Successful treatment of adult Dravet syndrome patients with cenobamate.

Dravet syndrome (DS) is a rare, drug-resistant, severe developmental and epileptic encephalopathy caused by pathogenic variants in the α subunit of the voltage-gated sodium channel gene SCN1A. Hyperexcitability in DS results from loss of function in inhibitory interneurons. Thus sodium channel blockers are usually contraindicated in patients with DS as they may lead to disease aggravation. Cenobamate (CNB) is a novel antiseizure medication (ASM) with promising rates of seizure freedom in patients with focal-onset, drug-resistant epilepsy. CNB blocks persistent sodium currents by promoting the inactive states of sodium channels. In a multi-center study, we analyzed retrospectively the effect of an add-on therapy of CNB in adult patients with DS. We report four adult patients with DS in whom the use of CNB resulted in a significant seizure reduction of more than 80%, with a follow-up of up to 542 days. CNB was the first drug in these patients that resulted in a long-lasting and significant seizure reduction. No severe adverse events occurred. We highlight CNB as an ASM that may lead to a clinically meaningful reduction of seizure frequency in adult patients with DS. It is unclear, however, if all patients with DS benefit, requiring further investigation and functional experiments.

Real-world use and acceptance of rituximab biosimilars in non-Hodgkin lymphoma in an oncologist network in Germany.

Aim: Present real-world data for rituximab (biosimilar and reference)-containing regimens in extrapolated indications in non-Hodgkin lymphoma (NHL)/chronic lymphocytic leukemia (CLL). Patients & methods: Data collected from office-based oncologic practices in Germany (July 2017-June 2019). Results: Of 1741 patients, 1241 had NHL; 500 had CLL. Of 7595 therapy cycles, 28.3% used reference rituximab; 55.2% used rituximab biosimilars; 2.0% used subcutaneous rituximab; 14.5% used rituximab, not otherwise specified. Rituximab biosimilars were used across all indications; 57.3% of cycles were administered in extrapolated indications. Over 24 months, the proportion of rituximab prescriptions that were for biosimilars increased from 12.0 to 83.0%. Conclusion: Our real-world data in NHL and CLL depicts increasing use of rituximab biosimilars across multiple treatment protocols, including extrapolated indications.

Effectiveness of eslicarbazepine acetate in dependency of baseline anticonvulsant therapy: Results from a German prospective multicenter clinical practice study.

Eslicarbazepine acetate (ESL) is a third-generation antiepileptic drug (AED) approved as monotherapy for partial-onset seizures in adults and as adjunctive therapy in patients aged above 6 years in the European Union (EU). The prospective observational Zebinix Effects in DEpendency of BAseline Conditions (ZEDEBAC) study aimed at investigating the effectiveness of ESL in clinical practice, with ESL being administered as monotherapy (mono group), as only add-on to a current monotherapy (1+ group), or as add-on to ≥2 baseline AEDs (≥2+ group). In total, 237 patients were included, 35 in the mono group, 114 in the 1+, and 88 in the ≥2+ group. Six-month retention rates were 93.9%, 78.0%, and 75.3% in the mono, 1+, and ≥2+ group. There were 90.5%, 77.6%, and 48.3% of patients in the mono, 1+, and ≥2+ groups who were responders (patients with a ≥50% reduction in seizure frequency at follow-up vs. baseline). Seizure freedom rates were 81.5%, 47.9%, and 23.4%, respectively. Adverse drug reactions (ADRs) occurred in 11.4% of patients of the mono, 19.3% of the 1+, and 28.4% of patients of the ≥2+ group. Hyponatremia was reported as ADR in 3.4% of all patients. Although baseline variables differed considerably, with most elderly patients with tumor-related and vascular etiologies in the mono group and most patients with refractory epilepsies with pronounced use of concomitant sodium channel blockers (SCBs) in the ≥2+ group, retention as a measure of real-life effectiveness turned out not to be substantially different and favorable in all groups.

Specific adverse effects of antiepileptic drugs--A true-to-life monotherapy study.

