Giessen School of Theology

Stereotactic radiotherapy (SRT) is astandard treatment for vestibular schwannoma (VS). Long-term comparative data on single-fraction radiosurgery (SRS) versus normofractionated SRT (NFSRT) are limited. We retrospectively analyzed 175 VS patients treated between 1998 and 2023 (SRS n = 69; NFSRT n = 106; median age61years; median follow-up 46months). Tumor control was evaluated with Kaplan-Meier and Cox regression. Group differences were tested with Mann-WhitneyU and chi-square/Fisher's exact tests. Symptom changes were assessed with McNemar tests, and binary logistic regression identified predictors of acute and late toxicity. Overall, in-field PFS was 94.3% and out-field was PFS was 99.4%. All 10recurrences (median 58.5months) occurred in NFSRT patients treated with 55.8-56 Gy. Higher total dose predicted recurrence (HR = 2.97; p = 0.003). At baseline, 97.1% reported symptoms (hearing loss 86.9%, vertigo 48.0%, tinnitus 42.3%). After therapy, symptoms remained stable, except the incidence of headache, which increased from 14.3% to 22.3% (p = 0.02). Early toxicities were more common after NFSRT, including headache (OR = 4.05; p = 0.01), fatigue (OR = 5.12; p = 0.01), and alopecia (OR = 19.9; p = 0.04), but had resolved by late follow-up. Age and prior surgery predicted vertigo patterns over time. Radionecrosis was rare (0.6%). Both SRS and NFSRT achieve excellent long-term tumor control with low severe toxicity. For NFSRT, normofractionated doses above 55 Gy did not improve efficacy and may increase the recurrence risk, supporting moderate-dose regimens (50-54 Gy). Symptom stabilization confirms the safety of SRT, though headache and vertigo remain relevant long-term issues. Careful dose selection, patient counseling, and rehabilitation are essential to optimize outcomes.

Background: Patients with inflammatory rheumatic diseases (IRD) are susceptible to influenza infections and their complications. However, they may avoid vaccination for fear of exacerbating their IRD. This study evaluates the 2023/24 influenza vaccine in IRD patients, aiming to provide recommendations for this group in the upcoming season. Methods: In this prospective, longitudinal study, we assessed the self-reported impact of influenza vaccination on patients with IRD. Participants were recruited nationwide between October and December 2023 and completed an online questionnaire after vaccination as well as at three and six months of follow-up. Results: Among 633 patients, 87.5% were female, with a median age of 50.4 (18-84) years. Post-vaccination, 50% experienced injection site pain; 41% reported no side effects. IRD flares occurred in 5%, with 1% requiring changes to immunomodulation. Among 428 patients with follow-up, influenza infections were reported in 38 patients (8.9%), including 10 (2.3%) with reinfections. No severe cases requiring hospitalization were reported. Spondyloarthritis patients had higher susceptibility to influenza (p = 0.002), accounting for 55.3% of infections. IRD flare-ups in the 12 months before vaccination predicted infections (p = 0.002). Conclusions: The 2023/24 vaccine was well tolerated by IRD patients, with no impact on the course of the disease in 95% of cases. Only 9% of patients reported influenza infections, none of which were severe. In light of these findings, physicians are advised to recommend vaccination to eligible IRD patients prior to or in the respective season.

ABSTRACT Phosphorylation plays a central role in coordinating transcription with pre-mRNA maturation, yet the mechanistic understanding of how transcription is regulated by phosphorylation remains limited. The PP1 phosphatase removes CDK9-dependent phosphorylation of Pol II and Spt5, triggering transcription termination. Here, we demonstrate that PNUTS enhances PP1 activity, whereas WDR82 mediates an interaction between PP1 and the pre-mRNA 3′ end processing machinery subunit Symplekin. We present the first structure of a PNUTS–WDR82–Symplekin–Ssu72 complex, revealing that PNUTS and Symplekin bind WDR82 through distinct interfaces using conserved short linear motifs. Mutations that inactivate PP1’s catalytic activity or disrupt its interaction with either PNUTS or the 3′ end processing machinery led to impaired transcription elongation, inefficient cleavage of nascent transcripts, altered poly(A) site selection, and widespread transcription termination defects. Our findings demonstrate that the PP1 complex is essential for coupling transcription to pre-mRNA 3′ end maturation, ensuring production of functional mRNA.

To find an item of interest among candidate objects we are directed by attentional sets that reflect our expectations and intentions and may also vary by whether items should be attended or ignored. We investigated how different attentional sets influence target search and the effect of prior experience on these attentional sets. Our participants had to identify a target object given a set of objects that either contained the target itself (direct attentional set) or contained only cues that defined the target by exclusion (indirect attentional set). We found that response times were significantly slower for indirect attentional sets and when sets were mixed within blocks. To analyze the impact of attentional sets on priming, we fitted behavioral time series using multiple dynamic ideal observer models based on a first-order memory mechanism with three consecutive stages: set identification (direct vs. indirect), target identification (based on set cues), and response. The different models involved different assumptions about each stage, and we compared them via information criterion to identify mechanisms that consistently lead to good expected out-of-sample performance. We found strong repetition priming when both set and target were repeated. For direct attentional set, repetition priming was consistent with a first-order memory mechanism that tracks objects and colors likely connected to feature-specific neural mechanisms and frontoparietal attention network. In contrast, the processing of indirect attentional sets relies on qualitatively different mechanisms and search strategies than conventional visual search, likely related to neural networks involved in task switching and generation of attentional set.

Repetitive transcranial magnetic stimulation (rTMS) induces long-term changes in synapses, but the mechanisms behind these modifications are not fully understood. Although there has been progress in the development of multi-scale modeling tools, no comprehensive module for simulating rTMS-induced synaptic plasticity in biophysically realistic neurons exists. We developed a modelling framework that allows the replication and detailed prediction of long-term changes of excitatory synapses in neurons stimulated by rTMS. We implemented a voltage-dependent plasticity model that has been previously established for simulating frequency-, time-, and compartment-dependent spatio-temporal changes of excitatory synapses in neuronal dendrites. The plasticity model can be incorporated into biophysical neuronal models and coupled to electrical field simulations. We show that the plasticity modelling framework replicates long-term potentiation (LTP)-like plasticity in hippocampal CA1 pyramidal cells evoked by 10-Hz repetitive magnetic stimulation (rMS). In line with previous experimental studies, this plasticity was strongly distance dependent and localised to the proximal synapses of the neuron. We predicted a decrease in the plasticity amplitude for 5 Hz and 1 Hz protocols with decreasing frequency. Finally, we successfully modelled plasticity in distal synapses upon local electrical theta-burst stimulation (TBS) and predicted proximal and distal plasticity for rMS TBS. Notably, the rMS TBS-evoked synaptic plasticity exhibited robust facilitation by dendritic spikes and low sensitivity to inhibitory suppression. The plasticity modelling framework enables precise simulations of LTP-like cellular effects with high spatio-temporal resolution, enhancing the efficiency of parameter screening and the development of plasticity-inducing rTMS protocols.