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Parkinson’s disease (PD) is a progressive neurodegenerative disorder affecting 1% of the population above sixty years. It is caused by an interaction between genetic and environmental risk factors. Loss of dopaminergic neurons in substantia nigra pars compacta (SNpc) is pathologically characterizing the disease and responsible for the cardinal motor symptoms, most notably, bradykinesia, rest tremors, rigidity, and loss of postural reflexes. Non-motor signs such as olfactory deficits, cognitive impairment, sleep behavior disorders, and gastrointestinal disturbances are reflecting disturbances in the non-dopaminergic system. They precede dopaminergic neuronal degenerations by 5–10 years and are considered the main contributors to patients’ disability, particularly after the successful implementation of levodopa (L-dopa) treatment of motor symptoms. The present general review aimed to briefly update non-motor signs and their underlying pathophysiology in PD.

Aim This European multicentric study aimed to prove safety and performance of the Bonebridge BCI 602 in children and adults suffering from either conductive hearing loss (CHL), mixed hearing loss (MHL), or single-sided sensorineural deafness (SSD). Methods 33 patients (13 adults and 10 children with either CHL or MHL and 10 patients with SSD) in three study groups were included. Patients were their own controls (single-subject repeated measures), comparing the unaided or pre-operative to the 3-month post-operative outcomes. Performance was evaluated by sound field thresholds (SF), word recognition scores (WRS) and/or speech reception thresholds in quiet (SRT) and in noise (SNR). Safety was demonstrated with a device-specific surgical questionnaire, adverse event reporting and stable pure-tone measurements. Results The Bonebridge BCI 602 significantly improved SF thresholds (+ 25.5 dB CHL/MHL/SSD), speech intelligibility in WRS (+ 68.0% CHL/MHL) and SRT in quiet (− 16.5 dB C/MHL) and in noise (− 3.51 dB SNR SSD). Air conduction (AC) and bone conduction (BC) thresholds remained stable over time. All adverse events were resolved, with none unanticipated. Mean audio processor wearing times in hours [h] per day for the CHL/MHL group were ~ 13 h for adults, ~ 11 h for paediatrics and ~ 6 h for the SSD group. The average surgical length was 57 min for the CHL/MHL group and 42 min for the SSD group. The versatility of the BCI 602 (reduced drilling depth and ability to bend the transition for optimal placement) allows for treatment of normal, pre-operated and malformed anatomies. All audiological endpoints were reached. Conclusions The Bonebridge BCI 602 significantly improved hearing thresholds and speech understanding. Since implant placement follows the patient’s anatomy instead of the shape of the device and the duration of surgery is shorter than with its predecessor, implantation is easier with the BCI 602. Performance and safety were proven for adults and children as well as for the CHL/MHL and SSD indications 3 months post-operatively.

To investigate the therapeutic effect of intravitreal pegcetacoplan on the inhibition of photoreceptor (PR) loss and thinning in geographic atrophy (GA) on conventional spectral-domain OCT (SD-OCT) imaging by deep learning-based automated PR quantification.Post hoc analysis of a prospective, multicenter, randomized, sham (SM)-controlled, masked phase II trial investigating the safety and efficacy of pegcetacoplan for the treatment of GA because of age-related macular degeneration.Study eyes of 246 patients, randomized 1:1:1 to monthly (AM), bimonthly (AEOM), and SM treatment.We performed fully automated, deep learning-based segmentation of retinal pigment epithelium (RPE) loss and PR thickness on SD-OCT volumes acquired at baseline and months 2, 6, and 12. The difference in the change of PR loss area was compared among the treatment arms. Change in PR thickness adjacent to the GA borders and the entire 20° scanning area was compared between treatment arms.Square-root transformed PR loss area in μm or mm, PR thickness in μm, and PR loss/RPE loss ratio.A total of 31 556 B-scans of 644 SD-OCT volumes of 161 study eyes (AM 52, AEOM 54, SM 56) were evaluated from baseline to month 12. Comparison of the mean change in PR loss area revealed statistically significantly less growth in the AM group at months 2, 6, and 12 than in the SM group (-41 μm ± 219 vs. 77 μm ± 126; P = 0.0004; -5 μm ± 221 vs. 156 μm ± 139; P0.0001; 106 μm ± 400 vs. 283 μm ± 226; P = 0.0014). Photoreceptor thinning was significantly reduced under AM treatment compared with SM within the GA junctional zone, as well as throughout the 20° area. A trend toward greater inhibition of PR loss than RPE loss was observed under therapy.Distinct and reliable quantification of PR loss using deep learning-based algorithms offers an essential tool to evaluate therapeutic efficacy in slowing disease progression. Photoreceptor loss and thinning are reduced by intravitreal complement C3 inhibition. Automated quantification of PR loss/maintenance based on OCT images is an ideal approach to reliably monitor disease activity and therapeutic efficacy in GA management in clinical routine and regulatory trials.

