Annette Aigner

ObjectivesLipoprotein receptor-related protein 4 antibody-positive myasthenia gravis (LRP4-Ab-positive MG) is a rare serologic subgroup with poorly defined clinical phenotype. This study investigat...

Joint models offer an unbiased statistical approach for analyzing the effects of longitudinal biomarkers on time-to-event outcomes, providing an alternative to time-varying Cox proportional-hazards regression and the two-stage approach. However, whether available implementations of these methods perform reliably across different practically relevant scenarios remains insufficiently studied. We conducted a simulation study based on the Berlin Initiative Study examining kidney function and survival in older adults. In a manner comparable to phase IV studies in clinical research, our evaluation aims to provide insights into the practical performance of commonly used R package implementations of these methods, mostly under their default settings. By varying data generating scenarios, we assessed how different numbers of events and longitudinal measurements affect performance of Bayesian (JMbayes2) and frequentist joint model implementations (JM and joineRML), time-varying Cox PH regression (survival), and the two-stage approach (nlme and survival), focusing on bias in parameter estimates. Results revealed substantial variability across implementations. The JM package exhibited considerable bias and frequent convergence issues. In contrast, joineRML performed robustly with approximately unbiased estimates for association parameters and high convergence frequencies comparable to the implementations of the simpler methods across diverse scenarios. However, both frequentist packages systematically underestimated the effects of baseline covariates in the survival model. The Bayesian JMbayes2 was largely unbiased, but performance deteriorated under two conditions: with few events (< 70), convergence was low and bias persisted even in converged models; and with observation-to-event ratios below 2, convergence declined, although estimates from converged models remained approximately unbiased. Time-varying Cox PH regression and the two-stage approach showed more bias than JMbayes2 in certain settings but tended to achieve more robust performance and convergence across most scenarios.

Background and objective: Data on chronic autoimmune neuropathies (CAN) requiring intensive care unit (ICU) treatment are limited. This study investigated clinical and neuropathological features, immunotherapies, and outcomes of ICU-treated CAN patients. Methods: Retrospectively, we analyzed patients with CAN admitted to the ICU between 2007 and 2024. Outcomes, assessed by Inflammatory Neuropathy Cause and Treatment (INCAT) score and modified Rankin scale (mRS), were compared to age, sex, and diagnosis-matched non-ICU outpatients using ordinal and binary logistic regression. Results: Among 21 included patients (chronic inflammatory demyelinating neuropathies (CIDP): n = 15, other CAN: n = 6), 95% required mechanical ventilation and exhibited severe tetraparesis at disease nadir. Biopsies from CIDP patients revealed moderate-to-severe chronic axonal loss with variable CD8 + T-cell infiltration (9/11), and complement deposition (C5b-9) was detected in all samples ( n = 8/8). All patients received first-line immunotherapy at ICU, 62% required “escalation” (rituximab: n = 13, cyclophosphamide: n = 3). Five (24%) remained refractory, receiving daratumumab ( n = 3), efgartigimod ( n = 1), or autologous stem cell transplantation ( n = 1). Six patients (29%) died, whereas survivors showed marked improvement with median change of − 2 mRS points (95% CI − 5 to − 2) and − 6 INCAT points (95% CI − 8 to− 5) at last follow-up. However, ICU-treated patients had significantly higher odds of worse long-term outcomes than matched non-ICU patients (adjusted cumulative OR: mRS 7.1 95% CI 1.9–27.3, INCAT 6.4 95% CI 1.7–23.2). Conclusion: Severe CAN requiring ICU treatment is associated with high mortality, but meaningful recovery is possible in survivors. Neuropathology confirmed combined cellular and humoral mechanisms, supporting personalized, mechanism-guided therapeutic approaches.

