Johannes Gutenberg University Mainz

Précis Larger choriocapillaris microvasculature dropout area and wider angular circumference are significantly associated with 24-2C central visual field damage in primary open-angle glaucoma eyes with and without axial myopia. Purpose To evaluate the relationship between a juxtapapillary choriocapillaris microvasculature dropout (MvD) and central visual field (VF) damage in primary open-angle glaucoma (POAG) patients with or without axial myopia. Methods This cross-sectional study included 125 patients with POAG or glaucoma suspects stratified into no axial myopia (axial length (AL) ≤24 mm; 46 eyes), mild axial myopia (24 mm< AL ≤26 mm; 81 eyes), and high axial myopia (AL >26 mm; 59 eyes). Presence, area, and angular circumference of juxtapapillary MvD were evaluated on OCT-A en-face choroidal images and B-scans. Perimetry was conducted using the 24-2C and 10-2 Humphrey program. Results Mean 24-2C VF mean deviation was significantly worse in eyes with MvD compared to eyes without MvD across all groups (all P <0.042). Central VF defects detected in the 24-2C and 10-2 VF tests were significantly more prevalent among eyes with MvD (68.3% and 81.7%, respectively) compared to eyes without MvD (19.0% and 38.1%, respectively) ( P <0.001) in the mild axial myopia group. In multivariable analysis, larger MvD area ( P =0.014) and wider MvD angular circumference ( P =0.006) were significantly associated with higher likelihood of the presence of 24-2C central VF damage in overall cohort. Conclusions MvD area and angular circumference are significantly associated with central VF damage detected by VF 24-2C in POAG eyes with and without axial myopia. Choriocapillaris MvD assessment shows promise for identifying POAG patients with a higher risk of having central VF defects and may provide clinical insights into the pathogenesis of glaucoma in myopia.

After acute lesions in the central nervous system (CNS), the interaction of microglia, astrocytes, and infiltrating immune cells decides over their resolution or chronification. However, this CNS-intrinsic cross-talk is poorly characterized. Analyzing cerebrospinal fluid (CSF) samples of Multiple Sclerosis (MS) patients as well as CNS samples of female mice with experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we identify microglia-derived TGFα as key factor driving recovery. Through mechanistic in vitro studies, in vivo treatment paradigms, scRNA sequencing, CRISPR-Cas9 genetic perturbation models and MRI in the EAE model, we show that together with other glial and non-glial cells, microglia secrete TGFα in a highly regulated temporospatial manner in EAE. Here, TGFα contributes to recovery by decreasing infiltrating T cells, pro-inflammatory myeloid cells, oligodendrocyte loss, demyelination, axonal damage and neuron loss even at late disease stages. In a therapeutic approach in EAE, blood-brain barrier penetrating intranasal application of TGFα attenuates pro-inflammatory signaling in astrocytes and CNS infiltrating immune cells while promoting neuronal survival and lesion resolution. Together, microglia-derived TGFα is an important mediator of glial-immune crosstalk, highlighting its therapeutic potential in resolving acute CNS inflammation.

Student ultrasound education (SUSE) is currently composed of heterogeneous curricular training formats, and new approaches are continually being explored to enhance undergraduate ultrasound training. Based on a literature review, this report aims to analyze and compare different forms and methods of assessment of acquired skills in ultrasound training. Therefore, the advantages and disadvantages of assessment formats and certification systems used in SUSE were discussed collaboratively between medical students, postgraduate physicians, and medical didactics experts. Ultrasound competency should be tested using structured examination formats that are objective and standardized. In addition to cognitive skills, the examination format should cover translational and behavioral components. Self-assessments and evaluations provide additional valuable perspectives. Certification systems can contribute to quality assurance by externally ensuring the achievement of milestones in SUSE. They also have the potential to support the necessary standardization of undergraduate ultrasound teaching by aligning the curricular learning objectives with qualifications to be achieved.

A bstract We present a minimal composite dark matter model, based on a SU( N d ) dark sector with n f dark quarks and a heavy t-channel mediator. For n f ≥ 4, the dark flavor symmetry guarantees the stability of a subset of the dark pions, which serve as our dark matter candidates. Their relic abundance is determined by dark sector annihilation with the remaining dark pions, which are unstable and decay. Due to their degenerate masses, the annihilation cross section is suppressed at low temperatures, thereby avoiding stringent constraints from indirect detection and opening up the GeV mass window. The decaying dark pions are naturally long lived. We obtain limits on the model from semi-visible or emerging jet searches and estimate the reach of future probes.