The optimal treatment for patients with asymptomatic carotid artery stenosis is under debate. Since best medical treatment (BMT) has improved over time, the benefit of carotid endarterectomy (CEA) or carotid artery stenting (CAS) is unclear. Randomised data comparing the effect of CEA and CAS versus BMT alone are absent. We aimed to directly compare CEA plus BMT with CAS plus BMT and both with BMT only.SPACE-2 was a multicentre, randomised, controlled trial at 36 study centres in Austria, Germany, and Switzerland. We enrolled participants aged 50-85 years with asymptomatic carotid artery stenosis at the distal common carotid artery or the extracranial internal carotid artery of at least 70%, according to European Carotid Surgery Trial criteria. Initially designed as a three-arm trial including one group for BMT alone (with a randomised allocation ratio of 2·9:2·9:1), the SPACE-2 study design was amended (due to slow recruitment) to become two substudies with two arms each comparing CEA plus BMT with BMT alone (SPACE-2a) and CAS plus BMT with BMT alone (SPACE-2b); in each case in a 1:1 randomisation. Participants and clinicians were not masked to allocation. The primary efficacy endpoint was the cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years. The primary safety endpoint was any stroke or death from any cause within 30 days after CEA or CAS. The primary analysis was by intention-to treat, which included all randomly assigned patients in SPACE-2, SPACE-2a, and SPACE-2b, analysed using meta-analysis of individual patient data. We did two-step hierarchical testing to first show superiority of CEA and CAS to BMT alone then to assess non-inferiority of CAS to CEA. Originally, we planned to recruit 3640 patients; however, the study had to be stopped prematurely due to insufficient recruitment. This report presents the primary analysis at 5-year follow-up. This trial is registered with ISRCTN, number ISRCTN78592017.513 patients across SPACE-2, SPACE-2a, and SPACE-2b were recruited and surveyed between July 9, 2009, and Dec 12, 2019, of whom 203 (40%) were allocated to CEA plus BMT, 197 (38%) to CAS plus BMT, and 113 (22%) to BMT alone. Median follow-up was 59·9 months (IQR 46·6-60·0). The cumulative incidence of any stroke or death from any cause within 30 days or any ipsilateral ischaemic stroke within 5 years (primary efficacy endpoint) was 2·5% (95% CI 1·0-5·8) with CEA plus BMT, 4·4% (2·2-8·6) with CAS plus BMT, and 3·1% (1·0-9·4) with BMT alone. Cox proportional-hazard testing showed no difference in risk for the primary efficacy endpoint for CEA plus BMT versus BMT alone (hazard ratio [HR] 0·93, 95% CI 0·22-3·91; p=0·93) or for CAS plus BMT versus BMT alone (1·55, 0·41-5·85; p=0·52). Superiority of CEA or CAS to BMT was not shown, therefore non-inferiority testing was not done. In both the CEA group and the CAS group, five strokes and no deaths occurred in the 30-day period after the procedure. During the 5-year follow-up period, three ipsilateral strokes occurred in both the CAS plus BMT and BMT alone group, with none in the CEA plus BMT group.CEA plus BMT or CAS plus BMT were not found to be superior to BMT alone regarding risk of any stroke or death within 30 days or ipsilateral stroke during the 5-year observation period. Because of the small sample size, results should be interpreted with caution.German Federal Ministry of Education and Research (BMBF) and German Research Foundation (DFG).

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).

