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We recently reported that the transketolase from Geobacillus stearothermophilus (TKgst) upon acyl transfer to nitrosoarenes generates N‐aryl hydroxamic acids (HA). The latter are metal chelating compounds that in the presence of Fe(III) ions form deep‐red complexes. Here, we applied this principle to the development of a colorimetric assay in both solid‐ and liquid‐phase formats for the high‐throughput screening of TKgst and its variants. Screening a set of positive hits from a L382X/D470X library validated the specificity and sensitivity of the assays. The solid surface assay allows a clear distinction between positive and negative colonies by the naked eye in qualitative mode, and further also to measure activity in semi‐quantitative fashion in the liquid‐phase format. The assay will be important for engineering the TKgst enzyme towards improved conversion of aromatic aldehydes by their close structural analogy to nitrosoarenes.

Univ. de Lausanne, Switzerland

Background & objective: Contralesional 1-Hz repetitive transcranial magnetic stimulation (rTMS) over the right pars triangularis combined with speech-language therapy (SLT) has shown positive results on the recovery of naming in subacute (5–45 days) post-stroke aphasia. NORTHSTAR-CA is an extension of the previously reported NORTHSTAR trial to chronic aphasia (>6 months post-stroke) designed to compare the effectiveness of the same rTMS protocol in both phases. Methods: Sixty-seven patients with left middle cerebral artery infarcts (28 chronic, 39 subacute) were recruited (01-2014 to 07-2019) and randomized to receive rTMS (N = 34) or sham stimulation (N = 33) with SLT for 10 days. Primary outcome variables were Z-score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment. Chronic and subacute results were compared. Results: Adverse events were rare, mild, and did not differ between groups. Language outcomes improved significantly in all groups irrespective of treatment and recovery phase. At 30-day follow-up, there was a significant interaction of stimulation and recovery phase on naming recovery (P <.001). Naming recovery with rTMS was larger in subacute (Mdn = 1.91/IQR =.77) than chronic patients (Mdn =.15/IQR = 1.68/P =.015). There was no significant rTMS effect in the chronic aphasia group. Conclusions: The addition of rTMS to SLT led to significant supplemental gains in naming recovery in the subacute phase only. While this needs confirmation in larger studies, our results clarify neuromodulatory vs training-induced effects and indicate a possible window of opportunity for contralesional inhibitory stimulation interventions in post-stroke aphasia. NORTHSTAR trial registration: https://clinicaltrials.gov/ct2/show/NCT02020421.

The thesis covers a holistic approach for large-scale gravity field modelling which encompasses all processing steps from data validation/reduction strategies over localized gravity field modelling methods right up to global spherical resp. spheroidal harmonic combination approaches. The focus lies on (1) improving existing methodologies, (2) highlighting synergies between the processing steps and (3) revealing remaining limitations., Es wird ein ganzheitlicher Ansatz zur großräumig angelegten Schwerefeldmodellierung vorgestellt. Dieser umfasst alle Prozessierungsschritte ausgehend von Validierungs-/Reduktionsstrategien über Methoden zur lokalen Modellierung bis hin zu globalen sphärisch/ellipsoidisch-harmonischen Kombinationsansätzen. Der Fokus liegt dabei (1) auf der Verbesserung existierender Methoden, (2) dem Hervorheben von Synergien zwischen Prozessierungsschritten und (3) dem Aufzeigen verbleibender Einschränkungen.

ATAs engineered for having an enlarged small binding pocket were applied for the synthesis of enantiomerically pure (R)-benzo[1,3]dioxol-5-yl-butylamine, a chiral component of human leukocyte elastase inhibitor DMP 777 (L-694,458). Kinetic resolution of the racemic amine was performed by using the L59A variant of the (S)-selective ATA from Chromobacterium violaceum (Cv-ATA), providing the residual (R)-enantiomer in excellent yield and >99% ee. At moderate enzyme loading and absence of co-solvent, high volumetric productivity of 0.22 mol L-1 h(-1) (42.5 g L-1 h(-1)) was achieved. Complementarily, the (S)-enantiomer was generated via kinetic resolution using the (R)-selective ATA-117-Rd11 from Arthrobacter sp. with acetone as the amino acceptor. In an alternative approach, we employed ATA-117-Rd11 for the asymmetric amination of the prochiral ketone precursor, which at 86% conversion gave the (R)-benzo[1,3]dioxol-5-yl-butylamine with excellent >99% ee. We further evaluated the utility of Cv-ATA L59A for the asymmetric synthesis of pharmaceutically relevant (S)-1-phenylbutan-1-amine, a chiral component of the deubiquitinase inhibitor degrasyn (WP1130). The enzyme showed good tolerance to high concentrations of isopropylamine, producing (S)-1-phenylbutan-1-amine in enantiomerically pure form (>99% ee).

Im September 2020 ist es soweit: Der neue Medienstaatsvertrag löst den bisherigen Rundfunkstaatsvertrag ab. Er bedeutet nicht weniger als eine umfassende Neuregulierung der elektronischen Medien. Auch die Vorschriften zur Aufsicht erfahren umfangreiche Neuregelungen. Insgesamt lassen sich im Vergleich zum Rundfunkstaatsvertrag erhebliche Änderungen sowohl in der Systematik als auch in vielen Details verzeichnen. Der Medienstaatsvertrag trägt damit technischen Entwicklungen ebenso Rechnung wie der Umsetzung von neuen Vorgaben auf unionaler Ebene. Überarbeitet und geändert wurden Regelungen zum Rundfunkbegriff- und Zulassungsvorschriften sowie die Plattformregulierung. Teilweise völlig neu oder mindestens erheblich geändert sind die Abschnitte zu neuen Medienformen und -plattformarten, zu "Medienintermediären", "Benutzeroberflächen" und "Video-Sharing-Diensten". Unser Standardwerk zum bisherigen Rundfunkstaatsvertrag sowie Jugendmedienschutzstaatsvertrag trägt diesen weitreichenden Änderungen Rechnung und wird zum Heidelberger Kommentar Medienstaatsvertrag Jugendmedienschutz-Staatsvertrag. In gewohnter Qualität und Expertise - Herausgeber und Autoren sind namhafte Experten aus der deutschen Medienlandschaft - wird die gesamte historische Entwicklung des föderal vereinbarten Rundfunk- und Telemedienrechts einschließlich des Jugendmedienschutzrechts und der europäischen Entwicklungen berücksichtigt und es wird eine vollständige Informationsquelle zu verfassungsrechtlichen, einfachgesetzlichen und praktischen Streitfragen geboten. Dabei enthält der Kommentar neben dem Text der Staatsverträge sämtliche relevanten begleitenden Texte wie die amtlichen Begründungen, die Ratifizierungsgesetze sowie Dokumente aus dem Europarecht und von Landesmedienanstalten, Rundfunkanstalten und Selbstkontrollorganisationen. Ausführungen zur Entstehungsgeschichte geben wertvolle Erkenntnisse zu Hintergründen des Medienstaatsvertrags. Übersichtsbeiträge zur relevanten Verfassungsrechtsprechun