BACKGROUND: In patients taking antiepileptic drugs (AEDs) for epilepsy, adverse effects (AEs) often lead to unfavorable quality of life, impaired adherence, and, eventually, discontinuation of pharmacological treatment. In a true-to-life sample of subjects from our academic epilepsy outpatient clinic, we aimed to identify predictors for overall high AE burden and for specific AEs focusing on patients on monotherapy. METHODS: All patients ≥16years of age with epilepsy for ≥12months were routinely asked to complete the Liverpool Adverse Event Profile (LAEP) just before their appointment. Demographic, epilepsy, and treatment variables were derived from our comprehensive outpatient database. RESULTS: Out of 841 patients, 438 (61% female, mean age: 44.7±17.1years) on monotherapy were included in this study. Levetiracetam (n=151), lamotrigine (n=167), valproic acid (n=73), or controlled-release carbamazepine (n=47) were the most commonly used antiepileptic drugs (AEDs). Independent predictors for general high AE burden (LAEP score≥45) were duration of epilepsy, lack of 12-month seizure freedom, and partial epilepsy, but none of the four individual AEDs. The most frequent LAEP-defined specific AEs were sleepiness, difficulty concentrating, tiredness, and memory problems. The three most frequent independent predictors for each of the 19 AEs were lack of 12-month seizure freedom (13/19 AEs), individual AED (7/19 AEs), and partial epilepsy (6/19 AEs). Levetiracetam was independently associated with anger/aggression, nervousness/agitation, upset stomach, depression, and sleep disturbance; lamotrigine with nervousness/agitation, upset stomach, and difficulty concentrating; and valproic acid with upset stomach and shaky hands. CONCLUSION: Individual AEDs independently predicted some specific AEs, but not overall high AE burden. Our findings may help to characterize patients with epilepsy who are at high risk for specific AEs. Dose reduction or change to another AED may reduce LAEP score and potential nonadherence.

Dataset of volatile organic compound emission patterns from flowers and damaged leaves recorded with gas-chromatography coupled ion mobility spectrometry.

Plants emit a range of volatile organic compounds (VOCs) as a way of interacting with their biotic and abiotic surroundings. These VOCs can have various ecological functions, such as attracting pollinators, repelling herbivores, or may be emitted in response to abiotic stress. For the present dataset, we used gas chromatography coupled ion mobility spectrometry (GC-IMS) to analyse the VOCs emitted by different plant species under controlled conditions. GC-IMS is a rapid and sensitive technique for gas phase analysis, that separates VOCs based on their retention time and drift time, resulting in characteristic heatmaps where the xy-position of a signal corresponds to compound identity, while signal intensity reflects its abundance. In this dataset, rapid analysis by GC-IMS was used to record emission pattern of 140 plant species from different taxonomic groups. This includes both floral volatiles and emission from leaves after induced damage. The data was pre-evaluated and listed in one table, containing information on the plant material used, as well as information on the respective emission patterns (including already identified compounds). Thus, this dataset provides a broad overview over plant VOC emissions. These can be used to either check the distribution of knowns substances, or the specific emissions of plants for functional, ecological or physiological studies or as the starting point for chemotaxonomic studies. The extraordinary ease with which these data can be generated - with the suitable set-up - lends itself to larger scale systematic or ecological studies across plant (or animal) groups and even ecosystems.

A multicenter randomized controlled feasibility trial of a digital self-management intervention for adults with epilepsy.