Background: Gestational diabetes mellitus (GDM) complicates a significant number of pregnancies and is associated with both short- and long-term risks for the mother and child. Twin pregnancies are inherently high risk, and the coexistence of GDM may amplify these risks. While the effects of GDM in singleton pregnancies have been widely studied, data on its impact in twin gestations remain limited. The aim of this study was to determine differences regarding metabolic characteristics, treatment requirements, and maternal as well as fetal outcomes between twin and singleton pregnancies with GDM to contribute to improved perinatal care. Methods: This retrospective study included obstetric data from 73 twin pregnancies (146 neonates) and 1664 singleton pregnancies with a GDM diagnosis at a tertiary perinatal center in Berlin, Germany, between 2015 and 2022. Baseline characteristics and perinatal outcomes were assessed. Adjusted multiple linear and logistic regression analyses were used for group comparisons. Results: Women with GDM in twin and singleton pregnancies exhibited comparable glucose values in the 75 g oral glucose tolerance test (OGTT) (median fasting: 95 vs. 96 mg/dL; 1 h: 183 vs. 183 mg/dL; 2 h: 144 vs. 139 mg/dL). Despite this, insulin therapy was required significantly less often in twin (5.5%) compared to singleton pregnancies (22.3%) (OR = 0.86; 95% CI: 0.78–0.96). Among insulin-treated women, combined insulin therapy was most common in twins (75%), while singleton mothers most frequently received long-acting insulin alone (61.7%), followed by combined therapy (31.3%) and short-acting insulin alone (7%). Birthweight was significantly lower in twins (β = –0.83 kg; 95% CI: –0.98 to –0.69), and when evaluated using twin-based growth standards, twins were more likely to be classified as having intrauterine growth restriction (IUGR, <3rd percentile) (OR = 3.37; 95% CI: 0.96–9.11), being small for gestational age (SGA, 90th percentile) neonates were observed in the twin group. Conclusions: GDM manifests differently in twin and singleton pregnancies. Despite similar OGTT values, twin mothers require insulin less frequently. Growth-related complications such as IUGR and SGA are significantly more frequent in twins, likely reflecting the physiological constraints of multiple gestations rather than GDM itself. Conversely, LGA is predominantly a concern in singleton pregnancies. These findings underscore the need for individualized diagnostic criteria and management strategies for GDM in twin pregnancies.

BACKGROUND AND OBJECTIVES: Evidence on how different antithrombotic therapies influence microsurgical evacuation efficacy in spontaneous intracerebral hemorrhage (ICH) is limited. Antithrombotic agents may increase hematoma volume and impact postoperative outcomes, complicating surgical management. As growing evidence supports surgical ICH evacuation, understanding the role of antithrombotics and emergency reversal strategies is critical. The aim of this study was a comparative overview on how common types of antithrombotic therapy influence radiographic and clinical outcomes in surgically treated ICH. METHODS: In this retrospective study, we included consecutive patients who underwent microsurgical hematoma evacuation for supratentorial ICH between 2008 and 2022. Patient characteristics, antithrombotic therapy, reversal strategies, neuroimaging, and 12-month functional outcome (modified Rankin Scale) were reviewed. Preoperative antiplatelet therapy (APT), vitamin K antagonists, direct oral anticoagulants, and combined antiplatelet/anticoagulant therapy (Comb) was compared with no antithrombotic medication. Multivariable regression models were used to analyze the association between antithrombotic therapy, radiographic, and clinical outcomes. RESULTS: Overall, we included 232 patients with supratentorial ICH (APT: 53, vitamin K antagonists: 29, direct oral anticoagulant: 13, Comb: 17). Patients with any type of antithrombotic therapy presented with larger absolute preoperative hematoma volumes than patients without prior antithrombotic medication. Combined antiplatelet/anticoagulant therapy affected preoperative ICH volume to the greatest extent (volume difference: 14.9 mL; 95% CI: 0.9, 29.0). APT was associated with a 1.4-fold increase in relative postoperative ICH volume (95% CI: 0.9, 2.1), while combined therapy was associated with a 2.1-fold increase (95% CI: 1.1, 4.0). Unfavorable outcome (modified Rankin Scale ≥4) affected 73.5% of patients and was linked to larger preoperative hematomas (63 mL vs 49 mL) and higher relative postoperative hematoma volume (13.7% vs 7.5%). CONCLUSION: Despite preoperative emergency reversal, antithrombotics contributed to higher hematoma volumes, poorer microsurgical evacuation efficacy and worse functional outcome. Particularly for patients receiving APT, the findings underline the importance of optimizing antithrombotic reversal strategies.

