Gating modules of the AMPA receptor pore domain revealed by unnatural amino acid mutagenesis.

Ionotropic glutamate receptors (iGluRs) are responsible for fast synaptic transmission throughout the vertebrate nervous system. Conformational changes of the transmembrane domain (TMD) underlying ion channel activation and desensitization remain poorly understood. Here, we explored the dynamics of the TMD of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type iGluRs using genetically encoded unnatural amino acid (UAA) photocross-linkers, p-benzoyl-l-phenylalanine (BzF) and p-azido-l-phenylalanine (AzF). We introduced these UAAs at sites throughout the TMD of the GluA2 receptor and characterized the mutants in patch-clamp recordings, exposing them to glutamate and ultraviolet (UV) light. This approach revealed a range of optical effects on the activity of mutant receptors. We found evidence for an interaction between the Pre-M1 and the M4 TMD helix during desensitization. Photoactivation at F579AzF, a residue behind the selectivity filter in the M2 segment, had extraordinarily broad effects on gating and desensitization. This observation suggests coupling to other parts of the receptor and like in other tetrameric ion channels, selectivity filter gating.

Respiratory syncytial virus immunization patterns in Germany, 2015-2020.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection (LRTI) in infants and young children worldwide. Using routine statutory health insurance claims data including patients from all regions of Germany, we investigated the health-care resource use and costs associated with RSV prophylaxis with palivizumab in Germany. In the database, infants from the birth cohorts 2015-2019 eligible for palivizumab immunization were identified using codes of the 10th revision of the International Classification of Diseases (ICD-10). Health-care resource use and costs related to immunization were determined by inpatient and outpatient administrations. Over the study period, only 1.3% of infants received at least one dose of palivizumab in their first year of life. The mean number of doses per immunized infant was 4.6. From a third-party payer perspective, the mean costs of palivizumab per infant who received at least one dose in the first year of life was €5,435 in the birth cohorts 2015-2019. Despite the substantial risk of severe RSV infection, we found low rates of palivizumab utilization. Novel preventive interventions, featuring broader indications and single-dose administration per season, contribute to mitigating the burden of RSV disease across a more extensive infant population.

Inpatient burden of respiratory syncytial virus in children ≤2 years of age in Germany: A retrospective analysis of nationwide hospitalization data, 2019-2022.

BACKGROUND: Respiratory syncytial virus (RSV) causes respiratory tract disease in seasonal waves, primarily in infants and young children. This study aims to quantify the number of RSV-related hospitalizations in children ≤2 years of age and to determine corresponding resource use and costs in Germany. METHODS: We retrospectively analyzed population-wide hospital data from the Institute for the Hospital Remuneration System (InEK) from 2019 to 2022. RSV cases were identified using the RSV-specific 10th revision of the International Classification of Diseases (ICD-10) codes J12.1, J20.5, and J21.0. The RSV-associated proportion of all hospitalizations caused by severe acute respiratory infections (SARIs), clinical manifestations, length of stay (LOS), intensive care unit (ICU) admissions, ventilation rates, and hospitalization costs were retrieved. RESULTS: We identified 98,220 hospitalizations (26,052, 15,407, 31,362, and 25,399 in 2019, 2020, 2021, and 2022, respectively) with a principal RSV diagnosis in children aged ≤2 years in Germany. The majority of RSV hospitalizations (73,178) occurred in infants (<1 year), with annual incidence rates ranging from 14.9 to 28.6 per 1000 population. Fifty-eight percent of all SARI hospitalizations in this age group were attributable to RSV. In children aged ≤2 years, mean LOS was 4.5 days, 6.1% of cases were admitted to ICU, and 5.3% of cases were ventilated. Mean hospitalization costs per case ranged from €3001 to €3961 over the study period. CONCLUSIONS: RSV causes substantial disease burden and is a leading cause of SARI-related hospital admissions of children ≤2 years of age in Germany. Our results confirm the need to explore and evaluate strategies to prevent RSV in infants and young children.

Subthalamic and pallidal oscillatory activity in patients with Neurodegeneration with Brain Iron Accumulation type I (NBIA-I).

OBJECTIVES: Neurodegeneration with Brain Iron Accumulation type I (NBIA-I) is a rare hereditary neurodegenerative disorder with pallidal degeneration leading to disabling generalized dystonia and parkinsonism. Pallidal or subthalamic deep brain stimulation can partially alleviate motor symptoms. Disease-specific patterns of abnormally enhanced oscillatory neuronal activity recorded from the basal ganglia have been described in patients with movement disorders undergoing deep brain stimulation (DBS). Here we studied oscillatory activity recorded from the internal globus pallidus (GPi) and the subthalamic nucleus (STN) to characterize neuronal activity patterns in NBIA-I. METHODS: We recorded local field potentials (LFP) from DBS electrodes in 6 juvenile patients with NBIA-I who underwent functional neurosurgery. Four patients were implanted in the STN and two patients in the GPi. Recordings were performed during wakeful rest. An FFT-based approach was used to analyze the power spectrum in the target area. RESULTS: In all patients we found distinct peaks in the low frequency (7-12 Hz) and in 5 out 6 also in the beta frequency range (15-30 Hz) with the largest beta peak in the patient that presented with the most prominent bradykinesia. No distinct peaks occurred in the gamma frequency range (35-100 Hz). The oscillatory pattern did not differ between STN and GPi. CONCLUSIONS: Here we show for the first time the oscillatory activity pattern in the STN and the GPi in juvenile patients with dystonia plus syndrome due to NBIA-I. The low frequency peak we found is in line with previous studies in patients with isolated idiopathic dystonia. In our cohort, the pallidal beta band activity may be related to more severe motor slowing in dystonia plus syndrome such as NBIA-I. SIGNIFICANCE: Our results further support the link between hyperkinetic motor symptoms such as dystonia and enhanced basal ganglia low frequency activity irrespective of the underlying etiology of dystonia.