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We normally perceive a stable visual environment despite eye movements. To achieve such stability, visual processing integrates information across a given saccade, and laboratory hallmarks of such integration are robustly observed by presenting brief perisaccadic visual probes. In one classic phenomenon, probe locations are grossly mislocalized. This mislocalization is believed to depend, at least in part, on corollary discharge associated with saccade-related neuronal movement commands. However, we recently found that superior colliculus motor bursts, a known source of corollary discharge, can be different for different image appearances of the saccade target. Therefore, here we investigated whether perisaccadic mislocalization also depends on saccade-target appearance. We asked human participants to generate saccades to either low (0.5 cycles/deg) or high (5 cycles/deg) spatial frequency gratings. We always placed a high contrast target spot at grating center, to ensure matched saccades across image types. We presented a single, brief perisaccadic probe, which was high in contrast to avoid saccadic suppression, and the subjects pointed (via mouse cursor) at the seen probe location. We observed stronger perisaccadic mislocalization for low spatial frequency saccade targets, and for upper visual field probe locations. This was despite matched saccade metrics and kinematics across conditions, and it was also despite matched probe visibility for the different saccade target images (low versus high spatial frequency). Assuming that perisaccadic visual mislocalization depends on corollary discharge, our results suggest that such discharge might relay more than just spatial saccade vectors to the visual system; saccade-target visual features can also be transmitted.

Background: We recently described magnetic resonance imaging (MRI) features of children with transverse myelitis (TM) at first event with important and unique differences depending on the underlying disease entity., Objective: To study the resolution of lesions over time in children with TM due to MOG-antibody associated disorders (MOGAD), multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD) or double seronegative TM., Patients and Methods: In this prospective study, 78 children from 29 different medical centres with TM as part of MOGAD (n = 34), MS (n = 20), NMOSD (n = 5) and in double seronegative children (n = 19) were included. A grading system consisting of 4 grades (grade 0 = complete resolution; grade 3 = no resolution at all) was used to compare the degree of lesion resolution over time in the different disease entities. Time to lesion resolution was evaluated by Kaplan-Meier statistics and log-rank test., Results: Significant differences of the interval between first MRI until resolution of lesions were observed between the four disease entities. The most rapid and complete resolution was seen in MOGAD, followed by double seronegative, MS and NMOSD. Median periods until total resolution (grade 0) were 191 days (MOGAD), 750 days (double seronegative), 1117 days (MS), while none of the patients with NMOSD reached a complete resolution during the observation period. The better prognosis of MOGAD compared to MS was independent of sex, age, oligoclonal bands and cell count in the multivariate Cox analysis (P < 0.001)., Conclusion: Children with TM and antibodies to MOG show a faster resolution of radiological lesions compared to children with MS and NMOSD., Competing Interests: Declaration of competing interest Ines El Naggar: received travel grants from UCB. Eva-Maria Wendel: received travel grants from UCB. Annikki Bertolini: received travel grants from UCB. Markus Reindl: was supported by research grants from the Austrian Science Fund (FWF projects P32699 and IPN170), the Austrian Research Promotion Agency and Roche. Deiva Kumaran: received honoraria for invited talks for Biogen, Alexion, Sanofi and serves as consultant for Novartis and Horizon. Rinze Neuteboom: participated in pharmacological studies in demyelinating disorders with Roche, Horizon, Novartis and Sanofi-Genzym. Funding from Dutcht MS research foundation, Dreams Foundation, Postcode Loterij, Vrienden Sophia Foundation. Kevin Rostásy: received honoraria for invited talks from Horizon, UCB and serves as a consultant in the OperettaII study. Robert Cleaveland, Andreas Panzer, Sandy Molenaar, Laetitia Giorgi, Michael Karenfort, Charlotte Thiels, Zuzana Libá, Matthias Baumann, Steffen Leiz, Adela Della Marina, Jan G. Hengstler, members of the BIOMARKER study group (Steffen Berweck, Astrid Blaschek, Matthias Eckenweiler, Astrid Eisenkölbl, Tobias Geis, Annette Hackenberg, Verena Kraus, Heinz Lauffner, Daniela Pohl, Martin Pritsch, Michela Salandin, Torsten Sandrieser, Mareike Schimmel, Christoph von Kleist-Retzow, Gert Wiegand): no conflict of interest, (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH)., Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status., Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0-90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups., Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio., Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements)., Competing Interests: No author received financial support for the present manuscript. CW received honoraria for presentations and/or travel support from Novartis, Roche and Biogen and participated on advisory boards for Novartis, Roche and Biogen. JF received honoraria from Novartis for presentations. AB received honoraria for presentations from Roche and Pfizer and attend advisory boards for Roche and Pfizer. SI received honoraria for presentations and advisory board meetings from Novartis and Roche. OS received honoraria from Biogen, support for attending meetings from Novartis and participated on an advisory board for Novartis. GB received honoraria for advisory boards and/or presentations from Novartis, Roche and Biogen and support for attending meetings from Novartis. MvdH received grants from Deutsche Gesellschaft für Muskelkranke and Innovationsfond (INTEGRATE ATMP and KoCoN), honoraria from Pfizer, Biogen and PTC Therapeutics, and participated on advisory boards for Roche, Sarepta, Novartis, and Pfizer. RAH received consulting fees from Biogen and honoraria for presentations from Novartis, and participated on advisory boards by Novartis and Roche. KG participated on an industry symposium and an advisory board by Novartis. JK received funding for clinical research from Biogen, Novartis, Roche, ScholarRock and Biohaven, consulting fees from Biogen, Novartis and Roche, payment for educational activities from Biogen, Novartis and Roche and attended a data safety monitoring board for Biogen. AP received research funding form Roche, Novartis and Biogen. MFB received consulting fees for advisory boards from Roche, Novartis and Biogen and payment for presentations from Novartis and Biogen. GS received honoraria for a case report and participated on an advisory board for Novartis. US received honoraria for presentations from Biogen, Novartis and Roche and support for attending meetings from Roche and Novartis. BP received honoraria for a presentation from Biogen and participated on advisory boards for Novartis and Biogen. RT received honoraria for presentations from Desitin, PTC and Roche and participated on advisory boards for PTC, Roche and Santhera. VH attended an adivisory board for Biogen. MB received compensation for advisory boards and speakers honoraria from Novartis, Biogen and Roche and compensation for travel costs to meetings from Roche. AK is clinical lead of the Swiss Reg NMD, attended advisory board meetings of Novartis and received honorarium for a presentation by Novartis. AE received honoraria and payment for expert testimony from Biogen, Roche and Novartis, support for attending meetings from Biogen and Roche and participated on an advisory board for Biogen, Roche and Novartis. GMS participated on advisory boards from Biogen, Novartis and Roche and is member of the steering board for Swiss-Reg-NMD. SC received payment for a presentation. JJ received compensation for advisory boards and funding for travel or speaker honoraria from Avexis/Novartis, Biogen, IFT, Roche, PTC, Pfizer and Sarepta Therapeutics. AZ received compensation for advisory boards and funding for travel or speaker honoraria from Avexis/Novartis, Biogen, ITF, Roche, Pfizer and Sarepta Therapeutics. LLB, AH, EW, CK, OH, and SFG indicated no potential conflicts of interest to disclose., (© 2024 The Author(s).)

Microsaccades are known to be associated with a deficit in perceptual detection performance for brief probe flashes presented in their temporal vicinity. However, it is still not clear how such a deficit might depend on the visual environment across which microsaccades are generated. Here, and motivated by studies demonstrating an interaction between visual background image appearance and perceptual suppression strength associated with large saccades, we probed peripheral perceptual detection performance of human subjects while they generated microsaccades over three different visual backgrounds. Subjects fixated near the center of a low spatial frequency grating, a high spatial frequency grating, or a small white fixation spot over an otherwise gray background. When a computer process detected a microsaccade, it presented a brief peripheral probe flash at one of four locations (over a uniform gray background) and at different times. After collecting full psychometric curves, we found that both perceptual detection thresholds and slopes of psychometric curves were impaired for peripheral flashes in the immediate temporal vicinity of microsaccades, and they recovered with later flash times. Importantly, the threshold elevations, but not the psychometric slope reductions, were stronger for the white fixation spot than for either of the two gratings. Thus, like with larger saccades, microsaccadic suppression strength can show a certain degree of image dependence. However, unlike with larger saccades, stronger microsaccadic suppression did not occur with low spatial frequency textures. This observation might reflect the different spatiotemporal retinal transients associated with the small microsaccades in our study versus larger saccades.

Background and Objectives: Non-polyglutamine CACNA1A variants underlie an extremely variable phenotypic spectrum encompassing developmental delay, hemiplegic migraine, epilepsy, psychiatric symptoms, episodic and chronic cerebellar signs. We provide our experience with the long-term follow-up of CACNA1A patients and their response to interval therapy., Methods: Patients with genetically confirmed non-polyglutamine CACNA1A disease were prospectively followed at the Center for Rare Movement Disorders of the Medical University of Innsbruck from 2004 to 2024., Results: We recruited 41 subjects with non-polyglutamine CACNA1A disease, of which 38 (93%) familial cases. The mean age at the first examination was 35 ± 22 years. Disease onset was in the childhood/adolescence in 31/41 patients (76%). Developmental delay and episodic symptoms were the first disease manifestation in 9/41 (22%) and 32/41 (78%) patients respectively. Chronic neurological signs encompassed a cerebellar syndrome in 35/41 (85%), which showed almost no progression during the observation period, as well as cognitive deficits in 9/20 (45%, MOCA test score < 26), psychiatric and behavioral symptoms in 11/41(27%). Seizures occurred in two patients concomitant to severe hemiplegic migraine. At the last visit, 27/41 patients (66%) required an interval prophylaxis (including acetazolamide, flunarizine, 4-aminopyridine, topiramate), which was efficacious in reducing the frequency and severity of episodic symptoms in all cases. In one patient in his 70ies with progressively therapy resistant hemiplegic migraine, treatment with the anti-CGRP antibody galcanezumab successfully reduced the frequency of migraine days from 4 to 1/month., Conclusions: Non-polyglutamine CACNA1A disease show an evolving age-dependent presentation. Interval prophylaxis is effective in reducing the burden of episodic symptoms., (© 2024. The Author(s).)

