Depressive symptoms were identified in 45.7% of caregivers, associated with female sex of the caregiver, familial TSC clustering, special needs education, and presence of TSC-associated psychiatric symptoms of the child. Multivariate regression analysis revealed adolescence and drug-related adverse events as significant predictors for lower HRQOL in TSC children, and TSC2 variants predicted lower QOL and depressive symptoms in caregivers. Conclusion Compared with other chronic diseases, such as headache, diabetes or obesity, children with TSC have significantly lower HRQOL, which further decreases during adolescence. A decreased HRQOL of patients correlates with a lower QOL and increased symptoms of depression of their caregivers. These results may improve the comprehensive therapy and care of children and adolescents with TSC and their families and caregivers. Trial registration DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.

Objective To analyze the association between electroencephalographic (EEG) patterns and overall, short- and long-term mortality in patients with hypoxic encephalopathy (HE). Methods Retrospective, mono-center analysis of 199 patients using univariate log-rank tests (LR) and multivariate cox regression (MCR). Results Short-term mortality, defined as death within 30-days post-discharge was 54.8%. Long-term mortality rates were 69.8%, 71.9%, and 72.9%, at 12-, 24-, and 36-months post-HE, respectively. LR revealed a significant association between EEG suppression (SUP) and short-term mortality, and identified low voltage EEG (LV), burst suppression (BSP), periodic discharges (PD) and post-hypoxic status epilepticus (PSE) as well as missing (aBA) or non-reactive background activity (nrBA) as predictors for overall, short- and long-term mortality. MCR indicated SUP, LV, BSP, PD, aBA and nrBA as significantly associated with overall and short-term mortality to varying extents. LV and BSP were significant predictors for long-term mortality in short-term survivors. Rhythmic delta activity, stimulus induced rhythmic, periodic or ictal discharges and sharp waves were not significantly associated with a higher mortality. Conclusion The presence of several specific EEG patterns can help to predict overall, short- and long-term mortality in HE patients. Significance The present findings may help to improve the challenging prognosis estimation in HE patients.

Supplemental Digital Content is available in the text., Background: Even on optimal therapy, many patients with heart failure and atrial fibrillation experience cardiovascular complications. Additional treatments are needed to reduce these events, especially in patients with heart failure and preserved left ventricular ejection fraction. Methods: This prespecified subanalysis of the randomized EAST-AFNET4 trial (Early Treatment of Atrial Fibrillation for Stroke Prevention Trial) assessed the effect of systematic, early rhythm control therapy (ERC; using antiarrhythmic drugs or catheter ablation) compared with usual care (allowing rhythm control therapy to improve symptoms) on the 2 primary outcomes of the trial and on selected secondary outcomes in patients with heart failure, defined as heart failure symptoms New York Heart Association II to III or left ventricular ejection fraction [LVEF]

OBJECTIVE: To analyze satisfaction with and reliability of video-electroencephalography-monitoring systems (VEMS) in epilepsy diagnostics.; METHODS: A survey was conducted between December 2020 and January 2021 among German epilepsy centers using well-established customer satisfaction (CS) and quality assurance metrics.; RESULTS: Among 16 participating centers, CS with VEMS was low, with only 13% of customers actively recommending their system. Only 50% of users were satisfied with the overall performance of their VEMS, and a low 18% were satisfied with the manufacturer's customer service. User interface, software stability, lack of regular updates, and missing customer-oriented improvements were reported as frequent problems jeopardizing diagnosis in approximately every 10th patient. The greatest potential for improvement was identified for software and hardware stability as well as customer service.; CONCLUSION: Satisfaction with VEMS and their customer service was low, and diagnostics were regularly affected by software or hardware errors. Even if this can be partly explained by the technical complexity of VEMS, there is an urgent need for improvements with regard to the reliability and durability of system components as well as signal synchrony and data management.; SIGNIFICANCE: This analysis highlights low consumer satisfaction of users with VEMS and uncovers frequent problems and potential for improvement. Copyright © 2021 International Federation of Clinical Neurophysiology. Published by Elsevier B.V. All rights reserved.

A divide-and-conquer (DAC) machine learning approach was first proposed by Wang et al. to forecast the sea surface height (SSH) of the Loop Current System (LCS) in the Gulf of Mexico. In this DAC approach, the forecast domain was divided into non-overlapping partitions, each of which had their own prediction model. The full domain SSH prediction was recovered by interpolating the SSH across each partition boundaries. Although the original DAC model was able to predict the LCS evolution and eddy shedding more than two months and three months in advance, respectively, growing errors at the partition boundaries negatively affected the model forecasting skills. In the study herein, a new partitioning method, which consists of overlapping partitions is presented. The region of interest is divided into 50%-overlapping partitions. At each prediction step, the SSH value at each point is computed from overlapping partitions, which significantly reduces the occurrence of unrealistic SSH features at partition boundaries. This new approach led to a significant improvement of the overall model performance both in terms of features prediction such as the location of the LC eddy SSH contours but also in terms of event prediction, such as the LC ring separation. We observed an approximate 12% decrease in error over a 10-week prediction, and also show that this method can approximate the location and shedding of eddy Cameron better than the original DAC method.

Background Bevacizumab is an antiangiogenic recombinant humanized monoclonal antibody that inhibits tumor growth. FKB238, a bevacizumab biosimilar, has analytical pharmacokinetic and safety profiles similar to those of bevacizumab. Objective This phase III trial (NCT02810457) compared the efficacy and safety of FKB238 with that of bevacizumab in patients with advanced/recurrent non-squamous non-small-cell lung cancer (non-sq-NSCLC). Methods This global, multicenter, double-blind, parallel, randomized, comparative clinical trial enrolled and randomized patients with advanced/recurrent non-sq-NSCLC to receive intravenous infusions of either FKB238 15 mg/kg or bevacizumab 15 mg/kg. All patients received intravenous infusions of paclitaxel 200 mg/m2 and carboplatin (area under the curve 6.0) immediately prior to investigational products for 4–6 cycles. FKB238 and bevacizumab were administered on day 1 of each 21-day cycle until objective progressive disease by RECIST version 1.1 or other discontinuation criteria were met. The primary efficacy endpoint was overall response rate (ORR), including complete and partial response and based on blinded independent central review assessment. Other efficacy determinations included progression-free survival (PFS), overall survival (OS), and immunogenicity. Adverse events and severity were reported. Results The ORR for the intent-to-treat (ITT) population (N = 731) was 51.6% in the FKB238 arm (N = 364) and 53.7% in the bevacizumab arm (N = 367). The FKB238:bevacizumab ORR ratio (ITT population) was 0.96 (90% confidence interval [CI] 0.86–1.08), and the difference in ORR (per-protocol set) between FKB238 and bevacizumab was − 0.02 (95% CI − 0.09 to 0.06). Both CIs fell within the prespecified equivalence margins. Estimated median PFS was 7.72 and 7.62 months in the FKB238 and bevacizumab arms, respectively (hazard ratio 0.97; 95% CI 0.82–1.16). Treatment-emergent adverse events (TEAEs) were reported for 94.2% and 95.1% of patients in the FKB238 and bevacizumab arms, respectively. Grade 3 or higher TEAEs were reported for 53.6% and 55.5% of patients in the FKB238 and bevacizumab arms, respectively. Serious TEAEs were reported for 25.1% and 26.0% of patients treated with FKB238 and bevacizumab, respectively. Conclusions Efficacy equivalence was demonstrated between the two drugs, and safety profiles were similar. There were no meaningful differences in efficacy and safety between FKB238 or bevacizumab in patients with non-sq-NSCLC. Trial registration number NCT02810457.