ATAs engineered for having an enlarged small binding pocket were applied for the synthesis of enantiomerically pure (R)‐benzo[1,3]dioxol‐5‐yl‐butylamine, a chiral component of human leukocyte elastase inhibitor DMP 777 (L‐694,458). Kinetic resolution of the racemic amine was performed by using the L59A variant of the (S)‐selective ATA from Chromobacterium violaceum (Cv‐ATA), providing the residual (R)‐enantiomer in excellent yield and >99% ee. At moderate enzyme loading and absence of co‐solvent, high volumetric productivity of 0.22 mol L⁻¹ h⁻¹ (42.5 g L⁻¹ h⁻¹) was achieved. Complementarily, the (S)‐enantiomer was generated via kinetic resolution using the (R)‐selective ATA‐117‐Rd11 from Arthrobacter sp. with acetone as the amino acceptor. In an alternative approach, we employed ATA‐117‐Rd11 for the asymmetric amination of the prochiral ketone precursor, which at 86% conversion gave the (R)‐benzo[1,3]dioxol‐5‐yl‐butylamine with excellent >99% ee. We further evaluated the utility of Cv‐ATA L59A for the asymmetric synthesis of pharmaceutically relevant (S)‐1‐phenylbutan‐1‐amine, a chiral component of the deubiquitinase inhibitor degrasyn (WP1130). The enzyme showed good tolerance to high concentrations of isopropylamine, producing (S)‐1‐phenylbutan‐1‐amine in enantiomerically pure form (>99% ee).

Within the framework of the Physics Beyond Colliders initiative at CERN, discussions are underway on the feasibility of producing radio-frequency (RF) separated beams for Phase-2 of the AMBER experiment at the M2 beam line in the North experimental area of the CERN SPS. The technique of RF separation is applied to enrich the content of a certain particle type within a beam consisting of different species at the same momentum. It relies on the fact that each particle type has a different velocity, decreasing with rest mass. The successor of the COMPASS experiment, AMBER, requires for its Phase-2 measurements high-intensity, high-purity kaon (and antiproton) beams, which cannot be delivered with the currently existing conventional M2 beam line. The present contribution introduces the principle of RF separation and explains its dependence on different parameters of beam optics and hardware. The first examination of potential showstoppers for the RF-separated beam implementation is presented, based on the particle production rates, beam line transmission for specific optics settings, limitations for overall beam intensity and purity posed by beam line acceptance and radiation protection. Different beam optics settings have been examined, providing either focused or parallel beams inside the RF cavities. The separation and transmission capability of the different optics settings for realistic characteristics of RF cavities are discussed and the preliminary results of the potential purity and intensity of the RF-separated beam are presented. They illustrate the high importance of an RF-separated kaon beam for many of the AMBER Phase-2 data taking programs, such as spectroscopy, prompt-photon production, Primakoff reactions and kaon charge-radius measurement.

The thesis covers a holistic approach for large-scale gravity field modelling which encompasses all processing steps from data validation/reduction strategies over localized gravity field modelling methods right up to global spherical resp. spheroidal harmonic combination approaches. The focus lies on (1) improving existing methodologies, (2) highlighting synergies between the processing steps and (3) revealing remaining limitations., Es wird ein ganzheitlicher Ansatz zur großräumig angelegten Schwerefeldmodellierung vorgestellt. Dieser umfasst alle Prozessierungsschritte ausgehend von Validierungs-/Reduktionsstrategien über Methoden zur lokalen Modellierung bis hin zu globalen sphärisch/ellipsoidisch-harmonischen Kombinationsansätzen. Der Fokus liegt dabei (1) auf der Verbesserung existierender Methoden, (2) dem Hervorheben von Synergien zwischen Prozessierungsschritten und (3) dem Aufzeigen verbleibender Einschränkungen.

ImportanceBiologics account for a substantial proportion of health care expenditures. Their costs have been projected to reach US $452 billion in global spending by 2022. Given recent expiration of patent protection of biologics, a shift toward greater follow-on competition among biosimilars would be expected that would allow greater uptake and lower drug costs.ObjectiveTo assess uptake and prices of biosimilars in the US compared with 2 European countries (Germany and Switzerland) with national mechanisms for drug price negotiation.Design, Setting, and ParticipantsIn this cohort study, biologics and biosimilars that were approved in the US, Germany, and Switzerland until August 2020 were identified. Prices and sales data were extracted from public and commercial databases for the years 2011 to 2020. Data were analyzed from August 1, 2021, to February 28, 2022.Main Outcomes and MeasuresDescriptive statistics were used to show temporal trends in the uptake of biosimilars and relative prices compared with those of reference products (ie, biologic agents) for each country. Descriptive analysis was also performed to compare the uptake of biosimilars between the 3 countries limited to biologics that have biosimilars on the market in all countries. To test if biosimilar awareness in each country increased over the last decade, a linear least squares regression was applied.ResultsThe study cohort included 15 biosimilars and 6 biologics for the US, 52 biosimilars and 15 biologics for Germany, and 28 biosimilars and 13 biologics for Switzerland. Uptake of biosimilars increased over time in all countries. On average, the biosimilar market share at launch was highest in Germany; however, it increased at the fastest rate in the US. Monthly treatment costs of biosimilars in the US were a median of 1.94 (IQR, 1.78-2.44) and 2.74 (IQR, 1.91-3.46) higher than corresponding costs in Germany and Switzerland, respectively.Conclusions and RelevanceThe findings of this cohort study sugg

Objectives: Recently, an MRI quantification sequence has been developed which can be used to acquire T1- and T2-relaxation times as well as proton density (PD) values. Those three quantitative values can be used to describe soft tissue in an objective manner. The purpose of this study was to investigate the applicability of quantitative cardiac MRI for characterization and differentiation of ischaemic myocardial lesions of different age. Materials and methods: Fifty post-mortem short axis cardiac 3T MR examinations have been quantified using a quantification sequence. Myocardial lesions were identified according to histology and appearance in MRI images. Ischaemic lesions were assessed for mean T1-, T2- and proton density values. Quantitative values were plotted in a 3D-coordinate system to investigate the clustering of ischaemic myocardial lesions. Results: A total of 16 myocardial lesions detected in MRI images were histologically characterized as acute lesions (n = 8) with perifocal oedema (n = 8), subacute lesions (n = 6) and chronic lesions (n = 2). In a 3D plot comprising the combined quantitative values of T1, T2 and PD, the clusters of all investigated lesions could be well differentiated from each other. Conclusion: Post-mortem quantitative cardiac MRI is feasible for characterization and discrimination of different age stages of myocardial infarction. Key Points : • MR quantification is feasible for characterization of different stages of myocardial infarction. • The results provide the base for computer-aided MRI cardiac infarction diagnosis. • Diagnostic criteria may also be applied for living patients.