OBJECTIVE: Self-management interventions may enhance health-related quality of life (HRQoL) in epilepsy. However, several barriers often impair their implementation in the real world. Digital interventions may help to overcome some of these barriers. Considering this, the Helpilepsy Plus Prototype was developed as a prototype smartphone-delivered self-care treatment program for adults with epilepsy. METHODS: The 12-week Helpilepsy Plus Prototype was evaluated through a randomized controlled feasibility trial with a waiting-list control (WLC) group. Outcome measurement at baseline and at 12 weeks assessed adherence to the prototype intervention and changes in epilepsy-related outcomes. The primary endpoint was patient autonomy measured with EASE, and secondary endpoints included HRQoL measured with QOLIE-31, health literacy measured with HLQ, anxiety, and depression symptoms measured with HADS. Semi-structured interviews were conducted with a heterogeneous sample of participants to assess user-friendliness and usefulness. The prototype program was delivered through the Neuroventis Platform (Neuroventis, BV, Overijse, Belgium), a certified medical device (under EU/MDD Class I, and EU/MDR grace period). RESULTS: Ninety-two patients were included (46 in the intervention group, 46 in WLC). Most participants (63%, 58/92 women, median age 30 years) had pharmacoresistant epilepsy (61%, 56/92). Only 22% of participants (10/46) in the intervention group completed at least half of all intervention sessions. No significant differences between the intervention group and WLC were observed. Although there was a larger proportion of patients in the intervention group with meaningful improvements in HRQoL compared to WLC (19/46 versus 11/46), the difference was not significant (p = 0.119). Qualitative feedback showed that participants would appreciate more personalization, such as adaptation of the content to their current epilepsy knowledge level, a more interactive interface, shorter text sections, and interaction through reminders and notifications. SIGNIFICANCE: Digital interventions should allow sufficient scope for personalization and interaction to increase patient engagement and enable benefits from self-care apps. Feedback loops allow the participatory development of tailored interventions. PLAIN LANGUAGE SUMMARY: In this study, we investigated the effectiveness of an app-based self-help intervention. Study participants were either randomly assigned to a group that had access to the app or a group that received access to the app after the end of the study. Although a larger proportion of participants in the intervention group showed a relevant improvement in quality of life, the difference between the two groups was not statistically significant. Less than one-fifth of participants in the intervention group attended at least half of all intervention sessions; patient feedback showed that patients required more personalization and interactive options.

Therapeutic vaccination with recombinant adenovirus reduces splenic parasite burden in experimental visceral leishmaniasis.

Therapeutic vaccines, when used alone or in combination therapy with antileishmanial drugs, may have an important place in the control of a variety of forms of human leishmaniasis. Here, we describe the development of an adenovirus-based vaccine (Ad5-KH) comprising a synthetic haspb gene linked to a kmp11 gene via a viral 2A sequence. In nonvaccinated Leishmania donovani-infected BALB/c mice, HASPB- and KMP11-specific CD8(+) T cell responses were undetectable, although IgG1 and IgG2a antibodies were evident. After therapeutic vaccination, antibody responses were boosted, and IFNγ(+)CD8(+) T cell responses, particularly to HASPB, became apparent. A single vaccination with Ad5-KH inhibited splenic parasite growth by ∼66%, a level of efficacy comparable to that observed in early stage testing of clinically approved antileishmanial drugs in this model. These studies indicate the usefulness of adenoviral vectors to deliver leishmanial antigens in a potent and host protective manner to animals with existing L. donovani infection.

Evaluation of floral volatile patterns in the genus Narcissus using gas chromatography-coupled ion mobility spectrometry.

Premise: Daffodils (Narcissus, Amaryllidaceae) are iconic ornamentals with a complex floral biology and many fragrant species; however, little is known about floral plant volatile organic compounds (pVOCs) across the genus and additional sampling is desirable. The present study investigates whether the floral scent of 20 species of Narcissus can be characterized using gas chromatography-coupled ion mobility spectrometry (GC-IMS), with the aim of building a comparative pVOC data set for ecological and evolutionary studies. Methods: We used a commercial GC-IMS equipped with an integrated in-line enrichment system for a fast, sensitive, and automated pVOC analysis. This facilitates qualitative and (semi)-quantitative measurements without sample preparation. Results: The GC-IMS provided detailed data on floral pVOCs in Narcissus with very short sampling times and without floral enclosure. A wide range of compounds was recorded and partially identified. The retrieved pVOC patterns showed a good agreement with published data, and five "chemotypes" were characterized as characteristic combinations of floral volatiles. Discussion: The GC-IMS setup can be applied to rapidly generate large amounts of pVOC data with high sensitivity and selectivity. The preliminary data on Narcissus obtained here indicate both considerable pVOC variability and a good correspondence of the pVOC patterns with infrageneric classification, supporting the hypothesis that floral scent could represent a considerable phylogenetic signal.

Reversing the Inflammatory Process-25 Years of Tumor Necrosis Factor-α Inhibitors.