Background Uncertainty about the optimal respiratory support strategies in critically ill COVID-19 patients is widespread. While the risks and benefits of noninvasive techniques versus early invasive mechanical ventilation (IMV) are intensely debated, actual evidence is lacking. We sought to assess the risks and benefits of different respiratory support strategies, employed in intensive care units during the first months of the COVID-19 pandemic on intubation and intensive care unit (ICU) mortality rates. Methods Subanalysis of a prospective, multinational registry of critically ill COVID-19 patients. Patients were subclassified into standard oxygen therapy ≥10 L/min (SOT), high-flow oxygen therapy (HFNC), noninvasive positive-pressure ventilation (NIV), and early IMV, according to the respiratory support strategy employed at the day of admission to ICU. Propensity score matching was performed to ensure comparability between groups. Results Initially, 1421 patients were assessed for possible study inclusion. Of these, 351 patients (85 SOT, 87 HFNC, 87 NIV, and 92 IMV) remained eligible for full analysis after propensity score matching. 55% of patients initially receiving noninvasive respiratory support required IMV. The intubation rate was lower in patients initially ventilated with HFNC and NIV compared to those who received SOT (SOT: 64%, HFNC: 52%, NIV: 49%, p = 0.025). Compared to the other respiratory support strategies, NIV was associated with a higher overall ICU mortality (SOT: 18%, HFNC: 20%, NIV: 37%, IMV: 25%, p = 0.016). Conclusion In this cohort of critically ill patients with COVID-19, a trial of HFNC appeared to be the most balanced initial respiratory support strategy, given the reduced intubation rate and comparable ICU mortality rate. Nonetheless, considering the uncertainty and stress associated with the COVID-19 pandemic, SOT and early IMV represented safe initial respiratory support strategies. The presented findings, in agreement with classic ARDS literature, suggest that NIV should be avoided whenever possible due to the elevated ICU mortality risk.

ZusammenfassungTuberöse Sklerose („tuberous sclerosis complex“ [TSC]) ist eine seltene genetische Erkrankung, die neben kutanen und viszeralen Organmanifestationen typischerweise bereits in einem sehr frühen Erkrankungsstadium mit einer schweren, meist therapierefraktären Epilepsie einhergeht. Aufgrund seiner direkten Wirkung am durch TSC dysregulierten mTOR-Signalweg sowie der synergistischen Effekte auf andere Organmanifestationen kommt das Rapamycin-Derivat Everolimus (EVE) zunehmend zur Anwendung. Ziel dieses systematischen Reviews ist, die Wirksamkeit, Sicherheit und Verträglichkeit von EVE bei Patienten mit TSC-assoziierter, therapierefraktärer Epilepsie aufzuarbeiten.

Zusammenfassung Hintergrund Die stationäre Aufnahme von Patienten mit Prellungen wird in Kliniken der Akutversorgung regelhaft praktiziert. Dabei stehen die pathophysiologischen Unfallfolgen oft im Hintergrund. Ziel dieser retrospektiven monozentrischen Untersuchung war die Untersuchung der Ätiologie sowie der kostenverursachenden Faktoren und Refinanzierung bei Aufnahmen durch Prellungen. Methodik Es erfolgte die Abfrage der Patienten entsprechend den Entlassdiagnosen aus dem krankenhausinternen Informationssystem (KIS). Eingeschlossen wurden 117 Patienten in einem Zeitraum von 2 Jahren. Es erfolgten hier die Klassifizierung nach Unfallmechanismus sowie die Einteilung in Altersgruppen. Des Weiteren erfolgte die Kostenkalkulation anhand von abteilungs- und klinikspezifischen Tagessätzen. Ergebnisse Bezüglich der Ätiologie war der häusliche Sturz die häufigste Ursache (48,7 %), gefolgt von dem Hochrasanztrauma (22,8 %). Innerhalb der Gruppe des häuslichen Sturzes lag das Durchschnittsalter im Mittel bei 77,8 Jahre. Diese Gruppe zeigte die längste Verweildauer (VWD) mit 5,2 Tagen. Im Rahmen der kalkulierten Kosten zeigte die Gruppe nach häuslichem Sturz die höchsten Kosten mit 2596,24 € bei einem mittleren DRG-Erlös von 1464,51 €. Diskussion Die Auswertung der klinikinternen Daten bestätigte die subjektive Wahrnehmung, dass ein Großteil der nach Prellung aufgenommenen Patienten aus der Altersgruppe >65 Jahre stammt. Die Aufnahme erfolgt hier vor dem Hintergrund der in dieser Altersgruppe zunehmenden Komorbiditäten sowie zur Abwendung von Folgeerkrankungen und Folgen der Immobilisierung. Ebenfalls konnte gezeigt werden, dass die Versorgungskosten gesundheitsökomisch relevant sind und die Behandlung in diesen Fällen nicht kostendeckend ist.

BackgroundDespite improvements in the management of atrial fibrillation, patients with this condition remain at increased risk for cardiovascular complications. It is unclear whether early rhythm-control therapy can reduce this risk. MethodsIn this international, investigator-initiated, parallel-group, open, blinded-outcome-assessment trial, we randomly assigned patients who had early atrial fibrillation (diagnosed

The systematic analysis of disease-specific costs is becoming increasingly more relevant in an economically oriented healthcare system. Chronic diseases are of particular interest due to the long duration as well as frequent hospitalization and physician visits. Epilepsy is a frequent neurological disorder affecting all age groups with the clinical hallmark of paroxysmal epileptic seizures, which are often associated with injuries.The aim of this work was to process the inpatient treatment costs due to seizure-related injuries and fractures. Moreover, relevant cost-causing factors were addressed. Using an alternative calculation of the costs of care, the question of potential reimbursement problems in the current German diagnosis-related groups (G-DRG) system was additionally assessed.For this monocentric retrospective analysis the actual proceeds of 62 inpatients who were treated at the University Hospital Frankfurt between January 2010 and January 2018 for injuries and fractures due to epileptic seizures were used. The analysis of potential cost-causing factors was carried out with respect to relevant sociodemographic and clinical aspects. The alternative calculation of the costs of treatment was carried out using established health economic methods.The average DRG revenue was 7408€ (±8993€, median 5086€, range 563-44,519€), the average calculated costs were 9423€ (±11,113€, 5626€, range 587-49,830€). A length of stay ≥7 days (p = 0.014) was identified as a significant cost-driving factor. Due to the significant difference (p 0.001) between revenue and calculated costs, an analysis was made according to factors for potential reimbursement problems, which remained significant for a length of stay of ≥7 days (p = 0.014) and for treatment in the intensive care unit (p = 0.019).The inpatient treatment costs for patients with injuries and fractures due to epileptic seizures are high and therefore relevant from a health economic perspective. In general, reimbursement according to the G‑DRG appears to cover the actual costs, but there may be reimbursement problems for patients with a long period of hospitalization or a stay in an intensive care ward.HINTERGRUND: Die Analyse krankheitsspezifischer Kosten gewinnt in einem zunehmend ökonomisch ausgerichteten Gesundheitssystem an Relevanz, wobei vor allem chronische Erkrankungen aufgrund der langen Krankheitsdauer sowie häufiger Hospitalisierung und Arztbesuche von besonderem Interesse sind. Epilepsien stellen eine häufige neurologische Erkrankung dar, welche mit paroxysmal auftretenden epileptischen Anfällen und häufig hiermit assoziierten Verletzungen einhergeht und alle Altersgruppen betrifft. ZIEL: Ziel der Arbeit ist die Aufarbeitung der stationären Behandlungskosten anfallsbedingter Verletzungen sowie die Analyse hinsichtlich relevanter kostenverursachender Faktoren. Mittels alternativer Kalkulation der Versorgungskosten soll zusätzlich der Frage nach potenziellen Vergütungsproblemen im aktuellen DRG-System („diagnosis related groups“) nachgegangen werden.Grundlage dieser monozentrischen, retrospektiven Analyse ist der tatsächliche Erlös der stationären Behandlung von 62 Patienten, die zwischen 01/2010 und 01/2018 im Universitätsklinikum Frankfurt aufgrund von Verletzungen im Rahmen epileptischer Anfälle erfolgte. Die Analyse potenzieller kostenverursachender Faktoren bezog sich auf relevante soziodemographische und klinische Aspekte, die alternative Kalkulation der Versorgungskosten wurde mit gängigen gesundheitsökonomischen Methoden durchgeführt.Der mittlere DRG-Erlös betrug 7408 € (±8993 €, Median 5086 €, Spanne 563–44.519 €), die mittleren kalkulierten Kosten 9423 € (±11.113 €, 5626 €, Spanne 587–49.830 €). Als signifikant kostenverursachender Faktor konnte eine Liegedauer ≥7 Tage (p = 0,014) identifiziert werden. Aufgrund des signifikanten Unterschieds (p 0,001) zwischen Erlös und kalkulierten Kosten erfolgte eine Analyse nach Faktoren für potenzielle Vergütungsprobleme, welche für eine Aufenthaltsdauer von ≥7 Tagen (p = 0,014) sowie für eine Behandlung auf Intensivstation (p = 0,019) signifikant verblieb.Die stationären Versorgungskosten von Patienten mit Frakturen aufgrund epileptischer Anfälle sind hoch und daher gesundheitsökonomisch relevant. Generell scheint die auf Fallpauschalen basierende Vergütung nach G‑DRG die tatsächlichen Kosten zu decken, bei Patienten mit einer langen Liegedauer oder einen Aufenthalt auf Intensivstation können jedoch Vergütungsprobleme bestehen.