Objectives: To investigate and correct the temperature dependence of postmortem MR quantification used for soft tissue characterization and differentiation in thoraco-abdominal organs. Material and methods: Thirty-five postmortem short axis cardiac 3-T MR examinations were quantified using a quantification sequence. Liver, spleen, left ventricular myocardium, pectoralis muscle and subcutaneous fat were analysed in cardiac short axis images to obtain mean T1, T2 and PD tissue values. The core body temperature was measured using a rectally inserted thermometer. The tissue-specific quantitative values were related to the body core temperature. Equations to correct for temperature differences were generated. Results: In a 3D plot comprising the combined data of T1, T2 and PD, different organs/tissues could be well differentiated from each other. The quantitative values were influenced by the temperature. T1 in particular exhibited strong temperature dependence. The correction of quantitative values to a temperature of 37°C resulted in better tissue discrimination. Conclusion: Postmortem MR quantification is feasible for soft tissue discrimination and characterization of thoraco-abdominal organs. This provides a base for computer-aided diagnosis and detection of tissue lesions. The temperature dependence of the T1 values challenges postmortem MR quantification. Equations to correct for the temperature dependence are provided. Key points: • Postmortem MR quantification is feasible for soft tissue discrimination and characterization • Temperature dependence of the T1 values challenges the MR quantification approach • The results provide the basis for computer-aided postmortem MRI diagnosis • Diagnostic criteria may also be applied for living patients

The purpose of the present study was to investigate whether serous fluids, blood, cerebrospinal fluid (CSF), and putrefied CSF can be characterized and differentiated in synthetically calculated magnetic resonance (MR) images based on their quantitative T 1, T 2, and proton density (PD) values. Images from 55 postmortem short axis cardiac and 31 axial brain 1.5-T MR examinations were quantified using a quantification sequence. Serous fluids, fluid blood, sedimented blood, blood clots, CSF, and putrefied CSF were analyzed for their mean T 1, T 2, and PD values. Body core temperature was measured during the MRI scans. The fluid-specific quantitative values were related to the body core temperature. Equations to correct for temperature differences were generated. In a 3D plot as well as in statistical analysis, the quantitative T 1, T 2 and PD values of serous fluids, fluid blood, sedimented blood, blood clots, CSF, and putrefied CSF could be well differentiated from each other. The quantitative T 1 and T 2 values were temperature-dependent. Correction of quantitative values to a temperature of 37°C resulted in significantly better discrimination between all investigated fluid mediums. We conclude that postmortem 1.5-T MR quantification is feasible to discriminate between blood, serous fluids, CSF, and putrefied CSF. This finding provides a basis for the computer-aided diagnosis and detection of fluids and hemorrhages.

PURPOSE For patients with resectable stage IIIA(N2) non-small-cell lung cancer, neoadjuvant chemotherapy with cisplatin and docetaxel followed by surgery resulted in a 1-year event-free survival (EFS) rate of 48% in the SAKK 16/00 trial and is an accepted standard of care. We investigated the additional benefit of perioperative treatment with durvalumab. METHODS Neoadjuvant treatment consisted of three cycles of cisplatin 100 mg/m$^{2}$ and docetaxel 85 mg/m$^{2}$ once every 3 weeks followed by two doses of durvalumab 750 mg once every 2 weeks. Durvalumab was continued for 1 year after surgery. The primary end point was 1-year EFS. The hypothesis for statistical considerations was an improvement of 1-year EFS from 48% to 65%. RESULTS Sixty-eight patients were enrolled, 67 were included in the full analysis set. Radiographic response rate was 43% (95% CI, 31 to 56) after neoadjuvant chemotherapy and 58% (95% CI, 45 to 71) after sequential neoadjuvant immunotherapy. Fifty-five patients were resected, of which 34 (62%) achieved a major pathologic response (MPR; ≤ 10% viable tumor cells) and 10 (18%) among them a complete pathologic response. Postoperative nodal downstaging (ypN0-1) was observed in 37 patients (67%). Fifty-one (93%) resected patients had an R0 resection. There was no significant effect of pretreatment PD-L1 expression on MPR or nodal downstaging. The 1-year EFS rate was 73% (two-sided 90% CI, 63 to 82). Median EFS and overall survival were not reached after 28.6 months of median follow-up. Fifty-nine (88%) patients had an adverse event grade ≥ 3 including two fatal adverse events that were judged not to be treatment-related. CONCLUSION The addition of perioperative durvalumab to neoadjuvant chemotherapy in patients with stage IIIA(N2) non-small-cell lung cancer is safe and exceeds historical data of chemotherapy alone with a high MPR and an encouraging 1-year EFS rate of 73%.

BACKGROUND Using Injury Severity Score (ISS) data, this study aimed to give an overview of trauma mechanisms, causes of death, injury patterns, and potential survivability in prehospital trauma victims. METHODS Age, gender, trauma mechanism, cause of death, and ISS data were recorded regarding forensic autopsies and whole-body postmortem CT. Characteristics were analyzed for injuries considered potentially survivable at cutoffs of (I) ISS ≤ 75 vs. ISS = 75, (II) ISS ≤ 49 vs. ISS ≥ 50, and (III) ISS < lethal dose 50% (LD50) vs. ISS > LD50 according to Bull's probit model. RESULTS In n = 130 prehospital trauma victims (45.3 ± 19.5 years), median ISS was 66. Severity of injuries to the head/neck and chest was greater compared to other regions (p < 0.001). 52% died from central nervous system (CNS) injury. Increasing injury severity in head/neck region was associated with CNS-injury related death (odds ratio (OR) 2.7, confidence interval (CI) 1.8-4.4). Potentially survivable trauma was identified in (I) 56%, (II) 22%, and (III) 9%. Victims with ISS ≤ 75, ISS ≤ 49, and ISS < LD50 had lower injury severity across most ISS body regions compared to their respective counterparts (p < 0.05). CONCLUSION In prehospital trauma victims, injury severity is high. Lethal injuries predominate in the head/neck and chest regions and are associated with CNS-related death. The appreciable amount (9-56%) of victims dying at presumably survivable injury severity encourages perpetual efforts for improvement in the rescue of highly traumatized patients.

A protein engineering approach for expanding the substrate scope of the (S)-selective Chromobacterium violaceum amine transaminase is presented. Amino acid residues in the small binding pocket of the active site were targeted in order to increase the pocket size for acceptance of primary amines bearing two bulky groups. A highly sensitive fluorescence assay was then used to evaluate the generated enzyme variants for their activity towards propyl- and benzyl-substituted screening substrates. The best variant, L59A/F88A, was successfully applied in the kinetic resolution of 1,2-diphenylethylamine using different conditions and substrate loadings. The variant L59A/F88A generated enantiomerically pure (R)-1,2-diphenylethylamine with ee>99% under all tested conditions. The variant also holds great promise for synthesis of hydrophobic compounds as it shows optimum activity when 20-30% (v/v) DMSO is applied as cosolvent. The variant L59A/F88A provides a great addition to the available catalyst toolbox for synthesis of chiral amines, as it is the first published (S)-selective amine transaminase showing activity towards benzyl-substituted primary amines.