Land-use expansion is linked to major sustainability concerns including climate change, food security and biodiversity loss. This expansion is largely concentrated in so-called 'frontiers', defined here as places experiencing marked transformations owing to rapid resource exploitation. Understanding the mechanisms shaping these frontiers is crucial for sustainability. Previous work focused mainly on explaining how active frontiers advance, in particular, into tropical forests. Comparatively, our understanding of how frontiers emerge in territories considered marginal in terms of agricultural productivity and global market integration remains weak. We synthesize conceptual tools explaining resource and land-use frontiers, including theories of land rent and agglomeration economies, of frontiers as successive waves, spaces of territorialization, friction and opportunities, anticipation and expectation. We then propose a new theory of frontier emergence, which identifies exogenous pushes, legacies of past waves and actors' anticipations as key mechanisms by which frontiers emerge. Processes of differential rent creation and capture and the built-up of agglomeration economies then constitute key mechanisms sustaining active frontiers. Finally, we discuss five implications for the governance of frontiers for sustainability. Our theory focuses on agriculture and deforestation frontiers in the tropics but can be inspirational for other frontier processes including for extractive resources, such as minerals., Competing Interests: We declare we have no competing interests., (© 2024 The Authors.)

Introduction: This contribution highlights novel developments and innovations in psychological psychotherapy for patients with obesity. It underscores the importance of an interdisciplinary approach to treatment, which incorporates not only traditional methods but also contemporary psychotherapeutic modalities such as Acceptance and Commitment Therapy (ACT). Current research suggests that assessing the effectiveness of psychotherapy should not solely rely on changes in weight, but should also consider other outcomes such as subjective quality of life and mental health. Furthermore, the role of telemedicine and blended psychotherapy is emphasized as promising approaches to enhance accessibility and effectiveness of treatment. Through a case study of a 55-year-old woman with obesity and psychiatric comorbidities, the effectiveness of a multimodal psychotherapeutic approach is demonstrated., Competing Interests: Die Autoren haben keine Interessenkonflikte im Zusammenhang mit diesem Artikel deklariert., (© 2024 Aerzteverlag medinfo AG.)

Importance: There is increasing evidence that early diagnosis and treatment are key for outcomes in infants with spinal muscular atrophy (SMA), and newborn screening programs have been implemented to detect the disease before onset of symptoms. However, data from controlled studies that reliably confirm the benefits of newborn screening are lacking., Objective: To compare data obtained on patients with SMA diagnosed through newborn screening and those diagnosed after clinical symptom onset., Design, Setting, and Participants: This nonrandomized controlled trial used data from the SMARTCARE registry to evaluate all children born between January 2018 and September 2021 with genetically confirmed SMA and up to 3 SMN2 copies. The registry includes data from 70 participating centers in Germany, Austria, and Switzerland. Data analysis was performed in February 2023 so that all patients had a minimal follow-up of 18 months., Exposure: Patients born in 2 federal states in Germany underwent screening in a newborn screening pilot project. All other patients were diagnosed after clinical symptom onset. All patients received standard care within the same health care system., Main Outcomes: The primary end point was the achievement of motor milestones., Results: A total of 234 children (123 [52.6%] female) were identified who met inclusion criteria and were included in the analysis: 44 (18.8%) in the newborn screening cohort and 190 children (81.2%) in the clinical symptom onset cohort. The mean (SD) age at start of treatment with 1 of the approved disease-modifying drugs was 1.3 (2.2) months in the newborn screening cohort and 10.7 (9.1) months in the clinical symptom onset cohort. In the newborn screening cohort, 40 of 44 children (90.9%) gained the ability to sit independently vs 141 of 190 (74.2%) in the clinical symptom onset cohort. For independent ambulation, the ratio was 28 of 40 (63.6%) vs 28 of 190 (14.7%)., Conclusions and Relevance: This nonrandomized controlled trial demonstrated effectiveness of newborn screening for infants with SMA in the real-world setting. Functional outcomes and thus the response to treatment were significantly better in the newborn screening cohort compared to the unscreened clinical symptom onset group., Trial Registration: German Clinical Trials Register: DRKS00012699.

Newborn screening for 5qSMA offers the potential for early, ideally pre-symptomatic, therapeutic intervention. However, limited data exist on the outcomes of individuals with 4 copies of SMN2, and there is no consensus within the SMA treatment community regarding early treatment initiation in this subgroup. To provide evidence-based insights into disease progression, we performed a retrospective analysis of 268 patients with 4 copies of SMN2 from the SMArtCARE registry in Germany, Austria and Switzerland. Inclusion criteria required comprehensive baseline data and diagnosis outside of newborn screening. Only data prior to initiation of disease-modifying treatment were included. The median age at disease onset was 3.0 years, with a mean of 6.4 years. Significantly, 55% of patients experienced symptoms before the age of 36 months. 3% never learned to sit unaided, a further 13% never gained the ability to walk independently and 33% of ambulatory patients lost this ability during the course of the disease. 43% developed scoliosis, 6.3% required non-invasive ventilation and 1.1% required tube feeding. In conclusion, our study, in line with previous observations, highlights the substantial phenotypic heterogeneity in SMA. Importantly, this study provides novel insights: the median age of disease onset in patients with 4 SMN2 copies typically occurs before school age, and in half of the patients even before the age of three years. These findings support a proactive approach, particularly early treatment initiation, in this subset of SMA patients diagnosed pre-symptomatically. However, it is important to recognize that the register will not include asymptomatic individuals., (© 2024. The Author(s).)

Background and Objectives: Patients with myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) clinically present e.g. with acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis (TM) or aquaporin-4-IgG (AQP4-IgG) negative neuromyelitis optica spectrum disorders (NMOSD)-like phenotypes. We aimed to analyze and compare blood parameters in children with MOGAD, AQP4-IgG-positive NMOSD (hence NMOSD), multiple sclerosis (MS) and healthy controls (HC)., Methods: We evaluated differences in complete blood counts (CBC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and C-reactive protein (CRP) between these four groups and within the groups between clinical attack, acute treatment and remission., Results: Our cohort consisted of 174 children and adolescents with a total of 550 timepoints: 66 patients had MOGAD (202 timepoints), 11 NMOSD (76 timepoints), 58 MS (219 timepoints) and 39 were HC (53 timepoints). At clinical attack, leukocyte counts were elevated in MOGAD compared to remission (p < 0.001) and compared to all other groups (p < 0.001). NLR was high in MOGAD and NMOSD, and PLR was high in NMOSD, however, after correction for multiple testing these findings did not remain significant. While glucocorticoids caused an increase of leukocyte counts and NLR in NMOSD and MS, these values remained stable during acute treatment in MOGAD. In remission, NLR normalized in MOGAD, while it stayed high in NMOSD. PLR increased in NMOSD and was significantly higher compared to all other groups., Discussion: Some blood parameters, mainly leukocyte and differential counts, might help clinicians to evaluate disease activity, differentiate relapses from pseudo-relapses and even distinguish between different disease entities., Competing Interests: Declaration of competing interest Alina Peternell, Christian Lechner, Mareike Schimmel, Joachim Zobel, Martin Preisel, Eva-Maria Wendel and Astrid Eisenkölbl have nothing to declare. Markus Breu received speaker honoraria from Sanofi Genzyme. Markus Reindl is supported by research grants from the Euroimmun, and Roche, and consulting fees and advisory board from Roche (to institution). Markus Reindl works at the Clinical Department of the Medical University of Innsbruck (Innsbruck, Austria), which offers diagnostic testing for MOG-IgG and other autoantibodies. Matthias Baumann received compensation for advisory boards and speaker honoraria from Novartis, Biogen, and Roche. Kevin Rostásy serves as consultant for Roche in Operetta II trial and received speaker’ honoraria from Merck., (© 2024 Published by Elsevier Ltd on behalf of European Paediatric Neurology Society.)

Ocular position drifts during gaze fixation are significantly less well understood than microsaccades. We recently identified a short-latency ocular position drift response, of ∼1 min arc amplitude, that is triggered within <100 ms by visual onsets. This systematic eye movement response is feature-tuned and seems to be coordinated with a simultaneous resetting of the saccadic system by visual stimuli. However, much remains to be learned about the drift response, especially for designing better-informed neurophysiological experiments unraveling its mechanistic substrates. Here we systematically tested multiple new feature tuning properties of drift responses. Using highly precise eye tracking in three male rhesus macaque monkeys, we found that drift responses still occur for tiny foveal visual stimuli. Moreover, the responses exhibit size tuning, scaling their amplitude (both up and down) as a function of stimulus size, and they also possess a monotonically increasing contrast sensitivity curve. Importantly, short-latency drift responses still occur for small peripheral visual targets, which additionally introduce spatially directed modulations in drift trajectories toward the appearing peripheral stimuli. Drift responses also remain predominantly upward even for stimuli exclusively located in the lower visual field and even when starting gaze position is upward. When we checked the timing of drift responses, we found it was better synchronized to stimulus-induced saccadic inhibition than to stimulus onset. These results, along with a suppression of drift response amplitudes by peristimulus saccades, suggest that drift responses reflect the rapid impacts of short-latency and feature-tuned visual neural activity on final oculomotor control circuitry in the brain., Competing Interests: The authors declare no competing financial interests., (Copyright © 2024 the authors.)