Objective To evaluate the incidence and risk factors of generalized convulsive seizure (GCS)-related fractures and injuries during video-EEG monitoring. Methods We analyzed all GCSs in patients undergoing video-EEG-monitoring between 2007 and 2019 at epilepsy centers in Frankfurt and Marburg in relation to injuries, falls and accidents associated with GCSs. Data were gathered using video material, EEG material, and a standardized reporting form. Results A total of 626 GCSs from 411 patients (mean age: 33.6 years; range 3–74 years; 45.0% female) were analyzed. Severe adverse events (SAEs) such as fractures, joint luxation, corneal erosion, and teeth loosening were observed in 13 patients resulting in a risk of 2.1% per GCS (95% CI 1.2–3.4%) and 3.2% per patient (95% CI 1.8–5.2%). Except for a nasal fracture due to a fall onto the face, no SAEs were caused by falls, and all occurred in patients lying in bed without evidence of external trauma. In seven patients, vertebral body compression fractures were confirmed by imaging. This resulted in a risk of 1.1% per GCS (95% CI 0.5–2.2%) and 1.7% per patient (95% CI 0.8–3.3%). These fractures occurred within the tonic phase of a GCS and were accompanied by a characteristic cracking noise. All affected patients reported back pain spontaneously, and an increase in pain on percussion of the affected spine section. Conclusions GCSs are associated with a substantial risk of fractures and shoulder dislocations that are not associated with falls. GCSs accompanied by audible cracking, and resulting in back pain, should prompt clinical and imaging evaluations.

Background: Refractory status epilepticus (RSE) represents a serious medical condition requiring early and targeted therapy. Given the increasing number of elderly or multimorbid patients with a limitation of life-sustaining therapy (LOT) or within a palliative care setting (PCS), guidelines-oriented therapy escalation options for RSE have to be omitted frequently. Objectives: This systematic review sought to summarize the evidence for fourth-line antiseizure drugs (ASDs) and other minimally or non-invasive therapeutic options beyond guideline recommendations in patients with RSE to elaborate on possible treatment options for patients undergoing LOT or in a PCS. Methods: A systematic review of the literature in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, focusing on fourth-line ASDs or other minimally or non-invasive therapeutic options was performed in February and June 2020 using the MEDLINE, EMBASE and Cochrane databases. The search terminology was constructed using the name of the specific ASD or therapy option and the term ‘status epilepticus’ with the use of Boolean operators, e.g. “(brivaracetam) AND (status epilepticus)”. The respective Medical Subject Headings (MeSH) and Emtree terms were used, if available. Results: There is currently no level 1, grade A evidence for the use of ASDs in RSE. The best evidence was found for the use of lacosamide and topiramate (level 3, grade C), followed by brivaracetam, perampanel (each level 4, grade D) and stiripentol, oxcarbazepine and zonisamide (each level 5, grade D). Regarding non-medicinal options, there is little evidence for the use of the ketogenic diet (level 4, grade D) and magnesium sulfate (level 5, grade D) in RSE. The broad use of immunomodulatory or immunosuppressive treatment options in the absence of a presumed autoimmune etiology cannot be recommended; however, if an autoimmune etiology is assumed, steroid pulse, intravenous immunoglobulins and plasma exchange/plasmapheresis should be considered (level 4, grade D). Even if several studies suggested that the use of neurosteroids (level 5, grade D) is beneficial in RSE, the current data situation indicates that there is formal evidence against it. Conclusions: RSE in patients undergoing LOT or in a PCS represents a challenge for modern clinicians and epileptologists. The evidence for the use of ASDs in RSE beyond that in current guidelines is low, but several effective and well-tolerated options are available that should be considered in this patient population. More so than in any other population, advance care planning, advance directives, and medical ethical aspects have to be considered carefully before and during therapy.

Context: The detection and characterization of Earth-like exoplanets (exoEarths) from space requires exquisite wavefront stability at contrast levels of $10^{-10}$. On segmented telescopes in particular, aberrations induced by cophasing errors lead to a light leakage through the coronagraph, deteriorating the imaging performance. These need to be limited in order to facilitate the direct imaging of exoEarths. Aims: We perform a laboratory validation of an analytical tolerancing model that allows us to determine wavefront error requirements in the $10^{-6} - 10^{-8}$ contrast regime, for a segmented pupil with a classical Lyot coronagraph. We intend to compare the results to simulations, and we aim to establish an error budget for the segmented mirror on the High-contrast imager for Complex Aperture Telescopes (HiCAT) testbed. Methods: We use the Pair-based Analytical model for Segmented Telescope Imaging from Space (PASTIS) to measure a contrast influence matrix of a real high contrast instrument, and use an analytical model inversion to calculate per-segment wavefront error tolerances. We validate these tolerances on the HiCAT testbed by measuring the contrast response of segmented mirror states that follow these requirements. Results: The experimentally measured optical influence matrix is successfully measured on the HiCAT testbed, and we derive individual segment tolerances from it that correctly yield the targeted contrast levels. Further, the analytical expressions that predict a contrast mean and variance from a given segment covariance matrix are confirmed experimentally., Comment: 16 pages, 16 figures, accepted for publication in A&A

In einem zunehmend okonomisch ausgerichteten Gesundheitssystem gewinnt die Analyse krankheitsspezifischer Kosten zunehmend an Relevanz, insbesondere bei chronischen Erkrankungen mit langer Krankheitsdauer. Als haufige neurodegenerative Erkrankung verursacht das idiopathische Parkinson-Syndrom (IPS) hohe Versorgungskosten. Durch die pathognomonische Affektion von Mobilitat und Gleichgewicht kommt es im Laufe der Erkrankung haufig zu sturzbedingten Frakturen, die durch Hospitalisierung und ggf. operative Sanierung weitere Kosten verursachen. Ziel der Arbeit ist die Aufarbeitung stationarer Behandlungskosten sturzbedingter Frakturen bei IPS sowie die Analyse hinsichtlich relevanter kostenverursachender Faktoren. Zudem erfolgt eine alternative Kalkulation der Versorgungskosten mit der Frage nach potenziellen Vergutungsproblemen im aktuellen DRG-System. Grundlage dieser retrospektiven, monozentrischen Analyse ist der tatsachliche Erlos bei 95 Patienten, die zwischen 01/2011 und 01/2018 im Universitatsklinikum Frankfurt am Main behandelt wurden. Der Erlos wurde systematisch nach relevanten demographischen, versorgungsspezifischen und krankheitsbezogenen Aspekten aufgearbeitet und statistisch mittels univariater Analyse auf kostenverursachende Faktoren untersucht. Die alternative Kalkulation der Behandlungskosten erfolgte nach gangigen gesundheitsokonomischen Methoden. Der mittlere Erlos pro Fall und Verletzung betrug 9295 € (±8038 €, Median 7148 €) bei einer mittleren Verweildauer von 13,5 Tagen (±7,2 Tage, Median 13 Tage). Die alternative Kalkulation der Behandlungskosten belief sich pro Patienten im Mittel auf 9789 € (±6423 €, Median 8906 €). Hohe Behandlungskosten waren assoziiert mit einem Alter >75 Jahre (p = 0,028), einer operativen Versorgung (p = 0,004), einem Aufenthalt auf Intensivstation (p = 0,004), einer Fraktur der Extremitaten (p = 0,028) sowie einem fortgeschrittenen Erkrankungsstadium des IPS (p = 0,028). Signifikante Unterschiede zwischen tatsachlichem Erlos und kalkulierten Kosten ergaben sich bei Krankenhausaufenthalten von ≥14 Tagen (p = 0,009) sowie fortgeschrittenem Erkrankungsstadium (p = 0,036). Die Versorgungskosten bei Patienten mit IPS und sturzbedingten Frakturen sind hoch und gesundheitsokonomisch relevant. Generell scheint die auf Fallpauschalen basierende Vergutung der Kosten uberwiegend kostendeckend, insbesondere Patienten mit langer Liegedauer oder fortgeschrittenem IPS werden im DRG-System nicht genugend abgebildet.