© European Stroke Organisation 2020. Introduction: Non-invasive brain stimulation (NIBS) with speech therapy might improve recovery from post-stroke aphasia. This three-armed sham-controlled blinded prospective proof-of-concept study tested 1 Hz subthreshold repetitive transcranial magnetic stimulation (rTMS) and 2-mA cathodal transcranial direct current stimulation (ctDCS) on the right pars triangularis in subacute post-stroke aphasia. Patients and methods: Sixty-three patients with left middle cerebral artery infarcts were recruited in five hospitals (Canada/United States/Germany, 01–2014/03–2018) and randomized to receive rTMS (N = 20), ctDCS (N = 24) or sham stimulation (N = 19) with ST for 10 days. Primary outcome variables were Z-score changes in naming, semantic fluency and comprehension tests and adverse event frequency. Secondary outcome variable was the percent change in the Unified Aphasia Score. Intention-to-treat analyses tested between-group effects at days 1 and 30 post-treatment with a pre-planned subgroup analysis for lesion location (affecting Broca’s area or not). Results: Naming was significantly improved by rTMS (median = 1.91/interquartile range = 0.77/p =.01) at 30 days versus ctDCS (median = 1.11/interquartile range = 1.51) and sham stimulation (median = 1.02/interquartile range = 1.71). All other primary results were non-significant. The rTMS effect was driven by the patient subgroup with intact Broca’s area where NIBS tended to improve UnAS (median = 33.2%/interquartile range = 46.7%/p =.062) versus sham stimulation (median = 12.5%/interquartile range = 7.9%) at day 30. Conversely, in patients with infarcted Broca’s area, UnAS tended to improve more with sham stimulation (median = 75.0%/interquartile range = 86.9%/p =.053) versus NIBS (median = 12.7%/interquartile range = 31.7). Conclusion: We found a delayed positive effect of low-frequency rTMS targeting the right pars triangularis on the recovery of naming performance in subacute post-st

Nitrogen heterocycles are structural motifs found in many bioactive natural products and of utmost importance in pharmaceutical drug development. In this work, a stereoselective synthesis of functionalized N-heterocycles was accomplished in two steps, comprising the biocatalytic aldol addition of ethanal and simple aliphatic ketones such as propanone, butanone, 3-pentanone, cyclobutanone, and cyclopentanone to N -Cbz-protected aminoaldehydes using engineered variants of -fructose-6-phosphate aldolase from Escherichia coli (FSA) or 2-deoxy--ribose-5-phosphate aldolase from Thermotoga maritima (DERA) as catalysts. FSA catalyzed most of the additions of ketones while DERA was restricted to ethanal and propanone. Subsequent treatment with hydrogen in the presence of palladium over charcoal, yielded low-level oxygenated N-heterocyclic derivatives of piperidine, pyrrolidine and N-bicyclic structures bearing fused cyclobutane and cyclopentane rings, with stereoselectivities of 96-98 ee and 97:3 dr in isolated yields ranging from 35 to 79%.

Objective Accurate identification of the ischemic penumbra, the therapeutic target in acute clinical stroke, is of critical importance to identify patients who might benefit from reperfusion therapies beyond the established time windows. Therefore, we aimed to validate magnetic resonance imaging (MRI) mismatch-based penumbra detection against full quantitative positron emission tomography (O-15-PET), the gold standard for penumbra detection in acute ischemic stroke. Methods Ten patients (group A) with acute and subacute ischemic stroke underwent perfusion-weighted (PW)/diffusion-weighted MRI and consecutive full quantitative O-15-PET within 48 hours of stroke onset. Penumbra as defined by O-15-PET cerebral blood flow (CBF), oxygen extraction fraction, and oxygen metabolism was used to validate a wide range of established PW measures (eg, time-to-maximum [Tmax]) to optimize penumbral tissue detection. Validation was carried out using a voxel-based receiver-operating-characteristic curve analysis. The same validation based on penumbra as defined by quantitative O-15-PET CBF was performed for comparative reasons in 23 patients measured within 48 hours of stroke onset (group B). Results The PW map Tmax (area-under-the-curve = 0.88) performed best in detecting penumbral tissue up to 48 hours after stroke onset. The optimal threshold to discriminate penumbra from oligemia was Tmax >5.6 seconds with a sensitivity and specificity of >80%. Interpretation The performance of the best PW measure Tmax to detect the upper penumbral flow threshold in ischemic stroke is excellent. Tmax >5.6 seconds-based penumbra detection is reliable to guide treatment decisions up to 48 hours after stroke onset and might help to expand reperfusion treatment beyond the current time windows. ANN NEUROL 2019;85:875-886.

The effect of long-term environmental changes on sea bird populations with respect to changes in their breeding and foraging habitats is difficult to assess due to the scarcity of records that go beyond direct observational data. Information on the past distribution of snow petrel Pagodroma nivea (Forster) breeding colonies can be obtained from deposits of their proventricular stomach oil, so-called Antarctic mumiyo. In our study, we present C-14 ages of mumiyo deposits from northern and southern Prince Charles Mountains, East Antarctica, to reconstruct the timing of snow petrel occupation at these inland breeding localities. C-14 ages indicate a minimum age of snow petrel occupation of 3680calyear bp. The colonisation post-dates the de-glacial local and regional ice sheet retreat by several thousand years. This either suggests limited accessibility of the inland sites or a lack of suitable nesting locations prior to the Mid-Holocene and/or changes in the marine habitat affecting access to the foraging grounds. C-14 ages of mumiyo deposits from Vestfold and Larsemann Hills to the east of Prydz Bay point to a regional pattern of snow petrel dispersal starting in the Mid-Holocene. This suggests environmental changes in the foraging habitat to be the most likely drivers for extending breeding site locations of snow petrels to more inland ice-free areas in the Prydz Bay Region.

Mumiyo deposits form in the vicinity of snow petrel (Pagodroma nivea) nesting sites and consist of fossil stomach oil (mumiyo), guano, and minerogenic material. Here we evaluate mumiyo deposits from the inland mountain ranges of central Dronning Maud Land as high-resolution archives for paleoenvironmental reconstructions in Antarctica. Investigation of internal structures and chemical composition shows that the lamination reflects progressive sedimentation, despite the irregular outer morphology of the deposits. Detailed radiocarbon analysis demonstrates that stratigraphies are intact: 14C ages become successively younger upwards in the deposits. Fatty acid and n-alcohol composition was determined on samples from eight mumiyo deposits. Dominance of low molecular weight compounds (C14 to C18) points to a dietary signal; however, the relatively low proportions of unsaturated compounds compared to fresh stomach oils indicates some postdepositional degradation. We found marine diatoms in the mumiyo, which potentially provide a proxy for sea ice conditions in the foraging habitat of the petrels. Age ranges of the investigated deposits suggest occupation of the analyzed sites by snow petrels from 17 ka to >58 ka. Changes in deposition rates point to higher occupation frequency in Petermann Range from 46 to 42 ka compared to the late marine isotope stage 3 and the Last Glacial Maximum.