Objectives Opioid prescription rates worldwide suggest miscalibrated risk perceptions among those who prescribe, dispense, and take opioids. Findings from cognitive science show that risk perceptions can differ systematically depending on whether people learn about risks by description or experience. We investigated the effects of descriptive and simulated experience risk formats on patients’ risk perceptions and behavior regarding long-term strong opioid use. Methods 300 German patients with chronic noncancer pain were randomly assigned in an exploratory randomized controlled trial to either a descriptive format (fact box) or a simulated experience format (interactive simulation). Primary endpoints were subjective and objective risk perceptions and intended intake behavior. Results Both formats significantly improved patients’ objective risk perception; patients who saw the fact box estimated some outcomes more accurately (p = .031). Formats were equally effective in improving patients’ subjective risk perception in terms of opioids’ harms; however, patients receiving the simulation showed a greater reduction and termination of their opioid intake (p = .030) and a higher uptake of alternative therapies. Conclusions Descriptive and simulated experience risk formats improve risk perceptions and behavior regarding potent but highly risky drugs. Practice implications To eliminate risky behavior, simulated experience formats may be superior to descriptive formats.

Objectives To evaluate the quantitative impact of drusen and hyperreflective foci (HRF) volumes on mesopic retinal sensitivity in non-exudative age-related macular degeneration (AMD). Methods In a standardized follow-up scheme of every three months, retinal sensitivity of patients with early or intermediate AMD was assessed by microperimetry using a custom pattern of 45 stimuli (Nidek MP-3, Gamagori, Japan). Eyes were consecutively scanned using Spectralis SD-OCT (20° × 20°, 1024 × 97 × 496). Fundus photographs obtained by the MP-3 allowed to map the stimuli locations onto the corresponding OCT scans. The volume and mean thickness of drusen and HRF within a circle of 240 µm centred at each stimulus point was determined using automated AI-based image segmentation algorithms. Results 8055 individual stimuli from 179 visits from 51 eyes of 35 consecutive patients were matched with the respective OCT images in a point-to-point manner. The patients mean age was 76.85 ± 6.6 years. Mean retinal sensitivity at baseline was 25.7 dB. 73.47% of all MP-spots covered drusen area and 2.02% of MP-spots covered HRF. A negative association between retinal sensitivity and the volume of underlying drusen (p 3) and HRF volume (p = 0.002, Estimate -5.230 db/µm3) was found. During observation time, no eye showed conversion to advanced AMD. Conclusion A direct correlation between drusen and lower sensitivity of the overlying photoreceptors can be observed. For HRF, a small but significant correlation was shown, which is compromised by their small size. Biomarker quantification using AI-methods allows to determine the impact of sub-clinical features in the progression of AMD.

Geographic atrophy (GA) represents a late stage of age-related macular degeneration, which leads to irreversible vision loss. With the first successful therapeutic approach, namely complement inhibition, huge numbers of patients will have to be monitored regularly. Given these perspectives, a strong need for automated GA segmentation has evolved. The main purpose of this study was the clinical validation of an artificial intelligence (AI)-based algorithm to segment a topographic 2D GA area on a 3D optical coherence tomography (OCT) volume, and to evaluate its potential for AI-based monitoring of GA progression under complement-targeted treatment. 100 GA patients from routine clinical care at the Medical University of Vienna for internal validation and 113 patients from the FILLY phase 2 clinical trial for external validation were included. Mean Dice Similarity Coefficient (DSC) was 0.86 ± 0.12 and 0.91 ± 0.05 for total GA area on the internal and external validation, respectively. Mean DSC for the GA growth area at month 12 on the external test set was 0.46 ± 0.16. Importantly, the automated segmentation by the algorithm corresponded to the outcome of the original FILLY trial measured manually on fundus autofluorescence. The proposed AI approach can reliably segment GA area on OCT with high accuracy. The availability of such tools represents an important step towards AI-based monitoring of GA progression under treatment on OCT for clinical management as well as regulatory trials.