Objective: The K ⁺ /Cl ⁻ cotransporter (KCC2), which acts as the main Cl ⁻ extruder in the adult brain, coregulates the driving force and therewith indirectly the amount and polarity of γ‐aminobutyric acidergic (GABAergic) currents. Whether the net effect of active KCC2 is inhibitory via such Cl ⁻ extrusion or excitatory due to the concomitant increase of K ⁺ in the extracellular space is context‐dependent and difficult to predict. Consecutively, in rodent models, antiseizure‐ as well as seizure‐facilitating effects of KCC2 block have been reported. Here, we attempted to gain more insight into KCC2's role in the seizure propagation zone in human temporal neocortex. Methods: We induced network activity in postoperative acute neocortical brain slices from humans with temporal lobe epilepsy under low Mg ²⁺ conditions, with and without elevated K ⁺ , and recorded it using microelectrode arrays. We analyzed ictal‐like events and interictal‐like discharges with a developed source‐separating approach. Finally, we complemented these network‐related studies by patch‐clamp recordings of individual pyramidal neurons under regular ionic conditions to assess the inherent functionality of KCC2 and alternative transmembrane Cl ⁻ routes. Results: Modulation of KCC2 activity altered the induced network activity; KCC2 block reversibly led to substantially increased activity, preferentially in and propagating through supragranular layers. Correspondingly, enhancing KCC2 activity reduced network activity there. Almost all individual supragranular pyramidal neurons tested had functional KCC2, that is, certain Cl ⁻ extrusion capacity that was limited when loaded with higher Cl ⁻ and presented variable predominantly positive values of GABA _A receptor driving force. In addition, we found tonic inhibition that increases after prolonged KCC2 block and may either contribute to Cl ⁻ load or support Cl ⁻ extrusion in supragranular pyramidal neurons, depending on their intracellular Cl ⁻ concentration. Significance: Our data show that KCC2 mitigates ictal‐like activity in the seizure propagation zone of human neocortex, thereby further promoting KCC2 as a therapeutic target.

Background/Objectives: The COVID-19 pandemic significantly threatened cancer patients and oncologic care. The rollout of vaccines emerged as a critical milestone, despite the initial lack of evidence regarding their safety and efficacy in this population. This systematic review and meta-analysis evaluate the current evidence on COVID-19 vaccination in patients undergoing radiotherapy (RT). Methods: PubMed, Livivo, Scopus, and Cochrane Library were systematically reviewed for relevant publications on COVID-19 vaccination in the context of radiation oncology, published by 19 April 2024. The treatment effects were calculated as the proportion of seroconverted individuals. Results: A total of 22 studies published between 2021 and 2024 were included, covering various aspects of vaccination, including safety, tolerability, qualitative and quantitative humoral responses, cellular responses, vaccination efficacy, and booster vaccinations. Notably, patients undergoing RT exhibited a high willingness to receive vaccination. Vaccination was overall well tolerated and safe, with a low incidence of side effects, which were primarily mild. The primary meta-analysis showed a seroconversion proportion of 91% [95% CI: 84–96%] overall, with a somewhat higher proportion of 93% in patients receiving RT alone, compared to 90% in patients receiving either RT or RT combined with chemotherapy. Furthermore, immunization during RT led to a sustained increase in antibody titers, with a notable long-term persistence of IgG. Conclusions: COVID-19 vaccines demonstrate excellent safety, immunogenicity, and efficacy in patients receiving RT, who also exhibit a high willingness to be vaccinated. The outcomes observed are comparable to those in healthy controls and superior to those seen in patients receiving other cancer treatments, such as chemotherapy. The vaccination of radiation oncology patients in future pandemics or epidemics is strongly advocated even during active treatment.