Many people experience mild stress in modern society which raises the need for an improved understanding of psychophysiological responses to stressors. Heart rate variability (HRV) may be associated with a flexible network of intricate neural structures which are dynamically organized to cope with diverse challenges. HRV was obtained in thirty-three healthy participants performing a cognitive task both with and without added stressors. Markers of neural autonomic control and neurovisceral complexity (entropy) were computed from HRV time series. Based on individual anxiety responses to the experimental stressors, two subgroups were identified: anxiety responders and non-responders. While both vagal and entropy markers rose during the cognitive task alone in both subgroups, only entropy decreased when stressors were added and exclusively in anxiety responders. We conclude that entropy may be a promising marker of cognitive tasks and acute mild stress. It brings out a new central question: why is entropy the only marker affected by mild stress? Based on the neurovisceral integration model, we hypothesized that neurophysiological complexity may be altered by mild stress, which is reflected in entropy of the cardiac output signal. The putative role of the amygdala during mild stress, in modulating the complexity of a coordinated neural network linking brain to heart, is discussed.

Coupled slope and scintillation detection and ranging (CO-SLIDAR) is a very promising technique for the metrology of near ground C n 2 profiles. It exploits both phase and scintillation measurements obtained with a dedicated wavefront sensor and allows profiling on the full line of sight between pupil and sources. This technique is applied to an associated instrument based on a mid-IR Shack–Hartmann wavefront sensor coupled to a 0.35 m telescope, which observes two cooperative sources. This paper presents what we believe is the first comprehensive description of the CO-SLIDAR method in the context of near-ground optical turbulence metrology. It includes the presentation of the physics principles underlying the measurements of our unsupervised C n 2 profile reconstruction strategy together with the error bar estimation on the reconstructed values. The application to data acquired in a heterogeneous rural landscape during an experimental campaign in Lannemezan, France, demonstrates the ability to obtain profiles with a sampling pitch of about 220 m over a 2.7 km line of sight. The retrieved C n 2 profiles are presented and their variability in space and time is discussed.

Effective and accurate in-vivo diagnosis of retinal pathologies requires high performance imaging devices, combining a large field of view and the ability to discriminate the ballistic signal from the diffuse background in order to provide a highly contrasted image of the retinal structures. Here, we have implemented the Partial-Field Illumination Ophthalmoscope, a patterned illumination modality, integrated on a high pixel rate adaptive optics full-field microscope. This non-invasive technique enables us to mitigate the low signal-to-noise ratio, intrinsic of full-field ophthalmoscopes, by partially illuminating the retina with complementary patterns to reconstruct a wide field image. This new modality provides an image contrast spanning from the full-field to the confocal contrast, depending on the pattern size. As a result, it offers various trade-offs in terms of contrast and acquisition speed, guiding the users towards the most efficient system for a particular clinical application., 6 pages, 5 figures

Introduction The wearable cardioverter defibrillator (WCD) uses surface electrodes built into the vest to detect underlying arrhythmia before initiating a treatment sequence. However, it is also prone to inappropriate detection due to artefacts. Purpose The aim of this study was to assess the alarm burden in patients and its possible impact on clinical outcomes. Methods The Swiss WCD Registry is a nationwide, retrospective, observational registry. Patients were included from December 2011 until February 2018. Clinical characteristics and data from the WCDs, including alarm burden were analysed. Recordings ≥30 seconds of length were analysed and categorized as VT/VF, atrial fibrillation (AF), supraventricular tachycardia or artefact. Results A total of 10'653 device alarms were documented in 324 of 456 patients (71.1%) over a mean WCD wear-time of 2.0±1.6 months. Among these, the episode duration was 30 seconds or more in 2996 (28.2%). One hundred and eleven (3.7%) were VT/VF episodes. The remaining recordings were inappropriate arrhythmia detections (2736 (91%) due to artefacts; 117 (3.7%) AF; 48 (1.6%) supraventricular tachycardia). Two-hundred and seven patients (45.0%) had 3 or more alarms per month, whereas 49 patients (10.7%) had 1 or more alarms per day. Body mass index (BMI) was significantly higher in patients with 3 or more alarms per month (p=0.002, 25.6 vs. 27.3 kg/m2) High alarm burden was not associated with a lower average daily wear time (20.8 hours vs 20.7 hours, p=0.785) or a decreased implantable cardioverter defibrillator implantation rate after stopping WCD use (48% vs 47.3%, p=0.156). Conclusions In patients using WCDs, alarms emitted by the device and impending inappropriate shocks were frequent and most commonly caused by artefacts. A high alarm burden did not lead to a decreased adherence, as determined by average daily wear-times. Obesity was significantly associated with a higher alarm burden. Funding Acknowledgement Type of funding sources: None.

Inertial measurement unit sensors (IMU, i.e., accelerometer, gyroscope and magnetometer combinations) are frequently fitted to animals to better understand their activity patterns and energy expenditure. Capable of recording hundreds of data points a second, these sensors can quickly produce large datasets that require methods to automate behavioral classification. Here, we describe behaviors derived from a custom-built multi-sensor bio-logging tag attached to Atlantic Goliath grouper (Epinephelus itajara) within a simulated ecosystem. We then compared the performance of two commonly applied machine learning approaches (random forest and support vector machine) to a deep learning approach (convolutional neural network, or CNN) for classifying IMU data from this tag. CNNs are frequently used to recognize activities from IMU data obtained from humans but are less commonly considered for other animals. Thirteen behavioral classes were identified during ethogram development, nine of which were classified. For the conventional machine learning approaches, 187 summary statistics were extracted from the data, including time and frequency domain features. The CNN was fed absolute values obtained from fast Fourier transformations of the raw tri-axial accelerometer, gyroscope and magnetometer channels, with a frequency resolution of 512 data points. Five metrics were used to assess classifier performance, the deep learning approach performed better across all metrics (Sensitivity = 0.962, Specificity = 0.996, F1-score = 0.962, Matthew’s Correlation Coefficient = 0.959, Cohen’s Kappa = 0.833) than both conventional machine learning approaches. Generally, the random forest performed better than the support vector machine. In some instances, a conventional learning approach yielded a higher performance metric for particular classes (e.g., the random forest had a F1-score of 0.971 for backward swimming compared to 0.955 for the CNN). Deep learning approaches could potentially improve behavioral classification from IMU data, beyond that obtained from conventional machine learning methods.