Mutations in the PARK2 gene are associated with early onset Parkinsonism. The Park2 -/- mouse, however, does not exhibit neurodegeneration or other Parkinsons disease (PD) phenotypes. Previously, we discovered that translation of Mcl-1, a pro-survival factor, is upregulated in the Park2 -/- mouse, suggesting a compensatory mechanism during development. Here we generated the Park2 -/- Mcl-1 +/- mouse and show that by reducing Mcl-1 gene dosage by 50%, the Park2 -/- genotype is sensitized, conferring both dopaminergic neuron loss and motor impairments. We propose that this murine model could be a useful tool for dissecting PD etiology and developing treatment strategies against this neurodegenerative disease.

Die Erzeugung von DInSAR basierten Deformationszeitreihen, die mehrere Radarmissionen umfassen, stellt nach wie vor eine Herausforderung dar. Aufgrund des differentiellen Charakters der Beobachtungen ist es notwendig einen Bezugszeitpunkt für die Zeitreihen zu wählen, die aus radarinterferometrischen Auswertungen abgeleitet werden. Üblicherweise wird hier das Aufnahmedatum der ersten SAR Szene gewählt. Werden nun Zeitreihen aus mehreren Satellitenmissionen (z.B. ERS 1/2, EnviSat usw.) betrachtet, entsteht das Problem, dass jede einen unterschiedlichen zeitlichen Referenzpunkt besitzt. Erschwerend kommt hinzu, dass sich die Missionen oftmals nicht zeitlich überlappen. Aus diesem Grund lassen sich missionsüberspannende Zeitreihen nicht ohne Weiteres erzeugen. Außerdem ist es aus verschiedenen Gründen (Aufnahmegeometrie, Auflösung, identifizierte Rückstreuer usw.) zunächst nicht möglich identische Punkte zu identifizieren, deren Bewegung gemeinsam betrachtet werden soll. In diesem Beitrag wird ein mehrstufiges Verfahren präsentiert, mit dem es dennoch möglich ist, mehrere SBAS Einzelauswertungen der Satellitenmissionen ERS 1/2, EnviSat, TerraSAR X und Sentinel 1 zu gemeinsamen Punktbewegungszeitreihen zu verknüpfen. Ausgangspunkt hierfür sind punktbasierte Höhenunterschiede (vor der zeitlichen Integration) sowie die amtlichen Leitnivellements von 1993 bis 2017 im Bereich der Niederrheinischen Bucht. Unter der Annahme, dass sich nahe beieinander liegende Punkte ähnlich bewegen, werden Höhenunterschiede an den Koordinaten der Nivellementpunkte mittels inverser Distanzgewichtung der DInSAR Daten bestimmt. Für jeden Punkt mit einer \glqq Zeitreihe\grqq\ von Höhenunterschieden wird ein B-Spline basiertes, zeitlich kontinuierliches Bewegungsmodell angesetzt. Die amtlichen Höhendaten werden zur zwangsfreien Lagerung verwendet. Somit ist es möglich über einen Ausgleich mit zusätzlichen Restriktionen punktbasierte, absolute Bewegungsmodelle aus unabhängigen DInSAR Auswertungen

The quality of electricity system modelling heavily depends on the input data used. Although a lot of data is publicly available, it is often dispersed, tedious to process and partly contains errors. We argue that a central provision of input data for modelling has the character of a public good: it reduces overall societal costs for quantitative energy research as redundant work is avoided, and it improves transparency and reproducibility in electricity system modelling. This paper describes the Open Power System Data platform that aims at realising the efficiency and quality gains of centralised data provision by collecting, checking, processing, aggregating, documenting and publishing data required by most modellers. We conclude that the platform can provide substantial benefits to energy system analysis by raising efficiency of data pre-processing, providing a method for making data pre-processing for energy system modelling traceable, flexible and reproducible and improving the quality of original data published by data providers.

Longitudinal imaging is capable of capturing the static ana\-to\-mi\-cal structures and the dynamic changes of the morphology resulting from aging or disease progression. Self-supervised learning allows to learn new representation from available large unlabelled data without any expert knowledge. We propose a deep learning self-supervised approach to model disease progression from longitudinal retinal optical coherence tomography (OCT). Our self-supervised model takes benefit from a generic time-related task, by learning to estimate the time interval between pairs of scans acquired from the same patient. This task is (i) easy to implement, (ii) allows to use irregularly sampled data, (iii) is tolerant to poor registration, and (iv) does not rely on additional annotations. This novel method learns a representation that focuses on progression specific information only, which can be transferred to other types of longitudinal problems. We transfer the learnt representation to a clinically highly relevant task of predicting the onset of an advanced stage of age-related macular degeneration within a given time interval based on a single OCT scan. The boost in prediction accuracy, in comparison to a network learned from scratch or transferred from traditional tasks, demonstrates that our pretrained self-supervised representation learns a clinically meaningful information., Comment: Accepted for publication in the MICCAI 2019 PRIME workshop

Nitrogen heterocycles are structural motifs found in many bioactive natural products and of utmost importance in pharmaceutical drug development. In this work, a stereoselective synthesis of functionalized N-heterocycles was accomplished in two steps, comprising the biocatalytic aldol addition of ethanal and simple aliphatic ketones such as propanone, butanone, 3-pentanone, cyclobutanone, and cyclopentanone to N-Cbz-protected aminoaldehydes using engineered variants of d-fructose-6-phosphate aldolase from Escherichia coli (FSA) or 2-deoxy-d-ribose-5-phosphate aldolase from Thermotoga maritima (DERA Tma ) as catalysts. FSA catalyzed most of the additions of ketones while DERA Tma was restricted to ethanal and propanone. Subsequent treatment with hydrogen in the presence of palladium over charcoal, yielded low-level oxygenated N-heterocyclic derivatives of piperidine, pyrrolidine and N-bicyclic structures bearing fused cyclobutane and cyclopentane rings, with stereoselectivities of 96–98 ee and 97:3 dr in isolated yields ranging from 35 to 79%. © 2019 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

In the KOSMOS-2 project, a smart learning approach in form of a modern portal for students at Universities has been developed, called “MeinKosmos”. An important question from the point of view of universities and teachers is what the quality of such new tools are or what their benefits are. This article describes the evaluation approach defined in the KOSMOS-2 project for the “MeinKosmos” learning portal, and the results of using the approach in an undergraduate degree program. The focus of the evaluation is on the learning success of the students and the quality of the meta-search.

