Human Electroretinography Shows Little Polarity Specificity Following Full-Field Ramp Adaptation.

Purpose: The ramp aftereffect, a visual phenomenon in which perception of light changes dynamically after exposure to sawtooth-modulated light, was first described in 1967. Despite decades of psychophysical research, location and mechanisms of its generation remain unknown. In this study, we investigated a potential retinal contribution to effect formation with specific emphasis on on-/off-pathway involvement. Methods: A 100 ms flash electroretinogram (ERG) was employed to probe the adaptive state of retinal neurons after presentation of stimuli that were homogenous in space but modulated in time following a sawtooth pattern (upward or downward ramps at 2 Hz). Additionally, a psychophysical nulling experiment was performed. Results: Psychophysics data confirmed previous findings that the ramp aftereffect opposes the adapting stimuli in ramp direction and is stronger after upward ramps. The ERG study revealed significant changes of activity in every response component in the low-frequency range (a-wave, b-wave, on-PhNR, d-wave and off-PhNR) and high-frequency range (oscillatory potentials) in amplitudes, peak times, or both. The changes are neither specific to the on- or off-response nor antagonistic between ramp directions. With downward ramp adaptation, effects were stronger. Neither amplitudes nor peak times were correlated with perception strength. Amplitudes and peak times were uncorrelated, and the effect diminished over time, ceasing almost completely with three seconds. Conclusions: Despite abundant effects on retinal responses, the pattern of adaptational effects was not specific to the sawtooth nature of adaptation. Although not ruling out retinal contributions the present findings favor post-retinal mechanisms as the primary locus of the ramp aftereffect.

How enoxaparin underdosing and sex contribute to achieving therapeutic anti-Xa levels.

Introduction: Anti-Xa serves as a clinical surrogate for assessing the efficacy and bleeding risk in patients treated with enoxaparin for thromboembolic events. Evidence from the literature and empirical observations suggest that patients are underdosed in clinical practice to avoid bleeding complications. This study aimed to investigate such underdosing of enoxaparin and its potential impact on achieving therapeutic anti-Xa levels. Methods: This multicentric, retrospective, observational study included patients with acute ischemic stroke due to atrial fibrillation. All patients received enoxaparin in the therapeutic setting with subsequent anti-Xa measurements. The one-sample, one-tailed Wilcoxon signed-rank test was used to identify a significant difference between the doses administered and the recommended daily dose. Logistic regression model analysis was performed to identify additional predictors affecting achievement of the therapeutic anti-Xa target range. Stepwise forward-backward selection with Akaike's information criterion as metric was applied to refine the logistic regression model. Results: A total of 145 patients from the university hospitals of St. Pölten and Tulln in Lower Austria were included. The median daily enoxaparin dose administered was 1.23 mg/kg, resulting in an overall target range achievement rate of 66%. As compared to recommended therapeutic doses, significant underdosing of enoxaparin was evident in both participating centers (p < 0.001). The calculated threshold dose to achieve the therapeutic target range with a 90% probability was 1.5 mg/kg enoxaparin daily. Female sex was found to be a strong independent predictor of achieving a therapeutic target range (OR 9.44; 95% CI 3.40-30.05, p < 0.001). Conclusion: Despite the underdosing observed in both centers, therapeutic anti-Xa levels were achieved with lower than recommended doses of enoxaparin, and women required even lower doses than men. These findings warrant further confirmation by prospective studies.

Prospective Analysis of Radiation-Induced Contrast Enhancement and Health-Related Quality of Life After Proton Therapy for Central Nervous System and Skull Base Tumors.

PURPOSE: Intracerebral radiation-induced contrast enhancement (RICE) can occur after photon as well as proton beam therapy (PBT). This study evaluated the incidence, characteristics, and risk factors of RICE after PBT delivered to, or in direct proximity to, the brain and its effect on health-related quality of life (HRQoL). METHODS AND MATERIALS: Four hundred twenty-one patients treated with pencil beam scanning PBT between 2017 and 2021 were included. Follow-up included clinical evaluation and contrast-enhanced magnetic resonance imaging at 3, 6, and 12 months after treatment completion and annually thereafter. RICE was graded according to Common Terminology Criteria for Adverse Events version 4, and HRQoL parameters were assessed via European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ)-C30 questionnaires. RESULTS: The median follow-up was 24 months (range, 6-54), and median dose to 1% relative volume of noninvolved central nervous system (D1%CNS) was 54.3 Gy relative biologic effectiveness (RBE; range, 30-76 Gy RBE). The cumulative RICE incidence was 15% (n = 63), of which 10.5% (n = 44) were grade 1, 3.1% (n = 13) were grade 2, and 1.4% (n = 6) were grade 3. No grade 4 or 5 events were observed. Twenty-six of 63 RICE (41.3%) had resolved at the latest follow-up. The median onset after PBT and duration of RICE in patients in whom the lesions resolved were 11.8 and 9.0 months, respectively. On multivariable analysis, D1%CNS > 57.6 Gy RBE, previous in-field radiation, and diabetes mellitus were identified as significant risk factors for RICE development. Previous radiation was the only factor influencing the risk of symptomatic RICE. After PBT, general HRQoL parameters were not compromised. In a matched cohort analysis of 54/50 patients with and without RICE, no differences in global health score or functional and symptom scales were seen. CONCLUSIONS: The overall incidence of clinically relevant RICE after PBT is very low and has no significant negative effect on long-term patient QoL.

CXCL13 as a biomarker in the diagnostics of European lyme Neuroborreliosis - A prospective multicentre study in Austria.