RNA modifications are key regulators of cellular processes, yet selectively introducing these modifications into target RNAs remains challenging. We developed “designer organelles” to perform highly selective, guide-RNA-driven pseudouridylation of mRNA in living cells. Circular guide RNAs further enhance modification efficiency and specificity. These orthogonal RNA editing organelles (OREOs) thus represent a versatile new approach to precise RNA modification, with promising applications from basic research to therapeutic interventions.

Objective: RATIONALE-305 (NCT03777657) demonstrated that tislelizumab plus chemotherapy statistically improved overall survival versus placebo plus chemotherapy as first-line treatment in patients with advanced gastric/gastroesophageal junction adenocarcinoma (GC/GEJC). This analysis examined patient-reported outcomes (PROs) at final analysis. Methods: Adults with previously untreated, unresectable, or metastatic GC/GEJC were randomized (1:1) to tislelizumab or placebo intravenously once every 3 weeks plus chemotherapy. PROs assessed health-related quality of life (HRQoL) using EORTC QLQ-C30 and EORTC QLQ-STO22. A mixed model for repeated measures was used for PRO endpoints at treatment cycles 4 and 6, and time to deterioration was analyzed. Results: Tislelizumab arm had improved outcomes over placebo arm in least-squares (LS) mean change from baseline to cycle 6 for QLQ-C30 global health status/quality of life (GHS/QoL) (LS mean difference, 2.52 [95% CI: 0.29-4.74]), physical functioning (2.46 [0.49-4.43]), fatigue (-3.01 [-5.78 to -0.24]), and STO22 index score (-1.62 [-3.12 to -0.12]) as well as maintenance of upper gastrointestinal symptoms (-1.74 [-3.55-0.06]) and pain/discomfort (-1.88 [-4.03-0.27]). Patients receiving tislelizumab plus chemotherapy had a lower risk for deterioration of GHS/QoL (hazard ratio 0.77 [95% CI: 0.60-0.98]), physical functioning (0.72 [0.57-0.92]), STO22 index score (0.64 [0.45-0.92]), pain/discomfort (0.74 [0.58-0.96]), and upper gastrointestinal symptoms (0.73 [0.56-0.95]). Conclusions: Advanced GC/GEJC patients treated with tislelizumab plus chemotherapy versus placebo plus chemotherapy in first-line had sustained and improved HRQoL. These results, along with previous efficacy and safety data, support tislelizumab plus chemotherapy as a first-line treatment option for GC/GEJC. Trial registration: The RATIONALE-305 trial is registered on ClinicalTrials.gov (ClinicalTrials.gov identifier: NCT03777657).ClinicalTrials.gov identifier: NCT03777657.

Background Somatic symptoms significantly contribute to absenteeism and healthcare costs, particularly in physically demanding professions such as postal and delivery services. The FC-Fit Challenge, an app-based workplace health intervention, aims to promote healthier lifestyles through personalized feedback, social interaction, and professional guidance, targeting lifestyle changes and reducing somatic symptoms. Objectives This study evaluated the effect of the FC-Fit Winterchallenge 2021/22 on somatic symptoms over time, considering sociodemographic and work-related differences, and identified predictors of somatic symptoms to inform workplace health strategies. Methods A longitudinal design with three measurement points was employed: at the start of the intervention (T1), immediately post-intervention (T2), and three-month follow-up (T3). At T1, 497 participants completed the survey. Sociodemographic and work-related variables, health behaviors, and mental health indicators were analyzed. Multiple regression identified significant predictors of somatic symptoms. Results Somatic symptoms significantly decreased post-intervention (T1: 7.0 ± 4.6 vs. T2: 5.9 ± 4.5, p < 0.001), with sustained effects at T3. Women, full-time employees, and administrative staff showed the most pronounced reductions. Predictors of higher somatic symptom severity included female gender, lower education, painkiller use, stress, and burnout, while high physical activity was associated with lower severity. Subgroup analysis revealed variability in intervention effectiveness based on sociodemographic and occupational factors. Conclusions The FC-Fit Challenge is a promising, scalable tool for workplace health promotion. Tailoring interventions to specific employee profiles and addressing predictors like stress and burnout can optimize outcomes. Future studies should target underrepresented groups, such as delivery workers, and use randomized controlled designs to validate findings.