The purpose of the present study was to evaluate the ranges of Hounsfield unit (HU) found in body fluids, putrefaction fluids, and blood on postmortem CT and how these ranges are affected by postmortem interval, temperatures, and CT beam energy. Body fluids, putrefaction fluids, and blood from a total of 53 corpses were analyzed to determine the ranges of HU values from postmortem CT images that were taken prior to autopsy. The fluids measured in CT images were obtained at autopsy and examined in terms of macroscopic and microscopic appearances. Body fluids and blood were also collected in plastic bottles, which were subjected to CT scans at different beam energies (80-130kV) and at various fluid temperatures (4 to 40°C). At a postmortem interval of 1 to 4days, the ranges of HU values of the serous fluids (13-38HU) and the nonsedimented blood (40-88HU) did not overlap. In the sedimented blood, the upper serum layer exhibited HU value ranges that overlapped with those of the serous fluids. The putrefaction fluids exhibited a range of HU values between 80 and −130HU. Elevated HU values were observed in fluids with accretive cell impurities. HU values decreased slightly with increasing temperature and CT beam energy. We concluded that serous fluids and blood in fresh corpses can be characterized and differentiated from each other based on HU value ranges. In contrast, body fluids in decomposed corpses cannot be differentiated by their HU value ranges. Different beam energies and corpse temperatures had only minor influences on HU value ranges and therefore should not be obstacles to the differentiation and characterization of body fluids and blood.

Background: In acute stroke, the magnetic resonance (MR) imaging-based mismatch concept is used to select patients with tissue at risk of infarction for reperfusion therapies. There is however a controversy if non-deconvolved or deconvolved perfusion weighted (PW) parameter maps perform better in tissue at risk prediction and which parameters and thresholds should be used to guide treatment decisions. Methods: In a group of 22 acute stroke patients with consecutive MR and quantitative positron emission tomography (PET) imaging, non-deconvolved parameters were validated with the gold standard for penumbral-flow (PF) detection 15O-water PET. Performance of PW parameters was assessed by a receiver operating characteristic curve analysis to identify the accuracy of each PWI map to detect the - upper PF threshold as defined by PET cerebral blood flow < 20 mL/100 g/min. Results: Among normalized non-deconvolved parameters, PW-first moment without delay correction (FM without DC) > 3.6 s (area under the curve [AUC] = 0.89, interquartile range [IQR] 0.85-0.94), PW-maximum of the concentration curve (Cmax) < 0.66 (AUC = 0.92, IQR 0.84-0.96) and PW-time to peak (TTP) > 4.0 s (AUC = 0.92, IQR 0.87-0.94) perform significantly better than other non-deconvolved parameters to detect the PF threshold as defined by PET. Conclusions: Non-deconvolved parameters FM without DC, Cmax and TTP are an observer-independent alternative to established deconvolved parameters (e. g., Tmax) to guide treatment decisions in acute stroke. (c) 2018 S. Karger AG, Basel

Dose-dense induction with the S-HAM regimen was compared to standard double induction therapy in adult patients with newly diagnosed acute myeloid leukemia. Patients were centrally randomized (1:1) between S-HAM (2nd chemotherapy cycle starting on day 8 - dose-dense) and double induction with TAD-HAM or HAM(-HAM) (2nd cycle starting on day 21 - standard). 387 evaluable patients were randomly assigned to S-HAM (N - 203) and to standard double induction (N - 184). The primary endpoint overall response rate (ORR) consisting of complete remission (CR) and incomplete remission (CRi) was not significantly different (P = 0.202) between S-HAM (77%) and double induction (72%). The median overall survival was 35 months after S-HAM and 25 months after double induction (P = 0.323). Duration of critical leukopenia was significantly reduced after S-HAM (median 29 days) versus double induction (median 44 days)-P < 0.001. This translated into a significantly shortened duration of hospitalization after S-HAM (median 37 days) as compared to standard induction (median 49 days)-P < 0.001. In conclusion, dose-dense induction therapy with the S-HAM regimen shows favorable trends but no significant differences in ORR and OS compared to standard double induction. S-HAM significantly shortens critical leukopenia and the duration of hospitalization by 2 weeks.

Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (± SE) was 89.2 ± 1.3% and 92.3 ± 1.2% ( P = .04); cumulative incidence of relapse, 8.7 ± 1.2% and 6.4 ± 1.1% ( P = .09); and overall survival, 96.1 ± 0.8% and 98.0 ± 0.6% ( P = .06). Patients with ETV6-RUNX1-positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 ± 0.5% and 0.6 ± 0.4% for P-III and P-II, respectively ( P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity

The growth and microscopic characterization of two-dimensional germania films is presented. Germanium oxide monolayer films were grown on Ru(0001) by physical vapor deposition and subsequent annealing in oxygen. We obtain a comprehensive image of the germania film structure by combining intensity-voltage low-energy electron diffraction (I/V-LEED) and ab initio density functional theory (DFT) analysis with atomic-resolution scanning tunneling microscopy (STM) imaging. For benchmarking purposes, the bare Ru(0001) substrate and the (2×2)3O covered Ru(0001) were analyzed with I/V-LEED with respect to previous reports. STM topographic images of the germania film reveal a hexagonal network where the oxygen and germanium atom positions appear in different imaging contrasts. For quantitative LEED, the best agreement has been achieved with DFT structures where the germanium atoms are located preferentially on the top and fcc hollow sites of the Ru(0001) substrate. Moreover, in these atomically flat germania films, local site geometries, i.e., tetrahedral building blocks, ring structures, and domain boundaries, have been identified, indicating possible pathways towards two-dimensional amorphous networks.

Purpose Somatic deletions that affect the lymphoid transcription factor-coding gene IKZF1 have previously been reported as independently associated with a poor prognosis in pediatric B-cell precursor (BCP) acute lymphoblastic leukemia (ALL). We have now refined the prognostic strength of IKZF1 deletions by analyzing the effect of co-occurring deletions. Patients and Methods The analysis involved 991 patients with BCP ALL treated in the Associazione Italiana Ematologia ed Oncologia Pediatrica-Berlin-Frankfurt-Muenster (AIEOP-BFM) ALL 2000 trial with complete information for copy number alterations of IKZF1, PAX5, ETV6, RB1, BTG1, EBF1, CDKN2A, CDKN2B, Xp22.33/Yp11.31 (PAR1 region; CRLF2, CSF2RA, and IL3RA), and ERG; replication of findings involved 417 patients from the same trial. Results IKZF1 deletions that co-occurred with deletions in CDKN2A, CDKN2B, PAX5, or PAR1 in the absence of ERG deletion conferred the worst outcome and, consequently, were grouped as IKZF1plus. The IKZF1plus group comprised 6% of patients with BCP ALL, with a 5-year event-free survival of 53 6 6% compared with 7965% in patients with IKZF1 deletion who did not fulfill the IKZF1plus definition and 87 ± 1% in patients who lacked an IKZF1 deletion (P ≤.001). Respective 5-year cumulative relapse incidence rates were 44±6%, 11±4%, and 10±1%(P ≤.001). Results were confirmed in the replication cohort, and multivariable analyses demonstrated independence of IKZF1plus. The IKZF1plus prognostic effect differed dramatically in analyses stratified by minimal residual disease (MRD) levels after induction treatment: 5-year event-free survival for MRD standard-risk IKZF1plus patients was 94 6 5% versus 40 6 10% in MRD intermediate- and 30 ± 14% in high-risk IKZF1plus patients (P ≤.001). Corresponding 5-year cumulative incidence of relapse rates were 6 ± 6%, 60 ± 10%, and 60 ± 17% (P ≤.001). Conclusion IKZF1plus describes a new MRD-dependent very-poor prognostic profile in BCP ALL. Because current AIEOP-BF

The invention provides new and alternative fructose-6-phosphate aldolase (FSA) variants which enable the production of optically active building blocks with high chemoselectivity and stereoselectivity using aldehydes as starting material in aldol carboligation reactions, while avoiding the by-product formation and subsequent reactions.