Immune-mediated inflammatory diseases, such as rheumatoid arthritis, psoriatic arthritis, peripheral and/or axial spondyloarthritis, Crohn's disease, and ulcerative colitis, are characterized by molecular and cellular changes in the immune system. Due to the systemic nature of these diseases, organs such as the liver or cardiovascular system are often affected by the inflammatory process. Tumor necrosis factor-α inhibitor therapy reduces the activation of pro-inflammatory signaling cascades, mitigates the chronic inflammatory process by restoring cellular balance, and alleviates clinical consequences, such as pain and tissue damage.

Reagent-Based Scaffold Diversity for DNA-Encoded Library Design: Solid Phase Synthesis of DNA-Tagged sp3-Rich Heterocycles by SnAP Chemistry.

Reactions that require strictly dry conditions are challenging to translate to a DNA-encoded library format. Controlled pore glass solid support-connected DNA oligonucleotide-aldehyde conjugates could be condensed with SnAP reagents and cyclized to various sp3-rich heterocycles. The Boc-group of products provided a handle for product purification, and its facile removal under acidic conditions was tolerated by a chemically stabilized barcode. The reaction provides reagent-based scaffold diversity with functionalities for further library synthesis.

Optimal imaging of cortico-muscular coherence through a novel regression technique based on multi-channel EEG and un-rectified EMG.

Cortico-muscular coherence (CMC) reflects interactions between muscular and cortical activities as detected with EMG and EEG recordings, respectively. Most previous studies utilized EMG rectification for CMC calculation. Yet, recent modeling studies predicted that EMG rectification might have disadvantages for CMC evaluation. In addition, previously the effect of rectification on CMC was estimated with single-channel EEG which might be suboptimal for detection of CMC. In order to optimally detect CMC with un-rectified EMG and resolve the issue of EMG rectification for CMC estimation, we introduce a novel method, Regression CMC (R-CMC), which maximizes the coherence between EEG and EMG. The core idea is to use multiple regression where narrowly filtered EEG signals serve as predictors and EMG is the dependent variable. We investigated CMC during isometric contraction of the abductor pollicis brevis muscle. In order to facilitate the comparison with previous studies, we estimated the effect of rectification with frequently used Laplacian filtering and C3/C4 vs. linked earlobes. For all three types of analysis, we detected CMC in the beta frequency range above the contralateral sensorimotor areas. The R-CMC approach was validated with simulations and real data and was found capable of recovering CMC even in case of high levels of background noise. When using single channel data, there were no changes in the strength of CMC estimated with rectified or un-rectified EMG--in agreement with the previous findings. Critically, for both Laplacian and R-CMC analyses EMG rectification resulted in significantly smaller CMC values compared to un-rectified EMG. Thus, the present results provide empirical evidence for the predictions from the earlier modeling studies that rectification of EMG can reduce CMC.

Therapeutic vaccination for cancer immunotherapy: antigen selection and clinical responses.

BACKGROUND: Because of its high specificity and low toxicity therapeutic vaccination is considered a desirable treatment for cancer. So far, however, the results of cancer vaccination trials have been disappointing, which is often attributed to the problem identifying appropriate vaccine antigens. Tumorassociated antigens are mostly autoantigens and therefore expected to be subject to immunosuppressive mechanisms. Cancer-testis antigens are the most prominent exception as, still being self, they are physiologically only expressed in immunopriviledged tissues and should therefore not induce autotolerance. This leads to the widely accepted hypothesis that cancer-testis antigens should be more efficient inducers of anti-tumor cellular immune responses than differentiation antigens. Aim of the study was to test this hypothesis by evaluating the published reports on clinical therapeutic vaccination trials for the objective clinical response rates to vaccination with cancer testis antigen vs. differentiation antigens. APPROACH: The results of vaccination clinical trials with cancer testis and/or differentiation antigens published in literature and databanks were analyzed for clinical outcome versus vaccine antigens. 21 publications on cancer testis antigen-based trials in which clinical outcome was reported according to WHO or RECIST were identified and analyzed. RESULTS: The rate of objective responses to cancer testis antigen vaccines in 239 patients was 3.8% and for the 235 patients vaccinated with cancer testis plus 3 differentiation antigens 4.3% compared to 2.6% for the 496 patients vaccinated with differentiation antigens alone. CONCLUSIONS: Cancer testis antigen-based vaccines seem slightly superior over vaccines based on differentiation antigens providing support for the hypothesis.