Objective This study was undertaken to evaluate the long-term efficacy, retention, and tolerability of add-on brivaracetam (BRV) in clinical practice. Methods A multicenter, retrospective cohort study recruited all patients who initiated BRV between February and November 2016, with observation until February 2021. Results Long-term data for 262 patients (mean age = 40 years, range = 5-81 years, 129 men) were analyzed, including 227 (87%) diagnosed with focal epilepsy, 19 (7%) with genetic generalized epilepsy, and 16 (6%) with other or unclassified epilepsy syndromes. Only 26 (10%) patients had never received levetiracetam (LEV), whereas 133 (50.8%) were switched from LEV. The length of BRV exposure ranged from 1 day to 5 years, with a median retention time of 1.6 years, resulting in a total BRV exposure time of 6829 months (569 years). The retention rate was 61.1% at 12 months, with a reported efficacy of 33.1% (79/239; 50% responder rate, 23 patients lost-to-follow-up), including 10.9% reported as seizure-free. The retention rate for the entire study period was 50.8%, and at last follow-up, 133 patients were receiving BRV at a mean dose of 222 ± 104 mg (median = 200, range = 25-400), including 52 (39.1%) who exceeded the recommended upper dose of 200 mg. Fewer concomitant antiseizure medications and switching from LEV to BRV correlated with better short-term responses, but no investigated parameters correlated with positive long-term outcomes. BRV was discontinued in 63 (24%) patients due to insufficient efficacy, in 29 (11%) for psychobehavioral adverse events, in 25 (10%) for other adverse events, and in 24 (9%) for other reasons. Significance BRV showed a clinically useful 50% responder rate of 33% at 12 months and overall retention of >50%, despite 90% of included patients having previous LEV exposure. BRV was well tolerated; however, psychobehavioral adverse events occurred in one out of 10 patients. Although we identified short-term response and retention predictors, we could not identify significant predictors for long-term outcomes.

BACKGROUND The objective of the STREAM Trial was to evaluate the effect of simulation training on process times in acute stroke care. METHODS The multicenter prospective interventional STREAM Trial was conducted between 10/2017 and 04/2019 at seven tertiary care neurocenters in Germany with a pre- and post-interventional observation phase. We recorded patient characteristics, acute stroke care process times, stroke team composition and simulation experience for consecutive direct-to-center patients receiving intravenous thrombolysis (IVT) and/or endovascular therapy (EVT). The intervention consisted of a composite intervention centered around stroke-specific in situ simulation training. Primary outcome measure was the 'door-to-needle' time (DTN) for IVT. Secondary outcome measures included process times of EVT and measures taken to streamline the pre-existing treatment algorithm. RESULTS The effect of the STREAM intervention on the process times of all acute stroke operations was neutral. However, secondary analyses showed a DTN reduction of 5 min from 38 min pre-intervention (interquartile range [IQR] 25-43 min) to 33 min (IQR 23-39 min, p = 0.03) post-intervention achieved by simulation-experienced stroke teams. Concerning EVT, we found significantly shorter door-to-groin times in patients who were treated by teams with simulation experience as compared to simulation-naive teams in the post-interventional phase (-21 min, simulation-naive: 95 min, IQR 69-111 vs. simulation-experienced: 74 min, IQR 51-92, p = 0.04). CONCLUSION An intervention combining workflow refinement and simulation-based stroke team training has the potential to improve process times in acute stroke care.

Ocean current, fluid mechanics, and many other physical systems with spatio-temporal dynamics are essential components of the universe. One key characteristic of such systems is that they can be represented by certain physics laws, such as ordinary/partial differential equations (ODEs/PDEs), irrespective of time or location. Physics-informed machine learning has recently emerged to learn physics from data for accurate prediction, but they often lack a mechanism to leverage localized spatial and temporal correlation or rely on hard-coded physics parameters. In this paper, we advocate a physics-coupled neural network model to learn parameters governing the physics of the system, and further couple the learned physics to assist the learning of recurring dynamics. Here a spatio-temporal physics-coupled neural network (ST-PCNN) model is proposed to achieve three goals: (1) learning the underlying physics parameters, (2) transition of local information between spatio-temporal regions, and (3) forecasting future values for the dynamical system. The physics-coupled learning ensures that the proposed model can be tremendously improved by using learned physics parameters, and can achieve useful long-range forecasting (e.g., more than two weeks). Experiments using simulated wave propagation and field-collected ocean current data validate that ST-PCNN outperforms typical deep learning models and existing physics-informed models.

Background The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. Conclusions From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.

Aims Treatment patterns were compared between randomized groups in EAST-AFNET 4 to assess whether differences in anticoagulation, therapy of concomitant diseases, or intensity of care can explain the clinical benefit achieved with early rhythm control in EAST-AFNET 4. Methods and results Cardiovascular treatment patterns and number of visits were compared between randomized groups in EAST-AFNET 4. Oral anticoagulation was used in >90% of patients during follow-up without differences between randomized groups. There were no differences in treatment of concomitant conditions between groups. The type of rhythm control varied by country and centre. Over time, antiarrhythmic drugs were given to 1171/1395 (84%) patients in early therapy, and to 202/1394 (14%) in usual care. Atrial fibrillation (AF) ablation was performed in 340/1395 (24%) patients randomized to early therapy, and in 168/1394 (12%) patients randomized to usual care. 97% of rhythm control therapies were within class I and class III recommendations of AF guidelines. Patients randomized to early therapy transmitted 297 166 telemetric electrocardiograms (ECGs) to a core lab. In total, 97 978 abnormal ECGs were sent to study sites. The resulting difference between study visits was low (0.06 visits/patient/year), with slightly more visits in early therapy (usual care 0.39 visits/patient/year; early rhythm control 0.45 visits/patient/year, P Conclusion The clinical benefit of early, systematic rhythm control therapy was achieved using variable treatment patterns of antiarrhythmic drugs and AF ablation, applied within guideline recommendations.

Optical diagnostics of gas-phase pressure are relatively unusual. In this work, we demonstrate a novel, rapid, and robust method to use laser-induced grating scattering (LIGS) to derive this property in real time. Previous pressure measurements with LIGS have employed a signal fitting method, but this is relatively time-consuming and requires specialist understanding. In this paper, we directly measure a decay lifetime from a LIGS signal and then employ a calibration surface constructed using a physics-based model to convert this value to pressure. This method was applied to an optically accessible single-cylinder internal combustion engine, yielding an accuracy of better than 10% at all tested conditions above atmospheric pressure. This new approach complements the existing strength of LIGS in precisely and accurately deriving temperature with a simple analysis method, by adding pressure information with a similarly simple method.

Background Tuberous sclerosis complex (TSC) is a monogenetic, multisystemic disease characterised by the formation of benign tumours that can affect almost all organs, caused by pathogenic variations in TSC1 or TSC2. In this multicentre study from Germany, we investigated the influence of sociodemographic, clinical, and therapeutic factors on quality of life (QoL) among individuals with TSC. Methods We assessed sociodemographic and clinical characteristics and QoL among adults with TSC throughout Germany using a validated, three-month, retrospective questionnaire. We examined predictors of health-related QoL (HRQoL) using multiple linear regression analysis and compared the QoL among patients with TSC with QoL among patients with other chronic neurological disorders. Results We enrolled 121 adults with TSC (mean age: 31.0 ± 10.5 years; range: 18–61 years, 45.5% [n = 55] women). Unemployment, a higher grade of disability, a higher number of organ manifestations, the presence of neuropsychiatric manifestations or active epilepsy, and a higher burden of therapy-related adverse events were associated with worse QoL, as measured by two QoL instruments (EuroQoL-5 dimensions [EQ-5D] and Quality of Life in Epilepsy Patients [QOLIE-31]). Neuropsychiatric and structural nervous system manifestations, the number of affected organs, and therapy-related adverse events were also associated with higher depression, as measured by the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). In multiple regression analysis, more severe therapy-related adverse events (large effect, p p p = 0.003) were independently associated with worse HRQoL, explaining 65% of the variance (p p Conclusions Active epilepsy, neuropsychiatric manifestations (such as anxiety and depression), and therapy-related adverse events are important independent predictors of worse quality of life among adults with TSC. Generic quality of life in TSC with several manifestations is similar to uncontrolled severe chronic diseases and significantly negatively correlates with TSC severity. Trial registration DRKS, DRKS00016045. Registered 01 March 2019.