The goal of the present study was to evaluate if quantitative postmortem cardiac 3-T magnetic resonance (QPMCMR) T1 and T2 relaxation times and proton density values of histopathological early acute and chronic myocardial infarction differ to the quantitative values of non-pathologic myocardium and other histopathological age stages of myocardial infarction with regard to varying corpse temperatures. In 60 forensic corpses (25 female, 35 male), a cardiac 3-T MR quantification sequence was performed prior to autopsy and cardiac dissection. Core body temperature was assessed during MR examinations. Focal myocardial signal alterations in synthetically generated MR images were measured for their T1, T2, and proton density (PD) values. Locations of signal alteration measurements in PMCMR were targeted at heart dissection, and myocardial tissue specimens were taken for histologic examinations. Quantified signal alterations in QPMCMR were correlated to their according histologic age stage of myocardial infarction, and quantitative values were corrected for a temperature of 37 A degrees C. In QPMCMR, 49 myocardial signal alterations were detected in 43 of 60 investigated hearts. Signal alterations were diagnosed histologically as early acute (n = 16), acute (n = 10), acute with hemorrhagic component (n = 9), subacute (n = 3), and chronic (n = 11) myocardial infarction. Statistical analysis revealed that based on their temperature-corrected quantitative T1, T2, and PD values, a significant difference between early acute, acute, and chronic myocardial infarction can be determined. It can be concluded that quantitative 3-T postmortem cardiac MR based on temperature-corrected T1, T2, and PD values may be feasible for pre-autopsy diagnosis of histopathological early acute, acute, and chronic myocardial infarction, which needs to be confirmed histologically.

The fascinating many-body physics involved in the interaction of a single magnetic impurity with the conduction electrons of its nonmagnetic metallic host is reflected in unconventional phenomena in magnetism, transport properties and the specific heat. Characteristic low-energy excitations, termed the Kondo resonance, are generally believed to be responsible for this striking behaviour. However, in spite of an intense research for over more than 30 years, a direct spectroscopic observation of the Kondo resonance on individual magnetic adatoms withstood experimental efforts hitherto. The development of low-temperature scanning tunneling microscopes (STM) operating under ultrahigh vacuum (UHV) conditions has provided new opportunities for investigating locally the electronic structure at surfaces. At low temperatures, due to the reduced broadening of the Fermi level of the STM tip and the sample, rather high energy resolution (≤ 1 meV) in scanning tunneling spectroscopy (STS) is achievable. Moreover, the absence of diffusion together with the spatial resolution of the STM enables detailed studies of electronic states on and near single adsorbed atoms and other nanoscale structures. Recently, for the first time, two such STS/STM experiments spatially resolved the electronic properties of individual magnetic adatoms displaying the Kondo effect. In particular, the observed Fano lineshape of the Kondo resonance reveals unambiguously the details of the quantum mechanical interference between the localized orbital and the conduction electrons on an atomic length scale [1,2]. This achievement of the detection of individual magnetic atoms with atomic resolution opens new perspectives for probing magnetic nanostructures

Asymmetric aldol addition of simple aldehydes and ketones to electrophiles is a cornerstone reaction for the synthesis of unusual sugars and chiral building blocks. We investigated D-fructose-6-phosphate aldolase from E. coli (FSA) D6X variants as catalysts for the aldol additions of linear and cyclic non-functionalized aliphatic ketones or ethanal as nucleophiles to non-phosphorylated hydroxyaldehydes. Thus, addition of propanone, cyclobutanone, cyclopentanone or ethanal to 3-hydroxypropanal or (S)- or (R)-3-hydroxybutanal catalyzed by FSA D6H and D6Q variants furnished rare deoxysugars in 8-77% isolated yields with high stereoselectivity (97:3 dr and >95% ee). © 2018 American Chemical Society.

A structure‐guided engineering of fructose‐6‐phosphate aldolase was performed to expand its substrate promiscuity toward aliphatic nucleophiles, i.e., unsubstituted alkanones and alkanals. A "smart" combinatorial library was created targeting residues D6, T26 and N28 that form a binding pocket around the nucleophilic carbon atom. Double‐selectivity screening was executed by high‐performance TLC that allowed simultaneous determination of total activity as well as a preference for acetone versus propanal as competing nucleophiles. While any mutation of N28 resulted in inactivation of the enzyme, D6 turned out to be the key residue that enabled activity with non‐hydroxylated nucleophiles. Altogether 25 single‐ and double‐site variants (D6X and D6X/T26X) were discovered that show useful synthetic activity and a varying preference for ketone or aldehyde as the aldol nucleophiles. Remarkably, all of the novel variants had completely lost their native activity for cleavage of fructose 6‐phosphate.

The quality of electricity system modelling heavily depends on the input data used. Although a lot of data is publicly available, it is often dispersed, tedious to process and partly contains errors. We argue that a central provision of input data for modelling has the character of a public good: it reduces overall societal costs for quantitative energy research as redundant work is avoided, and it improves transparency and reproducibility in electricity system modelling. This paper describes the Open Power System Data platform that aims at realising the efficiency and quality gains of centralised data provision by collecting, checking, processing, aggregating, documenting and publishing data required by most modellers. We conclude that the platform can provide substantial benefits to energy system analysis by raising efficiency of data pre-processing, providing a method for making data pre-processing for energy system modelling traceable, flexible and reproducible and improving the quality of original data published by data providers., Comment: This is the postprint version of the article

"Es wird ein Konzept zur Ermittlung akkumulierter Kennzahlen für die 'Total Costs of Lifecycle' (TCL) einer IT-Konfiguration vorgestellt. Das Konzept basiert darauf, dass die IT-Leistungen gruppiert und zu 'Service-Modulen' zusammengefasst werden. Pro 'Service-Modul' werden als Kennzahlen die Sachkosten, der Personalaufwand, die technische Nutzungsdauer ('Lifecycle') aus den vorhandenen Budgetdaten berechnet / geschätzt. Die IT-Konfiguration und die IT-Leistungen werden durch die Stückzahlen pro Service-Modul vollständig abgebildet. Es wird eine Muster-Konfiguration beispielhaft durchgerechnet und wichtige Eigenschaften der TCL-Daten abgeleitet und beschrieben." (Autorenreferat)