Background: 'Definite Neuroborreliosis (NB)' is diagnosed with the presence of NB-specific symptoms, cerebrospinal fluid (CSF) pleocytosis and an elevated Borrelia Burgdorferi antibody index. However, some diagnostic uncertainties exist. The B-cell chemokine CXCL13 represents an emerging biomarker for the diagnosis and treatment of NB because its intrathecal concentration rises prior to the Borrelia antibody index and drops rapidly after antibiotic therapy. Nevertheless, due to lacking prospective data, a definite CXCL13 cut-off for the diagnosis of NB is still pending. Objective: Definition of a CSF CXCL13 cut-off for the diagnosis of acute and untreated NB in a prospective study setting. Design and methods: This multicentre prospective study involved 6 neurological departments treating patients in the Lower Austria district (1.7 million inhabitants). The controls were patients scheduled for a spinal tap but not clinically diagnosed with NB. Demographic data, clinical characteristics and blood counts, as well as inflammatory CSF values and CSF CXCL13-concentration were analysed. Results: We recruited 440 adult patients, of whom 42 have been diagnosed as having an acute and untreated 'definite NB'. Three hundred ninety-eight patients were assigned to the control group. The median intrathecal CXCL13 concentration was 2384 pg/ml for patients with NB and 0 pg/ml for controls. The difference was highly statistically significant (P ≤ .001). A CSF CXCL13 cut-off of 271 pg/ml resulted in a sensitivity of 95.2% and a specificity of 97.2% for the confirmation or exclusion of NB. Conclusion: Based on our results, we propose a CSF CXCL13 cut-off of 271 pg/ml with Euroimmun-Elisa for the diagnosis of acute and untreated NB. Due to its high sensitivity and specificity, CXCL13 is a strong candidate biomarker for routine NB assessment, especially in clinically unclear cases.

A novel function of STAT3ß in suppressing interferon response improves outcome in acute myeloid leukemia.

Signal transducer and activator of transcription 3 (STAT3) is frequently overexpressed in patients with acute myeloid leukemia (AML). STAT3 exists in two distinct alternatively spliced isoforms, the full-length isoform STAT3α and the C-terminally truncated isoform STAT3ß. While STAT3α is predominantly described as an oncogenic driver, STAT3ß has been suggested to act as a tumor suppressor. To elucidate the role of STAT3ß in AML, we established a mouse model of STAT3ß-deficient, MLL-AF9-driven AML. STAT3ß deficiency significantly shortened survival of leukemic mice confirming its role as a tumor suppressor. Furthermore, RNA sequencing revealed enhanced STAT1 expression and interferon (IFN) signaling upon loss of STAT3ß. Accordingly, STAT3ß-deficient leukemia cells displayed enhanced sensitivity to blockade of IFN signaling through both an IFNAR1 blocking antibody and the JAK1/2 inhibitor Ruxolitinib. Analysis of human AML patient samples confirmed that elevated expression of IFN-inducible genes correlated with poor overall survival and low STAT3ß expression. Together, our data corroborate the tumor suppressive role of STAT3ß in a mouse model in vivo. Moreover, they provide evidence that its tumor suppressive function is linked to repression of the STAT1-mediated IFN response. These findings suggest that the STAT3ß/α mRNA ratio is a significant prognostic marker in AML and holds crucial information for targeted treatment approaches. Patients displaying a low STAT3ß/α mRNA ratio and unfavorable prognosis could benefit from therapeutic interventions directed at STAT1/IFN signaling.

Favorable impact of PD1/PD-L1 antagonists on bone remodeling: an exploratory prospective clinical study and ex vivo validation.

BACKGROUND: Skeletal morbidity in patients with cancer has a major impact on the quality of life, and preserving bone health while improving outcomes is an important goal of modern antitumor treatment strategies. Despite their widespread use in early disease stages, the effects of immune checkpoint inhibitors (ICIs) on the skeleton are still poorly defined. Here, we initiated a comprehensive investigation of the impact of ICIs on bone health by longitudinal assessment of bone turnover markers in patients with cancer and by validation in a novel bioengineered 3D model of bone remodeling. METHODS: An exploratory longitudinal study was conducted to assess serum markers of bone resorption (C-terminal telopeptide, CTX) and formation (procollagen type I N-terminal propeptide, PINP, and osteocalcin, OCN) before each ICI application (programmed cell death 1 (PD1) inhibitor or programmed death-ligand 1 (PD-L1) inhibitor) for 6 months or until disease progression in patients with advanced cancer and no evidence of bone metastases. To validate the in vivo results, we evaluated osteoclast (OC) and osteoblast (OB) differentiation on treatment with ICIs. In addition, their effect on bone remodeling was assessed by immunohistochemistry, confocal microscopy, and proteomics analysis in a dynamic 3D bone model. RESULTS: During the first month of treatment, CTX levels decreased sharply but transiently. In contrast, we observed a delayed increase of serum levels of PINP and OCN after 4 months of therapy. In vitro, ICIs impaired the maturation of preosteoclasts by inhibiting STAT3/NFATc1 signaling but not JNK, ERK, and AKT while lacking any direct effect on osteogenesis. However, using our bioengineered 3D bone model, which enables the simultaneous differentiation of OB and OC precursor cells, we confirmed the uncoupling of the OC/OB activity on exposure to ICIs by demonstrating impaired OC maturation along with increased OB differentiation. CONCLUSION: Our study indicates that the inhibition of the PD1/PD-L1 signaling axis interferes with bone turnover and may exert a protective effect on bone by indirectly promoting osteogenesis.