Background: Effective dental plaque removal is essential for oral health. Different toothbrush parameters including head-size, filament-diameter and interdent-height and different brushing movements like horizontal, rotating and vertical may affect plaque removal efficacy. The purpose of the study was to examine plaque removal efficacy of different design parameters of manual toothbrushes. Methods: Eight manual toothbrushes were tested using a validated robot test to examine efficacy of toothbrush on replicated human teeth. Characteristics tested were: i) head-size, ii) filament-diameter, iii) cutting-height, iv) hardness, v) interdental-height. Each test ran five times in horizontal, rotating, vertical movements. Simulated Plaque removal was evaluated using automated plaque planimetry: 30 fields/tooth, 13 areas representing buccal, lingual, proximal tooth sites. The Kolmogorov-Smirnov-test was applied to test tooth surface variables for normal distribution of plaque removal values. Parameters were analysed by independent two-sample t-test to assess mean differences. Where null hypothesis of normality was rejected, the Wilcoxon-Mann-Whitney-U-test was used. Results: Plaque removal was significantly better with toothbrush having smaller head-size (compact vs. full-size); smaller filament-diameter (0.12 mm vs. 0.15 mm); larger cutting-height (12 mm vs. 9 mm); softer filaments (0.15 mm or 0.18 mm vs. 0.23 mm) and greater interdent-height difference (8.5/11 mm vs. 10/11 mm). Conclusions: Manual brushes allowing filaments free to flex with longer, softer and/or having a difference in filament length overall removed significantly more simulated plaque as compared to more standard flat trim, stiff brushes with shorter, harder bristles and a larger head size. This indicates that the advances in toothbrush design can further enhance plaque removal, thereby aiding in better oral health.

Supplementary Figure 1 from Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

Supplementary Figure 2 from Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

Supplementary Table 1 from Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia

Purpose: In childhood acute lymphoblastic leukemia (ALL), ∼25% of patients suffer from relapse. In recurrent disease, despite intensified therapy, overall cure rates of 40% remain unsatisfactory and survival rates are particularly poor in certain subgroups. The probability of long-term survival after relapse is predicted from well-established prognostic factors (i.e., time and site of relapse, immunophenotype, and minimal residual disease). However, the underlying biological determinants of these prognostic factors remain poorly understood.Experimental Design: Aiming at identifying molecular pathways associated with these clinically well-defined prognostic factors, we did gene expression profiling on 60 prospectively collected samples of first relapse patients enrolled on the relapse trial ALL-REZ BFM 2002 of the Berlin-Frankfurt-Münster study group.Results: We show here that patients with very early relapse of ALL are characterized by a distinctive gene expression pattern. We identified a set of 83 genes differentially expressed in very early relapsed ALL compared with late relapsed disease. The vast majority of genes were up-regulated and many were late cell cycle genes with a function in mitosis. In addition, samples from patients with very early relapse showed a significant increase in the percentage of S and G2-M phase cells and this correlated well with the expression level of cell cycle genes.Conclusions: Very early relapse of ALL is characterized by an increased proliferative capacity of leukemic blasts and up-regulated mitotic genes. The latter suggests that novel drugs, targeting late cell cycle proteins, might be beneficial for these patients that typically face a dismal prognosis.

File 3 L1236 Data from Dynamic Mathematical Modeling of IL13-Induced Signaling in Hodgkin and Primary Mediastinal B-Cell Lymphoma Allows Prediction of Therapeutic Targets

Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) share a frequent constitutive activation of JAK (Janus kinase)/STAT signaling pathway. Because of complex, nonlinear relations within the pathway, key dynamic properties remained to be identified to predict possible strategies for intervention. We report the development of dynamic pathway models based on quantitative data collected on signaling components of JAK/STAT pathway in two lymphoma-derived cell lines, MedB-1 and L1236, representative of PMBL and cHL, respectively. We show that the amounts of STAT5 and STAT6 are higher whereas those of SHP1 are lower in the two lymphoma cell lines than in normal B cells. Distinctively, L1236 cells harbor more JAK2 and less SHP1 molecules per cell than MedB-1 or control cells. In both lymphoma cell lines, we observe interleukin-13 (IL13)-induced activation of IL4 receptor α, JAK2, and STAT5, but not of STAT6. Genome-wide, 11 early and 16 sustained genes are upregulated by IL13 in both lymphoma cell lines. Specifically, the known STAT-inducible negative regulators CISH and SOCS3 are upregulated within 2 hours in MedB-1 but not in L1236 cells. On the basis of this detailed quantitative information, we established two mathematical models, MedB-1 and L1236 model, able to describe the respective experimental data. Most of the model parameters are identifiable and therefore the models are predictive. Sensitivity analysis of the model identifies six possible therapeutic targets able to reduce gene expression levels in L1236 cells and three in MedB-1. We experimentally confirm reduction in target gene expression in response to inhibition of STAT5 phosphorylation, thereby validating one of the predicted targets. Cancer Res; 71(3); 693–704. ©2010 AACR.