"Zweck der Studie ist die Evaluation aussagefähiger Nutzungs-Kennzahlen aus den Log-Dateien von WWW-Servern am Beispiel der Log-Ergebnisse des IIS-Servers www.gesis.org für die Jahre 2001 und 2002. Hierzu werden die prinzipiellen Eigenschaften der Log-Daten systematisch untersucht, u.a. die Problematik der Identifikation der Besucher anhand der IP-Adresse (DHCP, Proxy), die Behandlung von Suchmaschinen, die Unterscheidung von 'Hits', 'PageViews' und 'Visits', die Identifikation der angewählten URLs , Befehlstypen und Statuscodes und auf dieser Basis Empfehlungen für die routinemäßige Ermittlung von Kennzahlen entwickelt." (Autorenreferat)

"Die Studie untersucht und beschreibt ein vereinfachendes Verfahren zur Planung von WLAN-Konfigurationen nach den WiFi Standards 802.11 b/g unter Einbeziehung von Bridging und Wireless Distribution zur Ausleuchtung großer Areale. Auf der Grundlage von Messreihen und Herstellerangaben werden hierzu u. a. die Dämpfungen typischer Hindernisse und Verstärkungen typischer Richtantennen ermittelt, tabellarisch dokumentiert und gemessene Grenzwerte für die zuverlässige Datenübertragung empfohlen." (Autorenreferat)

"Als Beitrag zu den Wirtschaftlichkeitsüberlegungen von Informationsdienstleistungen werden sowohl die Nutzungszahlen der vom IZ produzierten Dokumentations-Einheiten als auch die Kosten zu deren Erstellung quantitativ abgeschätzt und miteinander verglichen. Das wichtigste Ergebnis: Der Nutzen der IZ-Datenbanken ist um den Faktor 30 größer als die Kosten." (Autorenreferat)

Purpose Clinical characteristics, therapeutic approaches, and prognosis of late relapse (LR) in patients with classic Hodgkin lymphoma (cHL) are poorly understood. We performed a comprehensive analysis of LR of Hodgkin lymphoma (LR-HL). Methods To estimate the incidence of LR-HL, we retrospectively analyzed 6,840 patients with cHL included in the German Hodgkin Study Group trials HD7 to HD12. Patients who experienced a relapse >5 years into remission were compared with patients in continued remission for >5 years and with those who experienced a relapse <= 5 years after first diagnosis. Results With a median observation time of 10.3 years, 141 incidences of LR-HL were observed. Cumulative incidences at 10, 15, and 20 years rose linearly and were 2.5%, 4.3%, and 6.9%, respectively. The standardized incidence ratio for HL with respect to age-and sex-matched German reference data was 84.5 (95% CI, 71.2 to 99.7). LR-HL was more frequently observed in patients with early-stage favorable than unfavorable or advanced stage at first diagnosis (15-year cumulative incidence, 5.3% v 3.9% and 3.9%, respectively; P =.01). Overall survival from first diagnosis was worse after LR compared with nonrelapse survivors (10-year estimate, 95.8% v 86.1%; hazard ratio, 2.5; 95% CI, 1.7 to 3.5; P<.001). In patients with LR-HL, survival was better compared with 466 patients with earlier relapse (hazard ratio, 0.6; 95% CI, 0.4 to 0.9, P =.01). Forty-four percent and 49% of patients with LR-HL and earlier relapse, respectively, received stem cell transplantations. Conclusion Apart from treatment-associated adverse effects, survivors after initially successful therapy for cHL are at an 85-fold risk for recurrence of disease compared with the general German population. After risk-adapted treatment strategies, especially in early-stage favorable HL, regular clinical follow-up is recommended for timely detection of LR-HL. With adequate treatment, prognosis of LR-HL is better compared with early r

Perfusion-weighted (PW) magnetic resonance imaging (MRI) is used to detect penumbral tissue in acute stroke, but the selection of optimal PW-maps and thresholds for tissue at risk detection remains a matter of debate. We validated the performance of PW-maps with 15O-water-positron emission tomography (PET) in a large comparative PET-MR cohort of acute stroke patients. In acute and subacute stroke patients with back-to-back MRI and PET imaging, PW-maps were validated with 15O-water-PET. We pooled two different cerebral blood flow (CBF) PET-maps to define the critical flow (CF) threshold, (i) quantitative (q) CBF-PET with the CF threshold <20 ml/100 g/min and (ii) normalized non-quantitative (nq) CBF-PET with a CF threshold of <70% (corresponding to < 20 ml/100 g/min according to a previously published normogram). A receiver operating characteristic (ROC) curve analysis was performed to specify the accuracy and the optimal critical flow threshold of each PW-map as defined by PET. In 53 patients, (stroke to imaging: 9.8 h; PET to MRI: 52 min) PW-time-to-maximum (Tmax) with a threshold >6.1 s (AUC = 0.94) and non-deconvolved PW-time-to-peak (TTP) >4.8 s (AUC = 0.93) showed the best performance to detect the CF threshold as defined by PET. PW-Tmax with a threshold >6.1 s and TTP with a threshold >4.8 s are the most predictive in detecting the CF threshold for MR-based mismatch definition.

Background The intensive polychemotherapy regimen eBEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone in escalated doses) is very active in patients with advanced-stage Hodgkin's lymphoma, albeit at the expense of severe toxicities. Individual patients might be cured with less burdensome therapy. We investigated whether metabolic response determined by PET after two cycles of standard regimen eBEACOPP (PET-2) would allow adaption of treatment intensity, increasing it for PET-2-positive patients and reducing it for PET-2-negative patients. Methods In this open-label, randomised, parallel-group phase 3 trial, we recruited patients aged 18-60 years with newly diagnosed, advanced-stage Hodgkin's lymphoma in 301 hospitals and private practices in Germany, Switzerland, Austria, the Netherlands, and the Czech Republic. After central review of PET-2, patients were assigned (1: 1) to one of two parallel treatment groups on the basis of their PET-2 result. Patients with positive PET-2 were randomised to receive six additional cycles of either standard eBEACOPP (8 x eBEACOPP in total) or eBEACOPP with rituximab (8 x R-eBEACOPP). Those with negative PET-2 were randomised between standard treatment with six additional cycles of eBEACOPP (8 x eBEACOPP) or experimental treatment with two additional cycles (4 x eBEACOPP). A protocol amendment in June, 2011, introduced a reduction of standard therapy to 6 x eBEACOPP; after this point, patients with positive PET-2 were no longer randomised and were all assigned to receive 6 x eBEACOPP and patients with negative PET-2 were randomly assigned to 6 x eBEACOPP (standard) or 4 x eBEACOPP (experimental). Randomisation was done centrally using the minimisation method including a random component, stratified according to centre, age (<45 vs >= 45 years), stage (IIB, IIIA vs IIIB, IV), international prognostic score (0-2 vs 3-7), and sex. eBEACOPP was given as previously described; rituximab