Many grassland ecosystems and their associated biodiversity depend on the interactions between fire and land-use, both of which are shaped by socioeconomic conditions. The Eurasian steppe biome, much of it situated in Kazakhstan, contains 10% of the world's remaining grasslands. The break-up of the Soviet Union in 1991, widespread land abandonment and massive declines in wild and domestic ungulates led to biomass accumulation over millions of hectares. This rapid fuel increase made the steppes a global fire hotspot, with major changes in vegetation structure. Yet, the response of steppe biodiversity to these changes remains unexplored. We utilized a unique bird abundance dataset covering the entire Kazakh steppe and semi-desert regions together with the MODIS burned area product. We modeled the response of bird species richness and abundance as a function of fire disturbance variables-fire extent, cumulative burned area, fire frequency-at varying grazing intensity. Bird species richness was impacted negatively by large fire extent, cumulative burned area, and high fire frequency in moderately grazed and ungrazed steppe. Similarly, overall bird abundance was impacted negatively by large fire extent, cumulative burned area and higher fire frequency in the moderately grazed steppe, ungrazed steppe, and ungrazed semi-deserts. At the species level, the effect of high fire disturbance was negative for more species than positive. There were considerable fire legacy effects, detectable for at least 8 years. We conclude that the increase in fire disturbance across the post-Soviet Eurasian steppe has led to strong declines in bird abundance and pronounced changes in community assembly. To gain back control over wildfires and prevent further biodiversity loss, restoration of wild herbivore populations and traditional domestic ungulate grazing systems seems much needed., (© 2023 The Authors. Global Change Biology published by John Wiley & Sons Ltd.)

This article obtains an overview of the health status of children and adolescents with neurofibromatosis type 1 (NF1) with a focus on the clinical course of the disease, neuropsychodiagnostic findings, and their impact on quality of life (QoL). In this observational study, data were collected from 24 children and adolescents with NF1 who were cared for at the University Hospital in Innsbruck, Austria, from 2008 to 2022. Data were collected every 6 to 12 months from routine check-ups, including clinical features and imaging findings. Results of neuropsychodiagnostic tests and the KINDL questionnaire to assess QoL were included. Of 24 patients, 15 underwent a neuropsychological examination. Attention performance was examined in 11 of them. Eight of 11 (72%) showed an attention deficit. Assessment for specific developmental disorders showed visual-spatial difficulties in 12/15 (80%) patients. The KINDL questionnaire values ranged from 58.22 to 97.92 (0 stands for reduced QoL, 100 for very good QoL). Patients with scoliosis had a lower range of QoL (56.33-73.96). No trend in QoL was observed in children and adolescents with plexiform neurofibromas, below-average intelligence or optic gliomas. NF1 patients show very different clinical courses. Regular neuropsychological assessment especially with regard to visual-spatial skills and attention deficits is necessary to offer appropriate support, promote children's development, and thus improve their QoL., Competing Interests: None declared., (Thieme. All rights reserved.)

Saccadic inhibition refers to a short-latency transient cessation of saccade generation after visual sensory transients. This oculomotor phenomenon occurs with a latency that is consistent with a rapid influence of sensory responses, such as stimulus-induced visual bursts, on oculomotor control circuitry. However, the neural mechanisms underlying saccadic inhibition are not well understood. Here, we exploited the fact that macaque monkeys experience robust saccadic inhibition to test the hypothesis that inhibition time and strength exhibit systematic visual feature tuning properties to a multitude of visual feature dimensions commonly used in vision science. We measured saccades in three monkeys actively controlling their gaze on a target, and we presented visual onset events at random times. Across seven experiments, the visual onsets tested size, spatial frequency, contrast, orientation, motion direction, and motion speed dependencies of saccadic inhibition. We also investigated how inhibition might depend on the behavioral relevance of the appearing stimuli. We found that saccadic inhibition starts earlier, and is stronger, for large stimuli of low spatial frequencies and high contrasts. Moreover, saccadic inhibition timing depends on motion direction and orientation, with earlier inhibition systematically occurring for horizontally drifting vertical gratings. On the other hand, saccadic inhibition is stronger for faster motions and when the appearing stimuli are subsequently foveated. Besides documenting a range of feature tuning dimensions of saccadic inhibition to the properties of exogenous visual stimuli, our results establish macaque monkeys as an ideal model system for unraveling the neural mechanisms underlying a ubiquitous oculomotor phenomenon in visual neuroscience. NEW & NOTEWORTHY Visual onsets dramatically reduce saccade generation likelihood with very short latencies. Such latencies suggest that stimulus-induced visual responses, normally jump-starting perceptual and scene analysis processes, can also directly impact the decision of whether to generate saccades or not, causing saccadic inhibition. Consistent with this, we found that changing the appearance of the visual onsets systematically alters the properties of saccadic inhibition. These results constrain neurally inspired models of coordination between saccade generation and exogenous sensory stimulation.

Movement control is critical for successful interaction with our environment. However, movement does not occur in complete isolation of sensation, and this is particularly true of eye movements. Here, we show that the neuronal eye movement commands emitted by the superior colliculus (SC), a structure classically associated with oculomotor control, encompass a robust visual sensory representation of eye movement targets. Thus, similar saccades toward different images are associated with different saccade-related "motor" bursts. Such sensory tuning in SC saccade motor commands appeared for all image manipulations that we tested, from simple visual features to real-life object images, and it was also strongest in the most motor neurons in the deeper collicular layers. Visual-feature discrimination performance in the motor commands was also stronger than in visual responses. Comparing SC motor command feature discrimination performance to that in the primary visual cortex during steady-state gaze fixation revealed that collicular motor bursts possess a reliable perisaccadic sensory representation of the peripheral saccade target's visual appearance, exactly when retinal input is expected to be most uncertain. Our results demonstrate that SC neuronal movement commands likely serve a fundamentally sensory function.

Objective: Currently, there are no data available on SARS-CoV-2 vaccine responses in pediatric-onset multiple sclerosis (POMS), and little is known about the course of SARS-CoV-2 infection in this age group. We therefore investigated humoral immune responses after COVID-19 vaccination and/or infection in POMS., Methods: We retrospectively analyzed seroconversion rates and SARS-CoV-2-specific antibody levels in 30 POMS and one pediatric CIS patient treated with no disease-modifying therapy (no DMT), immunomodulatory DMT (IM-DMT), or immunosuppressive DMT (IS-DMT) from two Austrian MS centers., Results: The median age at MS onset was 15.39 years (interquartile range [IQR]: 1.97). The median age at the first COVID-19 vaccination was 17.43 years (IQR: 2.76). After two vaccine doses, seroconversion (≥0.8 BAU/ml) was reached in 25 of 28 patients (89.3%). All patients with no DMT or IM-DMT generated robust immune responses to vaccination (seroconversion: no DMT: 6/6, IM-DMT: 7/7 [100%]; median titers: no DMT: 2075 BAU [IQR: 1268.50], IM-DMT: 2500 BAU [IQR: 0]). In the IS-DMT group, seroconversion was achieved in 12 of 14 patients (80%), and median titers were 50.8 BAU (IQR 254.63). Titers were significantly higher in no DMT versus IS-DMT (P = 0.012) and in IM-DMT versus IS-DMT (P = 0.001). Infection with SARS-CoV-2 occurred in 11 of 31 patients, and symptoms were mild in all cases. One relapse occurred after infection, but no relapses were documented after vaccination., Conclusions: Generally, mRNA vaccinations were well tolerated in POMS patients with and without DMT. Immune response was significantly reduced in patients treated with IS-DMT. No unexpected adverse events or relapses related to vaccinations were observed., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Although the diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is based on serum MOG antibodies (MOG-Abs) positivity, patients with coexisting or restricted MOG-Abs in the CSF have been reported. The aim of this study is to characterize the relevance of CSF MOG-Abs positivity in clinical practice., Methods: Eleven medical centers retrospectively collected clinical and laboratory data of adult and pediatric patients with suspected inflammatory CNS disease and MOG-Abs positivity in serum and/or CSF using live cell-based assays. Comparisons were performed using parametric or nonparametric tests, as appropriate. Potential factors of unfavorable outcomes were explored by Cox proportional hazard models and logistic regression., Results: The cohort included 255 patients: 139 (55%) women and 132 (52%) children (i.e., <18-year-old). Among them, 145 patients (56.8%) had MOG-Abs in both serum and CSF (MOG-Abs seropositive and CSF positive), 79 (31%) only in serum (MOG-Abs seropositive and CSF negative), and 31 (12%) only in CSF (MOG-Abs seronegative and CSF positive). MOG-Abs seronegative and CSF positive predominated in adults (22% vs 3% of children), presented more commonly with motor (n = 14, 45%) and sensory symptoms (n = 13, 42%), and all but 4 (2 multiple sclerosis, 1 polyradiculoneuritis, and 1 Susac syndrome) had a final diagnosis compatible with MOGAD. When comparing seropositive patients according to MOG-Abs CSF status, MOG-Abs seropositive and CSF positive patients had a higher Expanded Disability Status Scale (EDSS) at nadir during the index event (median 4.5, interquartile range [IQR] 3.0-7.5 vs 3.0, IQR 2.0-6.8, p = 0.007) and presented more commonly with sensory (45.5% vs 24%, p = 0.002), motor (33.6% vs 19%, p = 0.021), and sphincter symptoms (26.9% vs 7.8%, p = 0.001) than MOG-Abs seropositive and CSF negative. At the last follow-up, MOG-Abs seropositive and CSF positive cases had more often persistent sphincter dysfunction (17.3% vs 4.3%, p = 0.008) . Compared with seropositive patients, those MOG-Abs seronegative and CSF positive had higher disability at the last follow-up ( p ≤ 0.001), and MOG-Abs seronegative and CSF positive status were independently associated with an EDSS ≥3.0., Discussion: Paired serum and CSF MOG-Abs positivity are common in MOGAD and are associated with a more severe clinical presentation. CSF-only MOG-Abs positivity can occur in patients with a phenotype suggestive of MOGAD and is associated with a worse outcome. Taken together, these data suggest a clinical interest in assessing CSF MOG-Abs in patients with a phenotype suggestive of MOGAD, regardless of the MOG-Abs serostatus., (© 2022 American Academy of Neurology.)