File 2 MedB-1 Data from Dynamic Mathematical Modeling of IL13-Induced Signaling in Hodgkin and Primary Mediastinal B-Cell Lymphoma Allows Prediction of Therapeutic Targets

L1236 model from Dynamic Mathematical Modeling of IL13-Induced Signaling in Hodgkin and Primary Mediastinal B-Cell Lymphoma Allows Prediction of Therapeutic Targets

Supplementary Methods, Figures and References from Dynamic Mathematical Modeling of IL13-Induced Signaling in Hodgkin and Primary Mediastinal B-Cell Lymphoma Allows Prediction of Therapeutic Targets

MedB-1 model from Dynamic Mathematical Modeling of IL13-Induced Signaling in Hodgkin and Primary Mediastinal B-Cell Lymphoma Allows Prediction of Therapeutic Targets

A time span of 60 years covers the detection of catecholamines in the brain, their function in movement and correlation to Parkinson’s disease (PD). The clinical findings that orally given l-DOPA can alleviate or even prevent akinesia gave great hope for the treatment of PD. Attention focused on the role of tyrosine hydroxylase (TH) as the rate-limiting enzyme in the formation of catecholamines. It became evident that the enzyme driven formation is lowered in PD. Such results could only be obtained from studying human brain samples demonstrating the necessity for human brain banks. Originally, a TH enzyme deficiency was suspected in PD. Studies were conducted on the enzyme properties: its induction and turnover, the complex regulation starting with cofactor requirements as tetrahydrobiopterin and ferrous iron, and the necessity for phosphorylation for activity as well as inhibition by toxins or regulatory feedback inhibition by catecholamines. In the course of time, it became evident that neurodegeneration and cell death of dopaminergic neurons is the actual pathological process and the decrease of TH a cophenomenon. Nevertheless, TH immunochemistry has ever since been a valuable tool to study neuronal pathways, neurodegeneration in various animal models of neurotoxicity and cell cultures, which have been used as well to test potential neuroprotective strategies.

To investigate the functional associations of intraretinal fluid (IRF) and subretinal fluid (SRF) volumes at baseline and after the loading dose as well as fluid change after the first injection with best-corrected visual acuity (BCVA) in patients with neovascular age-related macular degeneration (nAMD) who received an anti-VEGF treatment over 24 months.Post hoc analysis of a phase III, randomized, multicenter trial in which ranibizumab was administered monthly or in a pro re nata regimen (HARBOR).Study eyes of 1094 treatment-naïve patients with nAMD.IRF and SRF volumes were segmented automatically on monthly spectral domain OCT images. Fluid volumes and changes thereof were included as covariates into longitudinal mixed-effects models, which modeled BCVA trajectories.BCVA estimates corresponding to baseline, follow-up, and persistent IRF/SRF volumes after the loading dose; BCVA estimates of change in fluid volumes after the first injection; and marginal and conditional RAnalysis of 22 494 volumetric scans revealed that foveal IRF consistently shows a negative correlation with BCVA at baseline and subsequent visits (-3.23 and -4.32 letters/100 nL, respectively). After the first injection, BCVA increased by +2.13 letters/100 nL decrease in foveal IRF. Persistent IRF was associated with lower baseline BCVA and less improvement. Foveal SRF correlated with better BCVA at baseline and subsequent visits (+6.52 and +1.42 letters/100 nL, respectively). After the first injection, SRF decrease was associated with significant vision gain (+5.88 letters/100 nL). Foveal fluid correlated more with BCVA than parafoveal IRF/SRF.Although IRF consistently correlates with decreased function and recovery throughout therapy, SRF is associated with a more pronounced functional improvement. Moreover, SRF resolution provides increased benefit. Fluid-function correlation represents an essential base for the development of personalized treatment regimens, optimizing functional outcomes, and reducing treatment burden.