Employer reviews (i.e., online workplace ratings authored by employees) attract broad interest and shape the opinions of potential employees. Thus, companies face the challenge of dealing with these workplace judgments that are outside their direct control. While prevailing theoretical perspectives suggest that responding to third‐party judgments may be an effective way for companies to deal with them, they focus on responses to negative judgments that threaten companies' reputations. Based on signaling theory, we argue that employer responsiveness, signaled by an employer's first response to an employer review, serves as a mechanism of indirect control over employer reviews. Applying a difference‐in‐differences approach—a statistical technique to estimate the causal effect of the treatment (i.e., responsiveness) by comparing it to a control group without the treatment—on a sample of 298,269 reviews of 21,099 employers over 45 quarters posted on the employer review website Kununu, we hypothesize and find that compared to nonresponsive employers, responsive employers receive more diverse (i.e., variety of topics covered) and extensive (i.e., amount of information provided) employer reviews. These effects are especially pronounced in the case of negative employer reviews. Our findings can serve as a guide for employers in dealing with third‐party judgments by demonstrating that employer responsiveness is a valuable signal enhancing online review quality. We contribute to the growing body of HRM research on employer reputation on social media, a critical factor influencing recruitment and retention outcomes. Our study opens new avenues for research to explore the role of responsiveness as a strategic signal in employer brand management.

We present a combination of experimental and theoretical approaches to decipher the molecular recognition event of benzoic acid complexed with Protein Kinase A. The publicly known crystal structure suggests the protonated form of benzoic acid to be complexed with Protein Kinase A. Such a protonation pattern of is unlikely for benzoic acid in aqueous enviromnent and must be induced by complexation to Protein Kinase A. Unfortunately, isothermal titration calorimetry does not reveal any binding event which might be caused by the low affinity. However, Poisson‐Boltzmann calculations and molecular dynamics simulations strengthen the initial hypothesis of a protonated benzoic acid binding to Protein Kinase A.

Background: Cardiovascular disease is among the most common causes of death worldwide. Interventions, such as percutaneous coronary intervention, used to recanalise coronary stents, require precise anatomical knowledge, particularly regarding vascular variations, to avoid complications. Materials and methods: In our study, we describe a rare anatomical variation of the superficial brachioulnar artery (SBUA). Results: We present an SBUA originating from the brachial artery in its upper third further running superficially in a straight course to the hand, where it comprises the full function of the ulnar artery. At the same time, the regular ulnar artery terminates as a hypoplastic vessel which exclusively supplies the local musculature. This combination expands the existing literature and highlights the clinical relevance of vascular variations. Conclusions: Our case report underscores the importance of precise preoperative imaging to identify vascular anomalies early on and at the same time minimise patient safety-related complications. Additionally, this new variation of the SBUA emphasises the need to integrate anatomical variations more thoroughly into medical education and research. The latter would ensure the systematical capture of their prevalence and implications to improve clinical practice in the long run. Keywords: anatomical variationbrachial arteryclinical implicationsforearm vascular anatomypreoperative imagingsuperficial brachioulnar arterysurgical complicationsulnar arteryvascular anomaliesvascular variations

Background Glaucoma is a progressive neurodegenerative disorder that leads to irreversible vision loss, with neuroinflammation recognized as a key factor. Overexpression of glial fibrillary acidic protein (GFAP) is linked to glaucoma pathogenesis and plays a pivotal role in astrocyte-driven neuroinflammation. This study aimed to assess the neuroprotective effects of a monoclonal antibody (mAb) targeting GFAP in glaucoma and to elucidate the underlying mechanisms. Methods An ocular hypertension (OHT) glaucoma model was established in female Sprague Dawley rats using episcleral vein occlusion. Three doses of GFAP mAb (2.5, 25, 50 µg) or vehicle were administered via intravitreal injection. Retinal nerve fiber layer (RNFL) thickness and photopic electroretinogram were monitored longitudinally. Retinal ganglion cell (RGC) survival and glial responses were evaluated with immunostaining. Western blot and microarray analyses were performed to investigate molecular and pathway alterations. Additionally, a cobalt chloride (CoCl2)-induced degenerative R28 cell model was used to validate the protective effects of GFAP mAb in vitro. A bioinformatics re-analysis of a public glaucomatous retina protein dataset was conducted using GSEA, GO, and Cytoscape with GENEMANIA. Results OHT resulted in a significant loss of RNFL thickness, PhNR amplitude, and RGC survival, all of which were preserved by GFAP mAb treatment. Retinal astrocyte reactivity was inhibited by GFAPmAb in a dose-dependent manner by suppressing GFAP protein overexpression. Notably, 25 µg GFAP mAb effectively regulated both astrocyte and microglial reactivity, leading to a substantial attenuation of neuroinflammation. Mechanistically, GFAP mAb inhibited the p38 MAPK and NF-κB pathways and the NLRP3/Caspase-1/GSDMD axis. In vitro, GFAP mAb improved R28 cell viability under CoCl2 exposure while reducing cell death via inhibition of pyroptosis. Bioinformatic re-analysis highlighted gliosis as a prominent pathway in the glaucomatous retina and indicated GFAP and Caspase1 as central nodes in the putative mechanism network modulated by GFAP mAb. Conclusions This study demonstrates that GFAP mAb inhibits astrogliosis and glial-glial activation, exerting neuroprotection through the inhibition of inflammation and pyroptosis. The findings suggest that targeting GFAP represents a promising immunotherapeutic strategy for glaucoma treatment. Graphical Abstract