5q-associated spinal muscular atrophy is a rare neuromuscular disorder with the leading symptom of a proximal muscle weakness. Three different drugs have been approved by the European Medicines Agency and Food and Drug Administration for the treatment of spinal muscular atrophy patients, however, long-term experience is still scarce. In contrast to clinical trial data with restricted patient populations and short observation periods, we report here real-world evidence on a broad spectrum of patients with early-onset spinal muscular atrophy treated with nusinersen focusing on effects regarding motor milestones, and respiratory and bulbar insufficiency during the first years of treatment. Within the SMArtCARE registry, all patients under treatment with nusinersen who never had the ability to sit independently before the start of treatment were identified for data analysis. The primary outcome of this analysis was the change in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and motor milestones considering World Health Organization criteria. Further, we evaluated data on the need for ventilator support and tube feeding, and mortality. In total, 143 patients with early-onset spinal muscular atrophy were included in the data analysis with a follow-up period of up to 38 months. We observed major improvements in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders. Improvements were greater in children >2 years of age at start of treatment than in older children. 24.5% of children gained the ability to sit independently. Major improvements were observed during the first 14 months of treatment. The need for intermittent ventilator support and tube feeding increased despite treatment with nusinersen. Our findings confirm the increasing real-world evidence that treatment with nusinersen has a dramatic influence on disease progression and survival in patients with early-onset spinal muscular atrophy. Major improvements in motor function are seen in children younger than 2 years at the start of treatment. Bulbar and respiratory function needs to be closely monitored, as these functions do not improve equivalent to motor function., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Objectives: Acute disseminated encephalomyelitis (ADEM) is the most common phenotype in pediatric myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease. A previous study demonstrated impaired brain growth in ADEM. However, the effect of MOG antibodies on brain growth remains unknown. Here, we performed brain volume analyses in MOG-positive and MOG-negative ADEM at onset and over time., Methods: In this observational cohort study, we included a total of 62 MRI scans from 24 patients with ADEM (54.2% female; median age 5 years), of which 16 (66.7%) were MOG positive. Patients were compared with healthy controls from the NIH pediatric MRI data repository and a matched local cohort. Mixed-effect models were applied to assess group differences and other relevant factors, including relapses., Results: At baseline and before any steroid treatment, patients with ADEM, irrespective of MOG antibody status, showed reduced brain volume compared with matched controls (median [interquartile range] 1,741.9 cm3 [1,645.1-1,805.2] vs 1,810.4 cm 3 [1,786.5-1,836.2]). Longitudinal analysis revealed reduced brain growth for both MOG-positive and MOG-negative patients with ADEM. However, MOG-negative patients showed a stronger reduction (-138.3 cm 3 [95% CI -193.6 to -82.9]) than MOG-positive patients (-50.0 cm 3 [-126.5 to -5.2]), independent of age, sex, and treatment. Relapsing patients (all MOG positive) showed additional brain volume loss (-15.8 cm 3 [-68.9 to 37.3])., Discussion: Patients with ADEM exhibit brain volume loss and failure of age-expected brain growth. Importantly, MOG-negative status was associated with a more pronounced brain volume loss compared with MOG-positive patients., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: Intrinsic or acquired resistance to HER2-targeted therapy is often a problem when small molecule tyrosine kinase inhibitors or antibodies are used to treat patients with HER2 positive breast cancer. Therefore, the identification of new targets and therapies for this patient group is warranted. Activated choline metabolism, characterized by elevated levels of choline-containing compounds, has been previously reported in breast cancer. The glycerophosphodiesterase EDI3 (GPCPD1), which hydrolyses glycerophosphocholine to choline and glycerol-3-phosphate, directly influences choline and phospholipid metabolism, and has been linked to cancer-relevant phenotypes in vitro. While the importance of choline metabolism has been addressed in breast cancer, the role of EDI3 in this cancer type has not been explored., Methods: EDI3 mRNA and protein expression in human breast cancer tissue were investigated using publicly-available Affymetrix gene expression microarray datasets (n = 540) and with immunohistochemistry on a tissue microarray (n = 265), respectively. A panel of breast cancer cell lines of different molecular subtypes were used to investigate expression and activity of EDI3 in vitro. To determine whether EDI3 expression is regulated by HER2 signalling, the effect of pharmacological inhibition and siRNA silencing of HER2, as well as the influence of inhibiting key components of signalling cascades downstream of HER2 were studied. Finally, the influence of silencing and pharmacologically inhibiting EDI3 on viability was investigated in vitro and on tumour growth in vivo., Results: In the present study, we show that EDI3 expression is highest in ER-HER2 + human breast tumours, and both expression and activity were also highest in ER-HER2 + breast cancer cell lines. Silencing HER2 using siRNA, as well as inhibiting HER2 signalling with lapatinib decreased EDI3 expression. Pathways downstream of PI3K/Akt/mTOR and GSK3β, and transcription factors, including HIF1α, CREB and STAT3 were identified as relevant in regulating EDI3 expression. Silencing EDI3 preferentially decreased cell viability in the ER-HER2 + cells. Furthermore, silencing or pharmacologically inhibiting EDI3 using dipyridamole in ER-HER2 + cells resistant to HER2-targeted therapy decreased cell viability in vitro and tumour growth in vivo., Conclusions: Our results indicate that EDI3 may be a potential novel therapeutic target in patients with HER2-targeted therapy-resistant ER-HER2 + breast cancer that should be further explored., (© 2023. The Author(s).)

Background and Objectives: Disease progression in patients with spinal muscular atrophy (SMA) has changed dramatically within the past years due to the approval of three different disease-modifying treatments. Nusinersen was the first drug to be approved for the treatment of SMA patients. Clinical trials provided data from infants with SMA type 1 and children with SMA type 2, but there is still insufficient evidence and only scarcely reported long-term experience for nusinersen treatment in ambulant patients. Here, we report data from the SMArtCARE registry of ambulant patients under nusinersen treatment with a follow-up period of up to 38 months., Methods: SMArtCARE is a disease-specific registry in Germany, Austria and Switzerland. Data are collected as real-world data during routine patient visits. Our analysis included all patients under treatment with nusinersen able to walk independently before start of treatment with focus on changes in motor function., Results: Data from 231 ambulant patients were included in the analysis. During the observation period, 31 pediatric walkers (27.2%) and 31 adult walkers (26.5%) experienced a clinically meaningful improvement of≥30 m in the 6-Minute-Walk-Test. In contrast, only five adult walkers (7.7%) showed a decline in walking distance≥30 m, and two pediatric walkers (1.8%) lost the ability to walk unassisted under treatment with nusinersen. HFMSE and RULM scores improved in pediatric and remained stable in adult patients., Conclusion: Our data demonstrate a positive effect of nusinersen treatment in most ambulant pediatric and adult SMA patients. We not only observed a stabilization of disease progression or lack of deterioration, but clinically meaningful improvements in walking distance.

Visual processing is segregated into ON and OFF channels as early as in the retina, and the superficial (output) layers of the primary visual cortex (V1) are dominated by neurons preferring dark stimuli. However, it is not clear how the timing of neural processing differs between "darks" and "brights" in general, especially in light of psychophysical evidence; it is also equally not clear how subcortical visual pathways that are critical for active orienting represent stimuli of positive (luminance increments) and negative (luminance decrements) contrast polarity. Here, we recorded from all visually-responsive neuron types in the superior colliculus (SC) of two male rhesus macaque monkeys. We presented a disk (0.51° radius) within the response fields (RFs) of neurons, and we varied, across trials, stimulus Weber contrast relative to a gray background. We also varied contrast polarity. There was a large diversity of preferences for darks and brights across the population. However, regardless of individual neural sensitivity, most neurons responded significantly earlier to dark than bright stimuli. This resulted in a dissociation between neural preference and visual response onset latency: a neuron could exhibit a weaker response to a dark stimulus than to a bright stimulus of the same contrast, but it would still have an earlier response to the dark stimulus. Our results highlight an additional candidate visual neural pathway for explaining behavioral differences between the processing of darks and brights, and they demonstrate the importance of temporal aspects in the visual neural code for orienting eye movements. SIGNIFICANCE STATEMENT Objects in our environment, such as birds flying across a bright sky, often project shadows (or images darker than the surround) on our retina. We studied how primate superior colliculus (SC) neurons visually process such dark stimuli. We found that the overall population of SC neurons represented both dark and bright stimuli equally well, as evidenced by a relatively equal distribution of neurons that were either more or less sensitive to darks. However, independent of sensitivity, the great majority of neurons detected dark stimuli earlier than bright stimuli, evidenced by a smaller response latency for the dark stimuli. Thus, SC neural response latency can be dissociated from response sensitivity, and it favors the faster detection of dark image contrasts., (Copyright © 2022 the authors.)

The primate superior colliculus (SC) contains a topographic map of space, such that the anatomical location of active neurons defines a desired eye movement vector. Complementing such a spatial code, SC neurons also exhibit saccade-related bursts that are tightly synchronized with movement onset. Current models suggest that such bursts constitute a rate code dictating movement kinematics. Here, using two complementary approaches, we demonstrate a dissociation between the SC rate code and saccade kinematics. First, we show that SC burst strength systematically varies depending on whether saccades of the same amplitude are directed towards the upper or lower visual fields, but the movements themselves have similar kinematics. Second, we show that for the same saccade vector, when saccades are significantly slowed down by the absence of a visible saccade target, SC saccade-related burst strengths can be elevated rather than diminished. Thus, SC saccade-related motor bursts do not necessarily dictate movement kinematics., (© 2022. The Author(s).)