Cancer drugs are a major component of pharmaceutical spending in the USA and Europe. The number of approved cancer drugs continues to increase. More new drugs with overlapping mechanisms of action and similar approved indications might be expected to decrease prices within drug classes. We compared patterns of price changes for cancer drugs within the same class in the USA and in two European countries (Germany and Switzerland) with national mechanisms for drug price negotiation.For this comparative analysis, we identified cancer drugs approved for the treatment of solid cancers in the USA and Europe (Germany and Switzerland) between Jan 1, 2009, and Dec 31, 2020, using the US Food and Drug Administration's Drugs@FDA database and the European Medicines Agency's publicly available database. We considered cancer drugs as within-class competitors if they were approved for the same indication and had the same biological mechanism. We calculated monthly treatment prices for each drug, median price changes at launch and over time, and differences within and across drug classes. European price data were converted to US dollars by applying the exchange rates on Dec 1, 2020, and prices were adjusted for inflation. Median changes in the drugs' monthly treatment prices at 2 and 4 years after market entry across and within drug classes were also assessed. For the USA, correlations in relative price changes between all pairs of drugs within and across drug classes were calculated with Spearman's rank correlation.Our study cohort comprised 12 drug classes covering nine indications. With the exception of one drug, increasing prices were observed within and across all drug classes in the USA (median 6·07% [range -3·60 to 33·83] 2 years after market entry, and 15·31% [-4·15 to 54·64] 4 years after market entry). By contrast, in Europe, prices generally decreased over time or did not increase more than inflation (2 years after market entry: -21·01% [range -50·72 to 12·71] in Germany and -1·48% [-26·81 to 1·69] in Switzerland; 4 years after market entry: -25·54% [-51·81 to 11·63] in Germany and -13·02% [-43·83 to 18·31] in Switzerland). In the USA, most prices changes within and across drug classes occurred at the end and beginning of the year (ie, from Dec 1 to Jan 31). In the USA, correlation for price changes was r=0·29 (SD 0·36) for within-class drugs and r=0·28 (0·36) for drugs across drug classes.Competition within classes of cancer drugs generally did not constrain rising prices in the USA. Price negotiations, as practised in Germany or Switzerland, could help address the high prices of cancer drugs in the USA.Swiss Cancer Research Foundation (Krebsforschung Schweiz), Swiss National Science Foundation, and Arnold Ventures.

International audience; The reaction catalyzed by ubiquitous thiamine pyrophosphate-dependent transketolase engaged in cells in the pentose phosphate pathway can be applied in vitro to the cleavage of aliphatic α-hydroxy ketones with thermostable transketolase variants from Geobacillus stearothermophilus obtained through rational design. The simple variant F435I gave the best activity toward (3S)-1,3-dihydroxyhexan-2-one 3, leading to the corresponding product with 92% yield after only 2 h of reaction time. Three triple variants H102L/H474 (S, G, or A)/F118I were found to cleave (±)-4-hydroxyhexan-3-one 6, giving the corresponding product with 90, 82, and 79% yield, respectively, after 24 h, whereas wild-type transketolase was almost ineffective. This biocatalytic strategy offers a promising one-step alternative to other multienzyme or chemical ways for the cleavage of aliphatic α-hydroxy ketones.

In mass spectrometry-based proteomics, heavy internal standards are used to validate target peptide detections and to calibrate peptide quantitation. Here, we report light contamination present in heavy labelled synthetic peptides of high isotopic enrichment. Application of such peptides as assay-internal standards potentially compromises the detection and quantitation especially of low abundant cellular peptides. Therefore, it is important to adopt guidelines to prevent false-positive identifications of endogenous light peptides as well as errors in their quantitation from biological samples.