The primary aim of this study was to analyze the frequency and characteristic patterns of fall-related fractures as well as consecutive hospitalization and management relating to such fractures. In addition, important pathognomonic and therapeutic aspects are discussed. This retrospective mono-center study was conducted at the University Hospital Frankfurt am Main, Germany. Between 2007 and 2017, a total of 145 PD patients with fall-related fractures were identified via a retrospective systematic query in the hospital information system using the ICD-10 German modification codes G20.0–G20.9. Patients with unclear or falsely coded PD were strictly excluded. The mean age of the cohort was 77.7 years (± 7.5, median 77.) and 57.9% of the cohort were females (n = 84). A total number of 151 fractures were reported, with 140 patients (96.6%) suffering from one, four patients from two (2.8%), and one patient from three fractures (0.6%) at a time. For 43.9% (n = 65) of the cohort, fractures concerned lower extremities (LE) followed by trunk (38.1%, n = 58) and upper extremities (UE, 17.9%, n = 27). Most common fracture types in LE were femoral neck fractures (52.3%, n = 34). Mean length of hospital stay (LOS) was 13.6 days (95% CI 12.4–14.7). In 43.4% (n = 63) of cases, an interim admission to an intensive-care unit (ICU) was necessary. Mean ICU LOS was 2.3 days (95% CI 1.5–3.0), and mean LOS for normal care unit was 10.5 days (95% CI 10.3–12.4). Surgical treatment was necessary in 75.9% of the cases (n = 110). Patients undergoing surgical treatment showed significantly longer LOS compared to conservatively treated patients (p

In this paper, a method is introduced for the classification of call types of red hind grouper, an important fishery resource in the Caribbean that produces sounds associated with reproductive behaviors during yearly spawning aggregations. For the undertaken task, two distinct call types of red hind are analyzed. An ensemble of stacked autoencoders (SAEs) is then designed by randomly selecting the hyperparameters of SAEs in the network. These hyperparameters include a number of hidden layers in each SAE and a number of nodes in each hidden layer. Spectrograms of red hind calls are used to train this randomly generated ensemble of SAEs one at a time. Once all individual SAEs are trained, this ensemble is used as a whole to classify call types of red hind. More specifically, the outputs of individual SAEs are combined with a fusion mechanism to produce a final decision on the call type of the input red hind sound. Experimental results show that the innovative approach produces superior results in comparison with those obtained by non-ensemble methods. The algorithm reliably classified red hind call types with over 90% accuracy and successfully detected some calls missed by human observers.

Quasi-static aberrations in coronagraphic systems are the ultimate limitation to the capabilities of exoplanet imagers both ground-based and space-based. These aberrations - which can be due to various causes such as optics alignment or moving optical parts during the observing sequence - create light residuals called speckles in the focal plane that might be mistaken for a planets. For ground-based instruments, the presence of residual turbulent wavefront errors due to partial adaptive optics correction causes an additional difficulty to the challenge of measuring aberrations in the presence of a coronagraph. In this paper, we present an extension of COFFEE, the coronagraphic phase diversity, to the estimation of quasi-static aberrations in the presence of adaptive optics-corrected residual turbulence. We perform realistic numerical simulations to assess the performance that can be expected on an instrument of the current generation. We perform the first experimental validation in the laboratory which demonstrates that quasistatic aberrations can be corrected during the observations by means of coronagraphic phase diversity., Comment: This is a pre-copyedited, author-produced PDF of an article accepted for publication in the Monthly Notices of the Royal Astronomical Society following peer review

Introduction: Antiseizure drugs (ASDs) play a central and crucial role in the treatment of epilepsy patients, as the majority require anticonvulsant treatment for an extended period of time. Since up to 30% of patients are refractory to medical treatment, new therapeutic options are necessary. Perampanel (PER) and brivaracetam (BRV) are the latest approved ASDs that may be considered in a variety of epilepsy syndromes. PER has a distinct and selective mode of action on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors and is licensed for use in focal and generalized epilepsies. BRV is a derivative of levetiracetam but exhibits a 20-fold higher affinity and a faster brain entry time as a synaptic vesicle glycoprotein 2A (SV2A) ligand. Areas covered: This article reviews the advances in the epileptic treatment and provides a comparison of PER and BRV. Both drugs have shown comparable results in randomized controlled trials, and both are well tolerated. Expert opinion: PER and BRV have the potential to perform as important, broad-spectrum ASDs with significant market shares. BRV's intravenous formulation and fast penetration into the brain and PER's unique mode of action will result in the more frequent use of both drugs in status epilepticus.

Introduction Stereoelectroencephalography (sEEG) is a diagnostic procedure for patients with refractory focal epilepsies that is performed to localize and define the epileptogenic zone. In contrast to grid electrodes, sEEG electrodes are implanted using minimal invasive operation techniques without large craniotomies. Previous studies provided good evidence that sEEG implantation is a safe and effective procedure; however, complications in asymptomatic patients after explantation may be underreported. The aim of this analysis was to systematically analyze clinical and imaging data following implantation and explantation. Results We analyzed 18 consecutive patients (mean age: 30.5 years, range: 12–46; 61% female) undergoing invasive presurgical video-EEG monitoring via sEEG electrodes (n = 167 implanted electrodes) over a period of 2.5 years with robot-assisted implantation. There were no neurological deficits reported after implantation or explantation in any of the enrolled patients. Postimplantation imaging showed a minimal subclinical subarachnoid hemorrhage in one patient and further workup revealed a previously unknown factor VII deficiency. No injuries or status epilepticus occurred during video-EEG monitoring. In one patient, a seizure-related asymptomatic cross break of two fixation screws was found and led to revision surgery. Unspecific symptoms like headaches or low-grade fever were present in 10 of 18 (56%) patients during the first days of video-EEG monitoring and were transient. Postexplantation imaging showed asymptomatic and small bleedings close to four electrodes (2.8%). Conclusion Overall, sEEG is a safe and well-tolerated procedure. Systematic imaging after implantation and explantation helps to identify clinically silent complications of sEEG. In the literature, complication rates of up to 4.4% in sEEG and in 49.9% of subdural EEG are reported; however, systematic imaging after explantation was not performed throughout the studies, which may have led to underreporting of associated complications.

Die Diagnose einer Epilepsie geht haufig mit relevanten Einschrankungen fur Patienten einher, wodurch eine Vielzahl verschiedener Probleme entstehen konnen, die einer gezielten und professionellen Beratung bedurfen. Seit 1996 existieren in einigen Bundeslandern spezialisierte Epilepsieberatungsstellen (EBS), die in solchen Fallen als Anlaufstelle dienen sollen. Ziel dieser prospektiven, multizentrischen Kohortenstudie an sechs EBS in Hessen und Unterfranken war es, Akzeptanz, Nachfrage und haufige Konsultationsgrunde von EBS zu erfassen und zu analysieren. Insgesamt wurden uber 12 Monate (06/2014 bis 05/2015) 435 Klienten, hiervon 74,3 % Erwachsene (n = 323, mittleres Alter 40,3 ± 14,7 Jahre; Spannweite 18–76 Jahre, 51,7 % weiblich) und 25,7 % Kinder und Jugendliche (n = 112, mittleres Alter 9,4 ± 4,8 Jahre; Spannweite 1–17 Jahre, 52,7 % weiblich) eingeschlossen. Im Mittel wurden 2,5 (Median 2,0; SD ± 2,8, Spannweite 1–20) ambulante Vorstellungen an EBS pro Jahr angegeben, wobei eine allgemeine Beratung zum Umgang mit Epilepsie (Erwachsene 55,7 %, Kinder 51,8 %), Aufklarung und Information uber die Erkrankung (43,7 % bzw. 41,1 %) und Hilfe bei der Beantragung von Hilfsleistungen (39,0 % bzw. 46,4 %) die haufigsten Vorstellungsgrunde waren. Die Distanz zwischen Wohnort und EBS war in Bayern signifikant kurzer als in Hessen (p

Objective: The aim of the present study was to assess the predictive value of the CHADS2, CHA2DS2-VASc, R2CHADS2, and APPLE scores for rhythm outcome in patients with atrial fibrillation (AF) after catheter ablation. Methods: The cohort of the present study consisted of 192 patients with AF who underwent a total of 265 ablations. Rhythm outcome was documented between 3 and 24 month after ablation. The mentioned scores were calculated for every patient. Results: Of the patients, 139 (72%) were successfully treated having freedom of any atrial tachyarrhythmia, whereas 21 (11%) had partial success, and 32 (17%) had failure. For univariate analysis, the APPLE score was the only significant predictor of outcome after ablation with an odds ratio (OR) of 1.485 [95% confidence interval (CI) 1.075–2.052, p-value 0.017]. A multivariate binary regression corrected for possible confounders showed that the APPLE score (OR 1.527, 95% CI 1.082–2.153, p-value 0.016) along with the number of previous ablations (OR 5.831, 95% CI 1.356–25.066, p-value 0.018) is a significant predictor of outcome. A novel score (SUCCESS) was created by adding one point to the APPLE score for each previously performed ablation. This novel score demonstrated an improvement in receiver operating characteristic curve analysis (area under the curve 0.657 vs. 0.620). However, these findings were not significant in our study (p-value 0.219). Conclusion: Both the APPLE and the novel SUCCESS scores are superior to the CHADS2, CHA2DS2-VASc, and R2CHADS2 scores in predicting AF recurrence after catheter ablation. The SUCCESS score appears to have a higher predictive value than the APPLE score and might be a valuable tool to estimate the risk of AF recurrence in patients eligible for catheter ablation.