Analysis of agonist-driven phosphorylation of G protein-coupled receptors (GPCRs) can provide valuable insights into the receptor activation state and ligand pharmacology. However, to date, assessment of GPCR phosphorylation using high-throughput applications has been challenging. We have developed and validated a bead-based immunoassay for the quantitative assessment of agonist-induced GPCR phosphorylation that can be performed entirely in multiwell cell culture plates. The assay involves immunoprecipitation of affinity-tagged receptors using magnetic beads followed by protein detection using phosphorylation state-specific and phosphorylation state-independent anti-GPCR antibodies. As proof of concept, five prototypical GPCRs (MOP, C5a1, D1, SST2, CB2) were treated with different agonizts and antagonists, and concentration-response curves were generated. We then extended our approach to establish selective cellular GPCR kinase (GRK) inhibitor assays, which led to the rapid identification of a selective GRK5/6 inhibitor (LDC8988) and a highly potent pan-GRK inhibitor (LDC9728). In conclusion, this versatile GPCR phosphorylation assay can be used extensively for ligand profiling and inhibitor screening., (© 2022. The Author(s).)

Background: Transverse myelitis (TM) occurs isolated or within other acquired demyelinating syndromes (ADS) such as neuromyelitis optica spectrum disorders (NMOSD), multiple sclerosis (MS) or myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD)., Objective: To describe and compare clinical and MRI features of children with ADS presenting with TM grouped according to antibody status and diagnosis of MS and NMOSD., Patients and Methods: Children with TM, radiological involvement of the myelon, MOG and aquaporin-4 antibody status were elegible., Results: 100 children were identified and divided into MOGAD (n=33), NMOSD (n=7), double seronegative TM (n=34), and MS (n=26). MOGAD children had mainly acute disseminated encephalomyelitis + TM/ longitudinally extensive TM (LETM) (42%) or isolated LETM (30%). In MOGAD, LETM was present in more than half of all children (55%) with predominant involvement of only the grey matter (73%). Leptomeningeal enhancement was highly predictive of MOGAD (16/30; p=0.003). In MS patients spinal MRI showed single (50%) or multiple short lesions (46%) with involvement of grey and white matter (68%). Double seronegative children presented with LETM (74%) and brain lesions were less frequent compared to the other groups (30%)., Conclusion: Children with ADS presenting with TM reveal important radiological differences such as LETM with predominant involvement of spinal grey matter and leptomeningeal enhancement in MOGAD., Competing Interests: Declaration of Competing Interest IN, RC, EW, ABe, KS, CTh, ADM, MSch, SL, AWP, NB, BB, SB, MBl, ABl, CC, KD, ME, AE, WF, TG, AH, KH, JK, BK, MN, DP, MP, MSa, TS, SS, JS, GW report no conflict of interest. Michael Karenfort served as consultant for Novartis. Christian Lechner has received compensation for consulting services from Roche. Matthias Baumann has received compensation for consulting services from Sanofi. Markus Reindl was supported by a research support from Euroimmun and Roche. The University Hospital and Medical University of Innsbruck (Austria, employer of Dr. Reindl) receive payments for antibody assays (MOG-, AQP4-, and other autoantibodies) and for MOG-and AQP4-antibody validation experiments organised by Euroimmun (Lübeck, Germany). Kevin Rostásy served as a consultant for the PARADIGM-Study/Novartis without payment and received honoraria for lectures given for MERCK. Andrea Klein did advisory activities for Novartis Gene Therapies, Biogen, Pfizer, Roche, Sarepta and Santhera and received speakers honoraria from Biogen, Roche, Sarepta and Santhera., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background: The development and approval of disease modifying treatments have dramatically changed disease progression in patients with spinal muscular atrophy (SMA). Nusinersen was approved in Europe in 2017 for the treatment of SMA patients irrespective of age and disease severity. Most data on therapeutic efficacy are available for the infantile-onset SMA. For patients with SMA type 2 and type 3, there is still a lack of sufficient evidence and long-term experience for nusinersen treatment. Here, we report data from the SMArtCARE registry of non-ambulant children with SMA type 2 and typen 3 under nusinersen treatment with a follow-up period of up to 38 months., Methods: SMArtCARE is a disease-specific registry with data on patients with SMA irrespective of age, treatment regime or disease severity. Data are collected during routine patient visits as real-world outcome data. This analysis included all non-ambulant patients with SMA type 2 or 3 below 18 years of age before initiation of treatment. Primary outcomes were changes in motor function evaluated with the Hammersmith Functional Motor Scale Expanded (HFMSE) and the Revised Upper Limb Module (RULM)., Results: Data from 256 non-ambulant, pediatric patients with SMA were included in the data analysis. Improvements in motor function were more prominent in upper limb: 32.4% of patients experienced clinically meaningful improvements in RULM and 24.6% in HFMSE. 8.6% of patients gained a new motor milestone, whereas no motor milestones were lost. Only 4.3% of patients showed a clinically meaningful worsening in HFMSE and 1.2% in RULM score., Conclusion: Our results demonstrate clinically meaningful improvements or stabilization of disease progression in non-ambulant, pediatric patients with SMA under nusinersen treatment. Changes were most evident in upper limb function and were observed continuously over the follow-up period. Our data confirm clinical trial data, while providing longer follow-up, an increased number of treated patients, and a wider range of age and disease severity., (© 2022. The Author(s).)

Background and Objective: The spectrum of myelin oligodendrocyte glycoprotein (MOG) antibody-associated disorder (MOGAD) comprises monophasic diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), and transverse myelitis and relapsing courses of these presentations. Persistently high MOG antibodies (MOG immunoglobulin G [IgG]) are found in patients with a relapsing disease course. Prognostic factors to determine the clinical course of children with a first MOGAD are still lacking. The objective of the study is to assess the clinical and laboratory prognostic parameters for a risk of relapse and the temporal dynamics of MOG-IgG titers in children with MOGAD in correlation with clinical presentation and disease course., Methods: In this prospective multicenter hospital-based study, children with a first demyelinating attack and complete data set comprising clinical and radiologic findings, MOG-IgG titer at onset, and clinical and serologic follow-up data were included. Serum samples were analyzed by live cell-based assay, and a titer level of ≥1:160 was classified as MOG-IgG-positive., Results: One hundred sixteen children (f:m = 57:59) with MOGAD were included and initially diagnosed with ADEM (n = 59), unilateral ON (n = 12), bilateral ON (n = 16), myelitis (n = 6), neuromyelitis optica spectrum disorder (n = 8) or encephalitis (n = 6). The median follow-up time was 3 years in monophasic and 5 years in relapsing patients. There was no significant association between disease course and MOG-IgG titers at onset, sex, age at presentation, or clinical phenotype. Seroconversion to MOG-IgG-negative within 2 years of the initial event showed a significant risk reduction for a relapsing disease course. Forty-two/one hundred sixteen patients (monophasic n = 26, relapsing n = 16) had serial MOG-IgG testing in years 1 and 2 after the initial event. In contrast to relapsing patients, monophasic patients showed a significant decrease of MOG-IgG titers during the first and second years, often with seroconversion to negative titers. During the follow-up, MOG-IgG titers were persistently higher in relapsing than in monophasic patients. Decrease in MOG-IgG of ≥3 dilution steps after the first and second years was shown to be associated with a decreased risk of relapses. In our cohort, no patient experienced a relapse after seroconversion to MOG-IgG-negative., Discussion: In this study, patients with declining MOG-IgG titers, particularly those with seroconversion to MOG-IgG-negative, are shown to have a significantly reduced relapse risk., (Copyright © 2022 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Tropical deforestation continues at alarming rates with profound impacts on ecosystems, climate, and livelihoods, prompting renewed commitments to halt its continuation. Although it is well established that agriculture is a dominant driver of deforestation, rates and mechanisms remain disputed and often lack a clear evidence base. We synthesize the best available pantropical evidence to provide clarity on how agriculture drives deforestation. Although most (90 to 99%) deforestation across the tropics 2011 to 2015 was driven by agriculture, only 45 to 65% of deforested land became productive agriculture within a few years. Therefore, ending deforestation likely requires combining measures to create deforestation-free supply chains with landscape governance interventions. We highlight key remaining evidence gaps including deforestation trends, commodity-specific land-use dynamics, and data from tropical dry forests and forests across Africa.

Objective: To assess the diagnostic and prognostic potential of serum neurofilament light chain (sNfL) in children with first acquired demyelinating syndrome (ADS)., Methods: We selected 129 children with first ADS including 19 children with myelin oligodendrocyte glycoprotein (MOG)-antibody associated disease (MOGAD), 36 MOG/AQP4-seronegative ADS, and 74 with multiple sclerosis (MS) from the BIOMARKER study cohort. All children had a complete set of clinical, radiological, laboratory data and serum for NfL measurement using a highly sensitive digital ELISA (SIMOA). A control group of 35 children with non-inflammatory neurological diseases was included. sNfL levels were compared across patient groups according to clinical, laboratory, neuroradiological features and outcome after 2 years., Results: sNfL levels were significantly increased in MOGAD, seronegative ADS and MS compared to controls ( p -value < 0.001), in particular in children with an acute disseminated encephalomyelitis (ADEM)-like magnetic resonance imaging (MRI) pattern ( p  < 0.001) or longitudinally extensive myelitis ( p  < 0.01). In pediatric MS, elevated sNfL levels were significantly associated with higher numbers of cerebral ( p  < 0.001) and presence of spinal ( p  < 0.05) MRI lesions at baseline and predicted a higher number of relapses ( p  < 0.05)., Conclusion: sNfL levels are significantly elevated in all three studied pediatric ADS subtypes indicating neuroaxonal injury. In pediatric MS high levels of sNfL are associated with risk factors for disease progression.