Zusammenfassung. Der Begriff der «Übertherapie» bezeichnet Situationen, in denen der Einsatz von diagnostischen oder therapeutischen Massnahmen negativ bewertet wird. Die negativen Bewertungen können sich zum einen auf die wissenschaftliche Fundierung der jeweils eingesetzten Massnahmen beziehen. Zum anderen werden im Kontext von «Übertherapie» häufig Fragen hinsichtlich der Angemessenheit des Einsatzes von medizinischen Massnahmen mit Blick auf die Förderung des Patientenwohls formuliert. Eine medizinisch wie ethisch reflektierte Indikationsstellung bildet einen möglichen Ausgangspunkt zur Vermeidung von «Übertherapie». Dem Thema medikamentöse Übertherapie von Patienten am Lebensende mit weit fortgeschrittenen, unheilbaren Krebserkrankungen haben sich in den letzten beiden Jahrzehnten zahlreiche Untersuchungen, besonders in den USA und Europa, gewidmet. Hingewiesen wurde dabei insbesondere auf das Problem der Überversorgung in den letzten Tagen beziehungsweise Monaten vor dem Tod durch Applikation von Chemotherapie, sogenannter zielgerichteter Arzneimittel und / oder Strahlentherapie, die assoziiert sind mit einem erhöhten Risiko für kardiopulmonale Wiederbelebung und / oder mechanische Beatmung sowie einem Versterben auf der Intensivstation. Der Nutzen einer frühzeitigen Einbeziehung palliativmedizinischer Massnahmen bei Patienten mit weit fortgeschrittenen Krebserkrankungen hat inzwischen verstärkte Aufmerksamkeit gefunden, da hierdurch die Lebensqualität am Lebensende verbessert werden kann. Elementar für die Vermeidung von Übertherapie ist deshalb das Arzt-Patienten-Gespräch, in dem nicht nur die Wünsche und Prioritäten des Patienten, sondern auch das Verständnis des Patienten über das nahende Lebensende geklärt werden sollte. Beides ist im klinischen Alltag nicht selbstverständlich, wobei die Gründe hierfür zu suchen sind in fehlender Ausbildung, strukturellen Hemmnissen, aber auch Projektionen und Vorannahmen auf beiden Seiten sind. Frühzeitiges und strukturiertes Vorgehen, gegebenenfalls mit Hilfe der Palliativmedizin, kann diese Mängel reduzieren.

Zu Beginn des zwanzigsten Jahrhunderts entdeckten Schauspielerinnen die Selbst- und Ausbildung als neuen Spielraum für sich, wie sich exemplarisch an der von Louise Dumont und Gustav Lindemann gegründeten Schauspielschule in Düsseldorf aufzeigen lässt. Sie sahen sich als Rollenmodell für die nächste Generation und konnten die strukturelle Ungleichheit der Rollenvergabe, die ältere Schauspielerinnen klar benachteiligte, kompensieren; Schüler*innen wiederum projizierten Emanzipationswünsche auf die neue Schauspielschule und die in ihnen autonom wirkenden Schauspieler*innen. Die im Beitrag untersuchten Quellen zeigen, in welcher Weise der neue Spielraum der Vermittlung geprägt war von realen Zwängen des Theaterbetriebs und einer bis ins Spirituelle überhöhten Idee der Reform.

Aim: This European multicentric study aimed to prove safety and performance of the Bonebridge BCI 602 in children and adults suffering from either conductive hearing loss (CHL), mixed hearing loss (MHL), or single-sided sensorineural deafness (SSD). Methods: 33 patients (13 adults and 10 children with either CHL or MHL and 10 patients with SSD) in three study groups were included. Patients were their own controls (single-subject repeated measures), comparing the unaided or pre-operative to the 3-month post-operative outcomes. Performance was evaluated by sound field thresholds (SF), word recognition scores (WRS) and/or speech reception thresholds in quiet (SRT) and in noise (SNR). Safety was demonstrated with a device-specific surgical questionnaire, adverse event reporting and stable pure-tone measurements. Results: The Bonebridge BCI 602 significantly improved SF thresholds (+ 25.5 dB CHL/MHL/SSD), speech intelligibility in WRS (+ 68.0% CHL/MHL) and SRT in quiet (− 16.5 dB C/MHL) and in noise (− 3.51 dB SNR SSD). Air conduction (AC) and bone conduction (BC) thresholds remained stable over time. All adverse events were resolved, with none unanticipated. Mean audio processor wearing times in hours [h] per day for the CHL/MHL group were ~ 13 h for adults, ~ 11 h for paediatrics and ~ 6 h for the SSD group. The average surgical length was 57 min for the CHL/MHL group and 42 min for the SSD group. The versatility of the BCI 602 (reduced drilling depth and ability to bend the transition for optimal placement) allows for treatment of normal, pre-operated and malformed anatomies. All audiological endpoints were reached. Conclusions: The Bonebridge BCI 602 significantly improved hearing thresholds and speech understanding. Since implant placement follows the patient’s anatomy instead of the shape of the device and the duration of surgery is shorter than with its predecessor, implantation is easier with the BCI 602. Performance and safety were proven for adults and children as well as for the CHL/MHL and SSD indications 3 months post-operatively.