MHC I stabilizing potential of computer-designed octapeptides.

Experimental results are presented for 180 in silico designed octapeptide sequences and their stabilizing effects on the major histocompatibility class I molecule H-2K(b). Peptide sequence design was accomplished by a combination of an ant colony optimization algorithm with artificial neural network classifiers. Experimental tests yielded nine H-2K(b) stabilizing and 171 nonstabilizing peptides. 28 among the nonstabilizing octapeptides contain canonical motif residues known to be favorable for MHC I stabilization. For characterization of the area covered by stabilizing and non-stabilizing octapeptides in sequence space, we visualized the distribution of 100,603 octapeptides using a self-organizing map. The experimental results present evidence that the canonical sequence motives of the SYFPEITHI database on their own are insufficient for predicting MHC I protein stabilization.

Synthesis of DNA-coupled isoquinolones and pyrrolidines by solid phase ytterbium- and silver-mediated imine chemistry.

DNA-encoded libraries of chemically synthesized compounds are an important small molecule screening technology. The synthesis of encoded compounds in solution is currently restricted to a few DNA-compatible and water-tolerant reactions. Encoded compound synthesis of short DNA-barcodes covalently connected to solid supports benefits from a broad range of choices of organic solvents. Here, we show that this encoded chemistry approach allows for the synthesis of DNA-coupled isoquinolones by an Yb(iii)-mediated Castagnoli-Cushman reaction under anhydrous reaction conditions and for the synthesis of highly substituted pyrrolidines by Ag(i)-mediated 1,3-dipolar azomethine ylide cycloaddition. An encoding scheme for these DNA-barcoded compounds based on a DNA hairpin is demonstrated.

Screening of metal ions and organocatalysts on solid support-coupled DNA oligonucleotides guides design of DNA-encoded reactions.

DNA-encoded compound libraries are a widely used technology for target-based small molecule screening. Generally, these libraries are synthesized by solution phase combinatorial chemistry requiring aqueous solvent mixtures and reactions that are orthogonal to DNA reactivity. Initiating library synthesis with readily available controlled pore glass-coupled DNA barcodes benefits from enhanced DNA stability due to nucleobase protection and choice of dry organic solvents for encoded compound synthesis. We screened the compatibility of solid-phase coupled DNA sequences with 53 metal salts and organic reagents. This screening experiment suggests design of encoded library synthesis. Here, we show the reaction optimization and scope of three sp3-bond containing heterocyclic scaffolds synthesized on controlled pore glass-connected DNA sequences. A ZnCl2-promoted aza-Diels-Alder reaction with Danishefsky's diene furnished diverse substituted DNA-tagged pyridones, and a phosphoric acid organocatalyst allowed for synthesis of tetrahydroquinolines by the Povarov reaction and pyrimidinones by the Biginelli reaction, respectively. These three reactions caused low levels of DNA depurination and cover broad and only partially overlapping chemical space though using one set of DNA-coupled starting materials.

Coordinated expression of clustered cancer/testis genes encoded in a large inverted repeat DNA structure.

Cancer/testis antigens (CTA) are expressed in cancers and testis or placenta only and, therefore are considered promising targets for cancer immunotherapy and diagnosis. One family of CTA is the MAGEA family which comprises 13 members and was shown to be expressed synchronously with members from the CSAG (TRAG-3) family of CTA. The MAGEA genes are arranged in 4 subclusters located on the X chromosome. Subcluster III exposes a remarkable gene organization with an inverted repeat (IR) DNA structure of a triplicated couplet of a MAGEA gene and a CSAG gene. Analyzing the mRNA expression pattern of all genes of the MAGEA and CSAG family of cancer/testis genes, we show that the MAGEA and CSAG genes encoded in the large IR are expressed coordinately and independent from the MAGEAs encoded outside the IR. These results reinforce our hypothesis that the large MAGEA/CSAG-IR DNA structure has an impact on the regulation of gene expression.