Introduction This multicenter, retrospective study aimed to evaluate the efficiency, retention, safety, and tolerability of brivaracetam (BRV) in children and adolescents with focal epilepsy. Methods All patients aged ≤ 17 years with focal epilepsy who started BRV in 2016 and 2017 were analyzed. Results Thirty-four patients (mean age: 12.2 years, range: 3–17 years, 56% female) were treated with BRV for 25 days to 24 months, with a total exposure time of 19.7 years. Overnight switch from levetiracetam (LEV) to BRV was performed in 20 patients at a median ratio of 10:1. Retention rate was 97% at three months, with only one patient reporting a discontinuation of BRV treatment. Further dropouts were reported in one patient after seven months and in two patients after one year of treatment, respectively. The median length of exposure to BRV was 180 days. Efficacy at three months was 47% (50% responder rate), with 10 patients (29%) reporting seizure freedom. A long-term 50% responder rate was present in 12 patients [35%; four patients seizure-free (12%)] for more than six months and in seven patients (21%; no seizure-free patients) for more than 12 months. Treatment-emergent adverse events were observed in 12% of patients, with the most common being sedation, somnolence, loss or gain of appetite, and psychobehavioral adverse events. Conclusions Use of BRV in children and adolescents seems to be safe and well-tolerated. The results with 50% responder rate of 47% are consistent with those from randomized controlled trials and postmarketing studies in adults. An immediate switch from LEV to BRV at a ratio of 10:1 is feasible. The occurrence of psychobehavioral adverse events seems less prominent than under LEV and a switch to BRV can be considered in patients with LEV-induced adverse events.

BackgroundVaccines against SARS-CoV-2 are still urgently needed as only 5% of the global population has been vaccinated. Here we report the safety and immunogenicity of a DNA vaccine (INO-4800) targeting the full-length Spike antigen of SARS-CoV-2 when given to adults at high-risk of exposure.MethodsINO-4800 was evaluated in 401 participants randomized at a 3:3:1:1 ratio to receive either INO-4800 (1 mg or 2 mg dose) or placebo (1 or 2 injections) intradermally (ID) followed by electroporation (EP) using CELLECTRA® 2000 at Days 0 and 28. ClinicalTrials.gov Identifier:NCT04642638FindingsThe majority of adverse events (AEs) were of Grade 1 and 2 in severity and did not appear to increase in frequency with the second dose. The number of participants experiencing each of the most common AEs did not differ appreciably between the two dosing groups. The geometric mean fold rise (GMFR) of binding and neutralizing antibody levels were statistically significantly greater in the 2.0 mg dose group versus the 1.0 mg dose group. The T cell immune responses measured by the ELISpot assay were also higher in the 2.0 mg dose group compared to the 1.0 mg dose group.InterpretationINO-4800 at both the 1.0 mg and 2.0 mg doses when administered in a 2-dose regimen appeared to be safe and well-tolerated in all adult ages. However, the comparative immunogenicity analysis favored selection of INO-4800 2.0 mg dose for advancement into a Phase 3 efficacy evaluation.FundingThe trial was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological and Nuclear Defense, (JPEO-CBRND) in coordination with the Office of the Assistant Secretary of Defense for Health Affairs (OASD(HA)) and the Defense Health Agency.Research in contextINO-4800 is among several vaccines being tested against SARS-CoV-2, the virus that causes COVID-19 with the goal of inducing a protective immune response. The DNA vaccine, INO-4800, administered by ID injection followed by electroporation (EP) using the CELLECTRA®2000 device, induces a balanced immune response that includes engagement of both T cells and B1-5.Added value of this studyThis is the first report of a randomized, blinded, placebo-controlled clinical trial of INO-4800, a DNA vaccine targeting the SARS-CoV-2 Spike antigen delivered ID followed by EP, in adults at high risk of SARS-CoV-2 exposure.

Robotic guidance might be an alternative to classic stereotaxy for biopsies of intracranial lesions. Both methods were compared regarding time efficacy, histopathological results and complications.A retrospective analysis enrolling all patients undergoing robotic- or stereotactic biopsies between 01/2015 and 12/2018 was conducted. Trajectory planning was performed on magnetic resonance imaging (MRI). With the Robotic Surgery Assistant (ROSA), patient registration was accomplished using a facial laser scan in the operating room (OR), immediately followed by biopsy. In stereotaxy, patients were transported to the CT for Leksell Frame registration, followed by biopsy in the OR.The average overall procedure time amounted in robotics to 169 min and in stereotaxy to 179 min (p = 0.005). The difference was greatest for temporal targets, amounting in robotics to 161 min and in stereotaxy to 188 min (p = 0,0007). However, the average time spent purely in the OR amounted in robotics to 140 min and in stereotaxy to 113 min (p 0.001). In 150 robotic biopsies, diagnostic yield amounted to 98%, in 266 stereotactic biopsies to 91%. Symptomatic postoperative hemorrhages were observed in 3 patients (2%) in robotic biopsy and 7 patients (2,7%) in stereotactic biopsy.Robotics showed a shorter overall procedure time as there is no need for a transport to the CT whereas the pure OR time was shorter in stereotaxy due to skipping the laser registration process. Diagnostic yield was higher in robotics, most likely due to case selection, complication rates were equal.

Purpose Epileptic seizures frequently result in distinct physical injuries, fractures, traumatic brain injuries and minor trauma. The aim of this study was to retrospectively determine the frequent injury patterns due to seizure episode and to analyze consecutive acute medical care. Methods This retrospective mono-center study was conducted at Frankfurt University Hospital, Frankfurt am Main, Germany between January 2007 and December 2017. Epilepsy patients with seizure-related fractures admitted to the emergency department were identified via a retrospective systematic query in the hospital information system using the ICD-10 German modification codes G40.0–G40.9. Patients with an unclear diagnosis of epilepsy were excluded. Sociodemographic as well as disease specific aspects were analyzed. Descriptive and Kruskal–Wallis one-way analysis of variance were used for statistical analysis. Results A total number of 62 epilepsy patients were included. The mean age was 58.1 years. Fractures concerned the upper extremity most frequently (43.5%, n = 20), and 70.0% (14/20) were humerus fractures. Admission to intensive care unit for acute trauma care was necessary in 29.0% patients (n = 18), and surgery in 45.2% patients (n = 28). Twenty-five patients (26.6%) showed clinical or radiological signs of traumatic brain injury. Provoking factors were identified in 20 patients (32.3%), i.e., acute withdrawal or excess of alcohol (n = 15), relevant sleep deprivation (n = 2), and intoxication or withdrawal of other illegal drugs or trivial infect (n = 1 for each) and non-compliance with anti-seizure drugs (n = 1). A decreased T-score (−1.04 ± 1.15) and Z-score (−0.84 ± 0.75) compared to healthy subjects were found. Conclusion Fractures in upper extremities, trunk and craniocerebral trauma occur frequently as seizure-induced injuries. Alcohol excess and withdrawal are important provoking factors and should be targeted with preventive measurements to avoid seizure related injuries and accidents.