In time series analysis auto regressive (AR) modelling of zero mean data is widely used for system identification, signal decorrelation, detection of outliers and forecasting. An AR process of order p is uniquely defined by r coefficients and the variance of the noise. The roots of the characteristic polynomial can be used as an alternative parametrization of the coefficients, which is used to construct a continuous covariance function of the AR processes or to verify that the AR processes are stationary. In this contribution we propose an approach to estimate an AR process of time varying coefficients (TVAR process). In the literature, roots are evaluated at discrete times, rather than a continuous function like we have for time varying systems. By introducing the assumption that the movement of the roots are linear functions in time, stationarity for all possible epochs in the time domain is easy to accomplish. We will illustrate how this assumption leads to TVAR coefficients where the k-th coefficient is a polynomial of order k with further restrictions on the parameters of the coefficients. At first we study how to estimate TVAR process parameters by using a Least Squares approach in general. As any AR process can be rewritten as a combination of AR processes of order two with two complex conjugated roots and AR processes of order one, we limit our investigations to these orders. Higher order TVAR processes are computed by successively estimating TVAR processes of orders one or two. Based on a simulation, we will demonstrate the advantages of a time varying model and compare them to the stationary time stable model. In addition, we will give a method to identify time series, for which the model of the TVAR processes with linear roots is suitable.

International audience; Hydroxamic acids are metal-chelating compounds that show important biological activity including anti-tumor effects. We have recently engineered the transketolase from Geobacillus stearothermopilus (TKgst) to convert benzaldehyde as a non-natural acceptor substrate. Realizing the structural and electronic similarity to nitrosobenzene, we studied the TK-catalyzed conversion of nitrosoarenes to yield N-arylated hydroxamic acids. Here we demonstrate that wild-type and variants of this versatile TKgst enzyme indeed induce the rapid biocatalytic conversion of variously p-, m- and o-substituted nitrosoarenes to produce a variety of corresponding N-aryl hydroxamic acids via creation of a carbon-nitrogen instead of a carbon-carbon bond. Further structural modifications can be introduced by varying the donor component, such as hydroxypyruvate or pyruvate.

Background: Well-developed assessment methods have a positive impact on students’ performance, and higher education institutes are usually encouraged to establish and use effective assessment methods that effectively enhance the learning process. Objectives: This study was designed to compare students’ performance in multiple choice questions (MCQs) including best single answer (BSA) and multiple true and false (MTF) types, and very short answer (VSA) questions, and to evaluate gender differences and feedback from students and faculty. Materials and methods: A test containing three different types of questions, BSA, MTF and VSA questions (10 each), was delivered to eight groups of veterinary pathology students (3rd level, Faculty of Veterinary Medicine, Assiut University, Assiut, Egypt) in April 2022. Students’ performance, test reliability and gender differences as well as feedback from students and faculty were evaluated. Results: Students did a significant higher performance in BSA and MTF questions compared to VSA questions. The reliability of BSA, MTF and VSA questions between different groups of students were 0.53, 0.52 and 0.13, respectively. Girl students achieved a higher performance in the whole test compared to boy students. Both boy and girl students showed nearly similar performance in BSA and MTF questions. However, girl students got significant higher score in VSA questions compared to boy students. Students’ and faculty opinions were in favor of BSA and MTF questions. Conclusion: Students did much better in MCQs than VSA questions. BSA and MTF questions are preferentially favored by students and faculty.

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 suggest that more biosimilars have been marketed in Germany and Switzerland than in the US. Policies that counter anticompetitive practices in the US could allow biosimilars to enter the market sooner and could also lower health care costs with improved access. Awareness of biosimilars should be promoted to increase uptake of biosimilars globally.