Visual perception remains stable across saccadic eye movements, despite the concurrent strongly disruptive visual flow. This stability is partially associated with a reduction in visual sensitivity, known as saccadic suppression, which already starts in the retina with reduced ganglion cell sensitivity. However, the retinal circuit mechanisms giving rise to such suppression remain unknown. Here, we describe these mechanisms using electrophysiology in mouse, pig, and macaque retina, 2-photon calcium imaging, computational modeling, and human psychophysics. We find that sequential stimuli, like those that naturally occur during saccades, trigger three independent suppressive mechanisms in the retina. The main mechanism is triggered by contrast-reversing sequential stimuli and originates within the receptive field center of ganglion cells. It does not involve inhibition or other known suppressive mechanisms like saturation or adaptation. Instead, it relies on temporal filtering of the inherently slow response of cone photoreceptors coupled with downstream nonlinearities. Two further mechanisms of suppression are present predominantly in ON ganglion cells and originate in the receptive field surround, highlighting another disparity between ON and OFF ganglion cells. The mechanisms uncovered here likely play a role in shaping the retinal output following eye movements and other natural viewing conditions where sequential stimulation is ubiquitous., (© 2022. The Author(s).)

Rheb is a small GTPase member of the Ras superfamily and an activator of mTORC1, a protein complex master regulator of cell metabolism, growth, and proliferation. Rheb/mTORC1 pathway is hyperactivated in proliferative diseases, such as Tuberous Sclerosis Complex syndrome and cancer. Therefore, targeting Rheb-dependent signaling is a rational strategy for developing new drug therapies. Rheb activates mTORC1 in the cytosolic surface of lysosomal membranes. Rheb's farnesylation allows its anchorage on membranes, while its proper localization depends on the prenyl-binding chaperone PDEδ. Recently, the use of PDEδ inhibitors has been proposed as anticancer agents because they interrupted KRas signaling leading to antiproliferative effects in KRas-dependent pancreatic cancer cells. However, the effect of PDEδ inhibition on the Rheb/mTORC1 pathway has been poorly investigated. Here, we evaluated the impact of a new PDEδ inhibitor, called Deltasonamide 1, in Tsc2 - null MEFs, a Rheb-dependent overactivated mTORC1 cell line. By using a yeast two-hybrid assay, we first validated that Deltasonamide 1 disrupts Rheb-PDEδ interaction. Accordingly, we found that Deltasonamide 1 reduces mTORC1 targets activation. In addition, our results showed that Deltasonamide 1 has antiproliferative and cytotoxic effects on Tsc2-null MEFs but has less effect on Tsc2-wild type MEFs viability. This work proposes the pharmacological PDEδ inhibition as a new approach to target the abnormal Rheb/mTORC1 activation in Tuberous Sclerosis Complex cells., Competing Interests: Authors BM and KBM were employed by Lead Discovery Center, Dortmund, Germany. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Armijo, Escalona, Peña, Farias, Morin, Baumann, Klebl, Pincheira and Castro.)

Despite the clinical efficacy of epidermal growth factor receptor (EGFR) inhibitors, a subset of patients with non-small cell lung cancer displays insertion mutations in exon20 in EGFR and Her2 with limited treatment options. Here, we present the development and characterization of the novel covalent inhibitors LDC8201 and LDC0496 based on a 1 H -pyrrolo[2,3- b ]pyridine scaffold. They exhibited intense inhibitory potency toward EGFR and Her2 exon20 insertion mutations as well as selectivity over wild type EGFR and within the kinome. Complex crystal structures with the inhibitors and biochemical and cellular on-target activity document their favorable binding characteristics. Ultimately, we observed tumor shrinkage in mice engrafted with patient-derived EGFR-H773&#95;V774insNPH mutant cells during treatment with LDC8201. Together, these results highlight the potential of covalent pyrrolopyridines as inhibitors to target exon20 insertion mutations.

Background: Monogenic causes of isolated dystonia are heterogeneous. Assembling cohorts of affected individuals sufficiently large to establish new gene-disease relationships can be challenging., Objective: We sought to expand the catalogue of monogenic etiologies for isolated dystonia., Methods: After the discovery of a candidate variant in a multicenter exome-sequenced cohort of affected individuals with dystonia, we queried online platforms and genomic data repositories worldwide to identify subjects with matching genotypic profiles., Results: Seven different biallelic loss-of-function variants in AOPEP were detected in five probands from four unrelated families with strongly overlapping phenotypes. In one proband, we observed a homozygous nonsense variant (c.1477C>T [p.Arg493*]). A second proband harbored compound heterozygous nonsense variants (c.763C>T [p.Arg255*]; c.777G>A [p.Trp259*]), whereas a third proband possessed a frameshift variant (c.696&#95;697delAG [p.Ala234Serfs*5]) in trans with a splice-disrupting alteration (c.2041-1G>A). Two probands (siblings) from a fourth family shared compound heterozygous frameshift alleles (c.1215delT [p.Val406Cysfs*14]; c.1744delA [p.Met582Cysfs*6]). All variants were rare and expected to result in truncated proteins devoid of functionally important amino acid sequence. AOPEP, widely expressed in developing and adult human brain, encodes a zinc-dependent aminopeptidase, a member of a class of proteolytic enzymes implicated in synaptogenesis and neural maintenance. The probands presented with disabling progressive dystonia predominantly affecting upper and lower extremities, with variable involvement of craniocervical muscles. Dystonia was unaccompanied by any additional symptoms in three families, whereas the fourth family presented co-occurring late-onset parkinsonism., Conclusions: Our findings suggest a likely causative role of predicted inactivating biallelic AOPEP variants in cases of autosomal recessive dystonia. Additional studies are warranted to understand the pathophysiology associated with loss-of-function variation in AOPEP. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Agricultural expansion into subtropical and tropical forests causes major environmental damage, but its wider social impacts often remain hidden. Forest-dependent smallholders are particularly strongly impacted, as they crucially rely on forest resources, are typically poor, and often lack institutional support. Our goal was to assess forest-smallholder dynamics in relation to expanding commodity agriculture. Using high-resolution satellite images across the entire South American Gran Chaco, a global deforestation hotspot, we digitize individual forest-smallholder homesteads ( n = 23,954) and track their dynamics between 1985 and 2015. Using a Bayesian model, we estimate 28,125 homesteads in 1985 and show that forest smallholders occupy much larger forest areas (>45% of all Chaco forests) than commonly appreciated and increasingly come into conflict with expanding commodity agriculture (18% of homesteads disappeared; n = 5,053). Importantly, we demonstrate an increasing ecological marginalization of forest smallholders, including a substantial forest resource base loss in all Chaco countries and an increasing confinement to drier regions (Argentina and Bolivia) and less accessible regions (Bolivia). Our transferable and scalable methodology puts forest smallholders on the map and can help to uncover the land-use conflicts at play in many deforestation frontiers across the globe. Such knowledge is essential to inform policies aimed at sustainable land use and supply chains., Competing Interests: The authors declare no competing interest.

Background: Immunotherapy in microsatellite stable colorectal or pancreatic cancer has not shown promising results. It has been hypothesized that targeting immunosuppressive molecules like SDF1-alpha/CXCL12 could contribute to immunotherapy and animal models showed promising results on T cell activation and migration in combination with immune checkpoint inhibition., Methods: Here, we describe the successful application of anti-CXCL12 (NOX-A12) in patients with advanced stage pretreated metastatic colorectal and pancreatic cancer (OPERA trial). The treatment consisted of 2 weeks of anti-CXCL12 monotherapy with NOX-A12 followed by combination therapy with pembrolizumab (n=20 patients) until progression or intolerable toxicity had occurred., Results: The treatment was safe and well tolerated with 83.8% grade I/II, 15.5% grade III and 0.7% grade V adverse events. Of note, for a majority of patients, time on trial treatment was prolonged compared with their last standard treatment preceding trial participation. Systematic serial biopsies revealed distinct patterns of modulation. Tissue and clinical responses were associated with Th1-like tissue reactivity upon CXCL12 inhibition. A downregulation of a cytokine cassette of interleukin (IL)-2/IL-16/CXCL-10 was associated with tumor resistance and furthermore linked to a rare, CXCL12-associated CD14 + CD15 + promonocytic population. T cells showed aggregation and directed movement towards the tumor cells in responding tissues. Serum analyses detected homogeneous immunomodulatory patterns in all patients, regardless of tissue responses., Conclusions: We demonstrate that the combination of CXCL12 inhibition and checkpoint inhibition is safe and grants further exploration of synergistic combinatorial strategies., Competing Interests: Competing interests: The University Clinics in Heidelberg received funding from NOXXON Pharma for the implementation of the first clinical trial, of which we here present the results, using combined CXCL12 inhibition and pembrolizumab-mediated immune checkpoint blockade in patients with microsatellite stable colorectal and pancreatic cancer., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Despite the established value of genomic testing strategies, practice guidelines for their use do not exist in many indications., Objectives: We sought to validate a recently introduced scoring algorithm for dystonia, predicting the diagnostic utility of whole-exome sequencing (WES) based on individual phenotypic aspects (age-at-onset, body distribution, presenting comorbidity)., Methods: We prospectively enrolled a set of 209 dystonia-affected families and obtained summary scores (0-5 points) according to the algorithm. Singleton (N = 146), duo (N = 11), and trio (N = 52) WES data were generated to identify genetic diagnoses., Results: Diagnostic yield was highest (51%) among individuals with a summary score of 5, corresponding to a manifestation of early-onset segmental or generalized dystonia with coexisting non-movement disorder-related neurological symptoms. Sensitivity and specificity at the previously suggested threshold for implementation of WES (3 points) was 96% and 52%, with area under the curve of 0.81., Conclusions: The algorithm is a useful predictive tool and could be integrated into dystonia routine diagnostic protocols. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson Movement Disorder Society.)