Design of MHC I stabilizing peptides by agent-based exploration of sequence space.

Identification of molecular features that determine peptide interaction with major histocompatibility complex I (MHC I) is essential for vaccine development. We have developed a concept for peptide design by combining an agent-based artificial ant system with artificial neural networks. A jury of feedforward networks classifies octapeptides that are recognized by mouse MHC I protein H-2K(b). Prediction accuracy yielded a correlation coefficient of 0.94. Peptides were designed in machina by the artificial ant system and tested in vitro for their MHC I stabilizing effect. The behavior of the search agents during the design process was controlled by the jury network. The experimentally determined prediction accuracy was 89% for the designed stabilizing and 95% for the non-stabilizing peptides. Novel H-2K(b) stabilizing peptides were conceived that reveal extensions of known residue motifs. The combined network-agent system recognized context dependencies of residue positions. A diverse set of novel sequences exhibiting substantial activity was generated.

The Berlin Brain-Computer Interface: EEG-based communication without subject training.

The Berlin Brain-Computer Interface (BBCI) project develops a noninvasive BCI system whose key features are 1) the use of well-established motor competences as control paradigms, 2) high-dimensional features from 128-channel electroencephalogram (EEG), and 3) advanced machine learning techniques. As reported earlier, our experiments demonstrate that very high information transfer rates can be achieved using the readiness potential (RP) when predicting the laterality of upcoming left- versus right-hand movements in healthy subjects. A more recent study showed that the RP similarily accompanies phantom movements in arm amputees, but the signal strength decreases with longer loss of the limb. In a complementary approach, oscillatory features are used to discriminate imagined movements (left hand versus right hand versus foot). In a recent feedback study with six healthy subjects with no or very little experience with BCI control, three subjects achieved an information transfer rate above 35 bits per minute (bpm), and further two subjects above 24 and 15 bpm, while one subject could not achieve any BCI control. These results are encouraging for an EEG-based BCI system in untrained subjects that is independent of peripheral nervous system activity and does not rely on evoked potentials even when compared to results with very well-trained subjects operating other BCI systems.

Handwriting performance in the absence of visual control in writer's cramp patients: initial observations.

BACKGROUND: The present study was aimed at investigating the writing parameters of writer's cramp patients and control subjects during handwriting of a test sentence in the absence of visual control. METHODS: Eight right-handed patients with writer's cramp and eight healthy volunteers as age-matched control subjects participated in the study. The experimental task consisted in writing a test sentence repeatedly for fifty times on a pressure-sensitive digital board. The subject did not have visual control on his handwriting. The writing performance was stored on a PC and analyzed off-line. RESULTS: During handwriting all patients developed a typical dystonic limb posture and reported an increase in muscular tension along the experimental session. The patients were significantly slower than the controls, with lower mean vertical pressure of the pen tip on the paper and they could not reach the endmost letter of the sentence in the given time window. No other handwriting parameter differences were found between the two groups. CONCLUSION: Our findings indicate that during writing in the absence of visual feedback writer's cramp patients are slower and could not reach the endmost letter of the test sentence, but their level of automatization is not impaired and writer's cramp handwriting parameters are similar to those of the controls except for even lower vertical pressure of the pen tip on the paper, which is probably due to a changed strategy in such experimental conditions.

Combined optimization of spatial and temporal filters for improving brain-computer interfacing.

Brain-computer interface (BCI) systems create a novel communication channel from the brain to an output device by bypassing conventional motor output pathways of nerves and muscles. Therefore they could provide a new communication and control option for paralyzed patients. Modern BCI technology is essentially based on techniques for the classification of single-trial brain signals. Here we present a novel technique that allows the simultaneous optimization of a spatial and a spectral filter enhancing discriminability rates of multichannel EEG single-trials. The evaluation of 60 experiments involving 22 different subjects demonstrates the significant superiority of the proposed algorithm over to its classical counterpart: the median classification error rate was decreased by 11%. Apart from the enhanced classification, the spatial and/or the spectral filter that are determined by the algorithm can also be used for further analysis of the data, e.g., for source localization of the respective brain rhythms.