Background: The wearable cardioverter defibrillator (WCD) uses surface electrodes to detect arrhythmia before initiating a treatment sequence. However, it is also prone to inappropriate detection due to artefacts. Objective: The aim of this study is to assess the alarm burden in patients and its impact on clinical outcomes. Methods: Patients from the nationwide Swiss WCD Registry were included. Clinical characteristics and data were obtained from the WCDs. Arrhythmia recordings ≥30 s in length were analysed and categorized as VT/VF, atrial fibrillation (AF), supraventricular tachycardia (SVT) or artefact. Results: A total of 10653 device alarms were documented in 324 of 456 patients (71.1%) over a mean WCD wear-time of 2.0 ± 1.6 months. Episode duration was 30 s or more in 2996 alarms (28.2%). One hundred and eleven (3.7%) were VT/VF episodes. The remaining recordings were inappropriate detections (2736 (91%) due to artefacts, 117 (3.7%) AF, 48 (1.6%) SVT). Two-hundred and seven patients (45%) had three or more alarms per month. Obesity was significantly associated with three or more alarms per month (p = 0.01, 27.7% vs. 15.9%). High alarm burden was not associated with a lower average daily wear time (20.8 h vs. 20.7 h, p = 0.785) or a decreased implantable cardioverter defibrillator implantation rate after stopping WCD use (48% vs. 47.3%, p = 0.156). Conclusions: In patients using WCDs, alarms emitted by the device and impending inappropriate shocks were frequent and most commonly caused by artefacts. A high alarm burden was associated with obesity but did not lead to a decreased adherence.

Aims Catheter ablation of frequent idiopathic pre-mature ventricular contractions (PVC) is increasingly performed. While potential benefits of contact force (CF)-sensing technology for atrial fibrillation ablation have been assessed in several studies, the impact of CF-sensing on ventricular arrhythmia ablation remains unknown. This study aimed to compare outcomes of idiopathic outflow tract PVC ablation when using standard ablation catheters as opposed to CF-sensing catheters. Methods and results In a retrospective multi-centre study, unselected patients undergoing catheter ablation of idiopathic outflow tract PVCs between 2013 and 2016 were enrolled. All procedures were performed using irrigated-tip ablation catheters and a 3D electro-anatomical mapping system. Sustained ablation success was defined as a ≥80% reduction of pre-procedural PVC burden determined by 24 h Holter ECG during follow-up. Overall, 218 patients were enrolled (median age 52 years, 51% males). Baseline and procedural data were similar in the standard ablation (24%) and the CF-sensing group (76%). Overall, the median PVC burden decreased from 21% (IQR 10–30%) before ablation to 0.2% (IQR 0–3.0%) after a median follow-up of 2.3 months (IQR 1.4–3.9 months). The rates of both acute (91% vs. 91%, P = 0.94) and sustained success (79% vs. 74%, P = 0.44) were similar in the standard ablation and the CF-sensing groups. No differences were observed in subgroups according to arrhythmia origin from the RVOT (65%) or LVOT (35%). Complications were rare (1.8%) and evenly distributed between the two groups. Conclusion The use of CF-sensing technology is not associated with increased success rate nor decreased complication rate in idiopathic outflow tract PVC ablation.

Focal plane wavefront sensing is an elegant solution for wavefront sensing since near-focal images of any source taken by a detector show distortions in the presence of aberrations. Non-Common Path Aberrations and the Low Wind Effect both have the ability to limit the achievable contrast of the finest coronagraphs coupled with the best extreme adaptive optics systems. To correct for these aberrations, the Subaru Coronagraphic Extreme Adaptive Optics instrument hosts many focal plane wavefront sensors using detectors as close to the science detector as possible. We present seven of them and compare their implementation and efficiency on SCExAO. This work will be critical for wavefront sensing on next generation of extremely large telescopes that might present similar limitations., Comment: SPIE proceeding : Astronomical Telescopes + Instrumentation 2020. arXiv admin note: text overlap with arXiv:1912.10179

Objective To investigate benefits of in-hospital, long-term video EEG monitoring (LVEM) for pediatric patients, from a therapeutic perspective and from the perspectives of patients and their families. Methods A monocentric retrospective cohort study was conducted. Patients aged 0–18 years who underwent LVEM for epilepsy surgery eligibility, epilepsy syndrome clarification, or medication adjustment were evaluated regarding paroxysmal event type, change in seizure frequency and patients’ benefits using a standardized evaluation protocol. Results A total of 163 (88 boys and 75 girls, mean age 10.9 years) pediatric patients underwent 178 LVEM sessions, with a mean duration of 5.4 days. The rate of habitual event detection was 69.1%. Epilepsy diagnosis was confirmed in 147 patients and excluded in 16 patients (9.8%). LVEM results altered the diagnosis of 37.4% of patients. Diagnosis remained unchanged in 49.1% of patients and was specified in 13.5% of patients. Epilepsy surgery was performed in 32 patients, and 64% of epilepsy patients deemed ineligible for epilepsy surgery underwent medication adjustments. Patients or their families found LVEM helpful in 75% of cases. Significant seizure reductions and improvements in the disease course were reported by 45% of epilepsy patients. Three episodes of non-convulsive status epilepticus occurred, representing 1.7% of admissions and 1.9% of patients diagnosed with epilepsy, while no injuries were observed. Conclusions LVEM is beneficial for pediatric patients from both a medical perspective and from the perspective of patients and their families, even if patients are ineligible for epilepsy surgery. LVEM is well-tolerated with a low risk of status epilepticus and injuries.

Drug dosing in encephalopathic neonates treated with therapeutic hypothermia is challenging; exposure is dependent on body size and maturation but can also be influenced by factors related to disease and treatment. A better understanding of underlying pharmacokinetic principles is essential to guide drug dosing in this population. The prospective multicenter cohort study PharmaCool was designed to investigate the pharmacokinetics of commonly used drugs in neonatal encephalopathy. In the present study, all data obtained in the PharmaCool study were combined to study the structural system specific effects of body size, maturation, recovery of organ function, and temperature on drug clearance using nonlinear mixed effects modeling. Data collected during the first 5 days of life from 192 neonates treated with therapeutic hypothermia were included. An integrated population pharmacokinetic model of seven drugs (morphine, midazolam, lidocaine, phenobarbital, amoxicillin, gentamicin, and benzylpenicillin) and five metabolites (morphine-3-glucuronide, morphine-6-glucuronide, 1-hydroxymidazolam, hydroxymidazolam glucuronide, and monoethylglycylxylidide) was successfully developed based on previously developed models for the individual drugs. For all compounds, body size was related to clearance using allometric relationships and maturation was described with gestational age in a fixed sigmoidal Hill equation. Organ recovery after birth was incorporated using postnatal age. Clearance increased by 1.23%/hours of life (95% confidence interval (CI) 1.03–1.43) and by 0.54%/hours of life (95% CI 0.371–0.750) for high and intermediate clearance compounds, respectively. Therapeutic hypothermia reduced clearance of intermediate clearance compounds only, by 6.83%/°C (95% CI 5.16%/°C–8.34%/°C). This integrated model can be used to facilitate drug dosing and future pharmacokinetic studies in this population.

A transfer learning approach is proposed to classify grouper species by their courtship-associated sounds produced during spawning aggregations. Vessel sounds are also included in order to potentially identify human interaction with spawning fish. Grouper sounds recorded during spawning aggregations were first converted to time-frequency representations. Two types of time frequency representations were used in this study: spectrograms and scalograms. These were converted to images, and then fed to pretrained deep neural network models: VGG16, VGG19, Google Net, and MobileNet. The experimental results revealed that transfer learning significantly outperformed the manually identified features approach for grouper sound classification. In addition, both time-frequency representations produced almost identical results in terms of classification accuracy.

Focal plane wavefront sensing is an appealing technique to cophase multiple aperture telescopes. Phase diversity, operable with any aperture configuration or source extension, generally suffers from high computing load. In this Letter, we introduce, characterize and experimentally validate the LAPD algorithm, based on a fast linearized phase diversity algorithm \rev{with a capture range comparable to classic phase diversity.} We demonstrate that a typical performance of lambda/75 RMS wavefront error can be reached., Comment: Accepted for publication in JATIS