Objective: To analyze serum immunoglobulin G (IgG) antibodies to major isoforms of myelin oligodendrocyte glycoprotein (MOG-alpha 1-3 and beta 1-3) in patients with inflammatory demyelinating diseases., Methods: Retrospective case-control study using 378 serum samples from patients with multiple sclerosis (MS), patients with non-MS demyelinating disease, and healthy controls with MOG alpha-1-IgG positive (n = 202) or negative serostatus (n = 176). Samples were analyzed for their reactivity to human, mouse, and rat MOG isoforms with and without mutations in the extracellular MOG Ig domain (MOG-ecIgD), soluble MOG-ecIgD, and myelin from multiple species using live cell-based, tissue immunofluorescence assays and ELISA., Results: The strongest IgG reactivities were directed against the longest MOG isoforms alpha-1 (the currently used standard test for MOG-IgG) and beta-1, whereas the other isoforms were less frequently recognized. Using principal component analysis, we identified 3 different binding patterns associated with non-MS disease: (1) isolated reactivity to MOG-alpha-1/beta-1 (n = 73), (2) binding to MOG-alpha-1/beta-1 and at least one other alpha, but no beta isoform (n = 64), and (3) reactivity to all 6 MOG isoforms (n = 65). The remaining samples were negative (n = 176) for MOG-IgG. These MOG isoform binding patterns were associated with a non-MS demyelinating disease, but there were no differences in clinical phenotypes or disease course. The 3 MOG isoform patterns had distinct immunologic characteristics such as differential binding to soluble MOG-ecIgD, sensitivity to MOG mutations, and binding to human MOG in ELISA., Conclusions: The novel finding of differential MOG isoform binding patterns could inform future studies on the refinement of MOG-IgG assays and the pathophysiologic role of MOG-IgG., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

We describe a genetic syndrome due to PGM2L1 deficiency. PGM2 and PGM2L1 make hexose-bisphosphates, like glucose-1,6-bisphosphate, which are indispensable cofactors for sugar phosphomutases. These enzymes form the hexose-1-phosphates crucial for NDP-sugars synthesis and ensuing glycosylation reactions. While PGM2 has a wide tissue distribution, PGM2L1 is highly expressed in the brain, accounting for the elevated concentrations of glucose-1,6-bisphosphate found there. Four individuals (three females and one male aged between 2 and 7.5 years) with bi-allelic inactivating mutations of PGM2L1 were identified by exome sequencing. All four had severe developmental and speech delay, dysmorphic facial features, ear anomalies, high arched palate, strabismus, hypotonia, and keratosis pilaris. Early obesity and seizures were present in three individuals. Analysis of the children's fibroblasts showed that glucose-1,6-bisphosphate and other sugar bisphosphates were markedly reduced but still present at concentrations able to stimulate phosphomutases maximally. Hence, the concentrations of NDP-sugars and glycosylation of the heavily glycosylated protein LAMP2 were normal. Consistent with this, serum transferrin was normally glycosylated in affected individuals. PGM2L1 deficiency does not appear to be a glycosylation defect, but the clinical features observed in this neurodevelopmental disorder point toward an important but still unknown role of glucose-1,6-bisphosphate or other sugar bisphosphates in brain metabolism., (Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.)

Across saccades, perceptual detectability of brief visual stimuli is strongly diminished. We recently observed that this perceptual suppression phenomenon is jumpstarted in the retina, suggesting that the phenomenon might be significantly more visual in nature than normally acknowledged. Here, we explicitly compared saccadic suppression strength when saccades were made across a uniform image of constant luminance versus when saccades were made across image patches of different luminance, width, and trans-saccadic luminance polarity. We measured perceptual contrast thresholds of human subjects for brief peri-saccadic flashes of positive (luminance increments) or negative (luminance decrements) polarity. Thresholds were >6-7 times higher when saccades translated a luminance stripe or edge across the retina than when saccades were made over a completely uniform image patch. Critically, both background luminance and flash luminance polarity strongly modulated peri-saccadic contrast thresholds. In addition, all of these very same visual dependencies also occurred in the absence of any saccades, but with qualitatively similar rapid translations of image patches across the retina. This similarity of visual dependencies with and without saccades supports the notion that perceptual saccadic suppression may be fundamentally a visual phenomenon, which strongly motivates neurophysiological and theoretical investigations on the role of saccadic eye movement commands in modulating its properties.

The primate superior colliculus (SC) has recently been shown to possess both a large foveal representation as well as a varied visual processing repertoire. This structure is also known to contribute to eye movement generation. Here, we describe our current understanding of how SC visual and movement-related signals interact within the realm of small eye movements associated with the foveal scale of visuomotor behavior. Within the SC's foveal representation, there is a full spectrum of visual, visual-motor, and motor-related discharge for fixational eye movements. Moreover, a substantial number of neurons only emit movement-related discharge when microsaccades are visually guided, but not when similar movements are generated toward a blank. This represents a particularly striking example of integrating vision and action at the foveal scale. Beyond that, SC visual responses themselves are strongly modulated, and in multiple ways, by the occurrence of small eye movements. Intriguingly, this impact can extend to eccentricities well beyond the fovea, causing both sensitivity enhancement and suppression in the periphery. Because of large foveal magnification of neural tissue, such long-range eccentricity effects are neurally warped into smaller differences in anatomical space, providing a structural means for linking peripheral and foveal visual modulations around fixational eye movements. Finally, even the retinal-image visual flows associated with tiny fixational eye movements are signaled fairly faithfully by peripheral SC neurons with relatively large receptive fields. These results demonstrate how studying active vision at the foveal scale represents an opportunity for understanding primate vision during natural behaviors involving ever-present foveating eye movements. NEW & NOTEWORTHY The primate superior colliculus (SC) is ideally suited for active vision at the foveal scale: it enables detailed foveal visual analysis by accurately driving small eye movements, and it also possesses a visual processing machinery that is sensitive to active eye movement behavior. Studying active vision at the foveal scale in the primate SC is informative for broader aspects of active perception, including the overt and covert processing of peripheral extra-foveal visual scene locations.

Water treadmill exercise has become popular in recent years for the training and rehabilitation of equine athletes. In 2019, an equine hydrotherapy working group was formed to establish what was commonly considered to be best practice in the use of the modality. This article describes the process by which general guidelines for the application of water treadmill exercise in training and rehabilitation programmes were produced by the working group. The guidelines describe the consensus reached to date on (1) the potential benefits of water treadmill exercise, (2) general good practice in water treadmill exercise, (3) introduction of horses to the exercise, (4) factors influencing selection of belt speed, water depth and duration of exercise, and (5) monitoring movement on the water treadmill. The long-term goal is to reach a consensus on the optimal use of the modality within a training or rehabilitation programme. Collaboration between clinicians, researchers and experienced users is needed to develop research programmes and further guidelines regarding the most appropriate application of the modality for specific veterinary conditions.

Land-use change is a root cause of the extinction crisis, but links between habitat change and biodiversity loss are not fully understood. While there is evidence that habitat loss is an important extinction driver, the relevance of habitat fragmentation remains debated. Moreover, while time delays of biodiversity responses to habitat transformation are well-documented, time-delayed effects have been ignored in the habitat loss versus fragmentation debate. Here, using a hierarchical Bayesian multi-species occupancy framework, we systematically tested for time-delayed responses of bird and mammal communities to habitat loss and to habitat fragmentation. We focused on the Argentine Chaco, where deforestation has been widespread recently. We used an extensive field dataset on birds and mammals, along with a time series of annual woodland maps from 1985 to 2016 covering recent and historical habitat transformations. Contemporary habitat amount explained bird and mammal occupancy better than past habitat amount. However, occupancy was affected more by the past rather than recent fragmentation, indicating a time-delayed response to fragmentation. Considering past landscape patterns is therefore crucial for understanding current biodiversity patterns. Not accounting for land-use history ignores the possibility of extinction debt and can thus obscure impacts of fragmentation, potentially explaining contrasting findings of habitat loss versus fragmentation studies.

Background: Dystonia is a clinically and genetically heterogeneous condition that occurs in isolation (isolated dystonia), in combination with other movement disorders (combined dystonia), or in the context of multisymptomatic phenotypes (isolated or combined dystonia with other neurological involvement). However, our understanding of its aetiology is still incomplete. We aimed to elucidate the monogenic causes for the major clinical categories of dystonia., Methods: For this exome-wide sequencing study, study participants were identified at 33 movement-disorder and neuropaediatric specialty centres in Austria, Czech Republic, France, Germany, Poland, Slovakia, and Switzerland. Each individual with dystonia was diagnosed in accordance with the dystonia consensus definition. Index cases were eligible for this study if they had no previous genetic diagnosis and no indication of an acquired cause of their illness. The second criterion was not applied to a subset of participants with a working clinical diagnosis of dystonic cerebral palsy. Genomic DNA was extracted from blood of participants and whole-exome sequenced. To find causative variants in known disorder-associated genes, all variants were filtered, and unreported variants were classified according to American College of Medical Genetics and Genomics guidelines. All considered variants were reviewed in expert round-table sessions to validate their clinical significance. Variants that survived filtering and interpretation procedures were defined as diagnostic variants. In the cases that went undiagnosed, candidate dystonia-causing genes were prioritised in a stepwise workflow., Findings: We sequenced the exomes of 764 individuals with dystonia and 346 healthy parents who were recruited between June 1, 2015, and July 31, 2019. We identified causative or probable causative variants in 135 (19%) of 728 families, involving 78 distinct monogenic disorders. We observed a larger proportion of individuals with diagnostic variants in those with dystonia (either isolated or combined) with coexisting non-movement disorder-related neurological symptoms (100 [45%] of 222; excepting cases with evidence of perinatal brain injury) than in those with combined (19 [19%] of 98) or isolated (16 [4%] of 388) dystonia. Across all categories of dystonia, 104 (65%) of the 160 detected variants affected genes which are associated with neurodevelopmental disorders. We found diagnostic variants in 11 genes not previously linked to dystonia, and propose a predictive clinical score that could guide the implementation of exome sequencing in routine diagnostics. In cases without perinatal sentinel events, genomic alterations contributed substantively to the diagnosis of dystonic cerebral palsy. In 15 families, we delineated 12 candidate genes. These include IMPDH2, encoding a key purine biosynthetic enzyme, for which robust evidence existed for its involvement in a neurodevelopmental disorder with dystonia. We identified six variants in IMPDH2, collected from four independent cohorts, that were predicted to be deleterious de-novo variants and expected to result in deregulation of purine metabolism., Interpretation: In this study, we have determined the role of monogenic variants across the range of dystonic disorders, providing guidance for the introduction of personalised care strategies and fostering follow-up pathophysiological explorations., Funding: Else Kröner-Fresenius-Stiftung, Technische Universität München, Helmholtz Zentrum München, Medizinische Universität Innsbruck, Charles University in Prague, Czech Ministry of Education, the Slovak Grant and Development Agency, the Slovak Research and Grant Agency., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Imaging plays a crucial role in differentiating the spectrum of paediatric acquired demyelinating syndromes (ADS), which apart from myelin oligodendrocyte glycoprotein antibody associated disorders (MOGAD) includes paediatric multiple sclerosis (MS), aquaporin-4 antibody neuromyelitis optica spectrum disorders (NMOSD) and unclassified patients with both monophasic and relapsing ADS. In contrast to the imaging characteristics of children with MS, children with MOGAD present with diverse imaging patterns which correlate with the main demyelinating phenotypes as well as age at presentation. In this review we describe the common neuroradiological features of children with MOGAD such as acute disseminated encephalomyelitis, optic neuritis, transverse myelitis, AQP4 negative NMOSD. In addition, we report newly recognized presentations also associated with MOG-ab such as the 'leukodystophy-like' phenotype and autoimmune encephalitis with predominant involvement of cortical and deep grey matter structures. We further delineate the features, which may help to distinguish MOGAD from other ADS and discuss the future role of MR-imaging in regards to treatment decisions and prognosis in children with MOGAD. Finally, we propose an MRI protocol for routine examination and discuss new imaging techniques, which may help to better understand the neurobiology of MOGAD., Competing Interests: Declaration of competing interest Matthias Baumann has no conflict of interest to declare. Frederik Bartels has no conflict of interest to declare. Carsten Finke has no conflict of interest to declare. Catherine Adamsbaum has no conflict of interest to declare. Yael Hacohen has no conflict of interest to declare. Kevin Rostásy has no conflict of interest to declare relevant to this manuscript., (Copyright © 2020 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.)

In recent years, the understanding about the different clinical phenotypes, diagnostic and prognostic factors of myelin oligodendrocyte glycoprotein-antibody-associated disorders (MOGAD) has significantly increased. However, there is still lack of evidence-based treatment protocols for acute attacks and children with a relapsing course of the disease. Currently used acute and maintenance treatment regimens are derived from other demyelinating central nervous system diseases and are mostly centre-specific. Therefore, this part of the Paediatric European Collaborative Consensus attempts to provide recommendations for acute and maintenance therapy based on clinical experience and evidence available from mainly retrospective studies. In the acute attack, intravenous methylprednisolone (IVMP) leads to a favourable outcome in the majority of patients and can be followed by tapering of oral steroids up to a maximum of three months to maintain the benefit of acute treatment by suppressing disease activity. Intravenous immunoglobulins (IVIG) and plasmapheresis constitute second-line therapies in case of insufficient response to IVMP. After a first relapse, maintenance treatment should be started in order to prevent further relapses and the possibility of permanent sequelae. Four first-line therapies consisting of rituximab (RTX), azathioprine, mycophenolate mofetil or monthly IVIG have been identified by the consensus group. In case of further relapses despite maintenance treatment, the consensus group recommends treatment escalation with RTX or IVIG, followed by combining those two, and ultimately adding maintenance oral steroids. Many open questions remain which need to be addressed in further international prospective evaluation of MOGAD treatment. This international collaboration is essential to expand the state of current knowledge., Competing Interests: Declaration of competing interest Arlette L. Bruijstens, Eva-Maria Wendel, Frederik Bartels, Carsten Finke, Markus Breu, Lorraine Flet-Berliac, Aliénor de Chalus, Catherine Adamsbaum, Giorgi Laetitia, Yael Hacohen and Matthias Baumann have no conflict of interest to declare. Christian Lechner has served as a consultant for Roche, but has no conflict of interest with this manuscript. Marco Capobianco has received consultation and speaker honoraria from Almirall, Biogen, Merck, Novartis, Roche, Sanofi, TEVA. Cheryl Hemingway serves as consultant for MS treatment for Biogen, Novartis and AQP4 treatment for Roche. She is an investigator in trials with Biogen, Roche and Novartis, but has no conflict of interest with this manuscript. Evangeline Wassmer has served as a consultant for Novartis and Biogen, PTC therapeutics, GMP-Orphan and Alexion. She is an investigator in trials with Alexion, Biogen Idec, Sanofi and Novartis. Her MS research projects have been funded by the UK MS Society, Action Medical Research and Birmingham Children’s Hospital Research Foundation. Ming Lim has received consultation fees from CSL Behring, Novartis and Octapharma; received travel grants from Merck Serono; and was awarded educational grants to organise meetings by Novartis, Biogen Idec, Merck Serono, and Bayer. Ronny Wickström has received consultation fees from Octapharma and Roche. Thaís Armangue has received speaker/consultant honoraria from Novartis and Biogen and travel expenses to attend to scientific meetings from Roche outside of the submitted work. Kevin Rostásy has no conflict of interest to declare relevant to this manuscript. Kumaran Deiva has received speaker/consultant honoraria from Novartis and Biogen, but has no COI with this manuscript. Rinze F. Neuteboom participates in trials by Sanofi and Novartis and has received honoraria from Novartis and Zogenix., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Mutated or amplified Her2 serves as a driver of non-small cell lung cancer or mediates resistance toward the inhibition of its family member epidermal growth factor receptor with small-molecule inhibitors. To date, small-molecule inhibitors targeting Her2 which can be used in clinical routine are lacking, and therefore, the development of novel inhibitors was undertaken. In this study, the well-established pyrrolopyrimidine scaffold was modified with structural motifs identified from a screening campaign with more than 1600 compounds, which were applied against wild-type Her2 and its mutant variant Her2-A775&#95;G776insYVMA. The resulting inhibitors were designed to covalently target a reactive cysteine in the binding site of Her2 and were further optimized by means of structure-based drug design utilizing a set of obtained complex crystal structures. In addition, the analysis of binding kinetics and absorption, distribution, metabolism, and excretion parameters as well as mass spectrometry experiments and western blot analysis substantiated our approach.

Background: New-generation, cell-based assays have demonstrated a robust association of serum autoantibodies to full-length human myelin oligodendrocyte glycoprotein (MOG-IgG) with (mostly recurrent) optic neuritis, myelitis, and brainstem encephalitis, as well as with neuromyelitis optica (NMO)-like or acute-disseminated encephalomyelitis (ADEM)-like presentations. However, only limited data are yet available on cerebrospinal fluid (CSF) findings in MOG-IgG-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disease, MOGAD)., Objective: To describe systematically the CSF profile in children with MOG-EM., Material and Methods: Cytological and biochemical findings (including white cell counts [WCC] and differentiation; frequency and patterns of oligoclonal bands; IgG/IgM/IgA and albumin concentrations and CSF/serum ratios; intrathecal IgG/IgM/IgA fractions; locally produced IgG/IgM/IgA concentrations; immunoglobulin class patterns; IgG/IgA/IgM reibergrams; Link index; measles/rubella/zoster [MRZ] reaction; other anti-viral and anti-bacterial antibody indices; CSF total protein; CSF L-lactate) from 108 lumbar punctures in 80 pediatric patients of mainly Caucasian descent with MOG-EM were analyzed retrospectively., Results: Most strikingly, CSF-restricted oligoclonal IgG bands, a hallmark of multiple sclerosis (MS), were absent in 89% of samples (N = 96), and the MRZ reaction, the most specific laboratory marker of MS known so far, in 100% (N = 29). If present at all, intrathecal IgG synthesis was low, often transient and mostly restricted to acute attacks. Intrathecal IgM synthesis was present in 21% and exclusively detectable during acute attacks. CSF WCC were elevated in 54% of samples (median 40 cells/μl; range 6-256; mostly lymphocytes and monocytes; > 100/μl in 11%). Neutrophils were present in 71% of samples; eosinophils, activated lymphocytes, and plasma cells were seen only rarely (all < 7%). Blood-CSF barrier dysfunction (as indicated by an elevated albumin CSF/serum ratio) was present in 46% of all samples (N = 79) and at least once in 48% of all patients (N = 67) tested. CSF alterations were significantly more frequent and/or more pronounced in patients with acute spinal cord or brain disease than in patients with acute ON and varied strongly depending on attack severity. CSF L-lactate levels correlated significantly with the spinal cord lesions load (measured in vertebral segments) in patients with acute myelitis (p = 0.0099). An analysis of pooled data from the pediatric and the adult cohort showed a significant relationship of QAlb (p < 0.0005), CST TP (p < 0.0001), and CSF L-lactate (p < 0.0003) during acute attacks with age., Conclusion: MOG-IgG-associated EM in children is characterized by CSF features that are distinct from those in MS. With regard to most parameters, no marked differences between the pediatric cohort and the adult cohort analyzed in Part 1 were noted. Our findings are important for the differential diagnosis of pediatric MS and MOG-EM and add to the understanding of the immunopathogenesis of this newly described autoimmune disease.