A bstract Previous computations of feebly interacting particle production have encountered issues with unphysical (negative) interaction rates at soft momenta. We address this problem by studying the production of Axion-Like Particles (ALPs) coupled to U(1)-gauge fields, employing the full form of 1PI-resummed gauge boson propagators. This approach avoids the need for matching or subtraction procedures. We find that the ALP production rate remains positive across all momentum scales and identify the dominant production mechanisms. At soft ALP momenta ( p ≲ g ² T ), interactions involving two spacelike gauge bosons dominate the production rate, surpassing other channels by an order of magnitude. In particular, using the full gauge boson propagator suggests that at even softer momenta ( p ≲ g ⁴ T ), production involving two timelike gauge bosons becomes significant, potentially exceeding other contributions by another order of magnitude. We also find that a leading order accurate result for momenta g ⁴ T ≲ p ≲ g ² T still requires extensions beyond the 1PI resummation. Using these insights, we update the thermal ALP abundance and refine the estimate of the average ALP momentum, providing important input for structure formation constraints on ALP dark matter in the keV mass range.

Children with attention-deficit/hyperactivity disorder (ADHD) typically experience social interaction problems. Neurocognitive functions, such as working memory and inhibitory control have been included in several studies of social problems in ADHD, with inconsistent findings emerging. Intraindividual reaction time variability (RTV) has been understudied as a factor explaining social problems in children with ADHD, despite being one of the most consistent cognitive impairments in the disorder. In the current study, we hypothesized that greater RTV would relate to greater parent-reported social problems and may reflect the negative impact of attentional fluctuations on social interactions in ADHD. We tested the association between RTV and social problems while accounting for the effects of working memory and inhibitory control in two independent samples of children with ADHD and typically developing (TD) peers. The neurocognitive functions were assessed through performance-based laboratory measures. Sample one, derived in Norway, included 41 children with ADHD and 35 TD children. Sample two, derived in the United States, included 73 children with ADHD and 26 TD children. Linear regression analyses, controlling for other relevant variables, indicated that greater RTV was associated with greater social problems across both samples. Our results support the view that attentional variability is linked to social problems in children with ADHD.

Experimental animal and human studies illustrate the effect of various stress forms on the thyroid gland and the regulation of thyroid hormones (TH) through the thyrotropic multi-loop control circuit. The hypothalamic–pituitary–thyroid axis (HPT) axis is part of the physiological stress system and mediates key regulators of metabolic activity during stress response. Genetically characterized individuals are more affected in their response to stressors, and their psychological response is extremely amplified. This leads to significant increases in TH serum levels as soon as a negative stressor appears. Physical stressors are used to induce psychological stress, e.g., physical exercise, starvation, sleep deprivation, hypoxia, and cold temperatures, all of which impact thyroid function. In addition, somatic illnesses may also affect the thyroid gland or may be related to a thyroidal dysfunction. As a psychosocial stressor in animal models, neonatal separation from the mother was used, affecting energy homeostasis and causing an increase in thyroliberin (TRH) expression in female rats and an increase in TRH degrading ectoenzyme in male rats. In mice with restrained stress, TH are important mediators of accelerated tumor growth. In human studies, isolated sexual abuse in childhood doubles the risk of thyroid dysfunction, with puerperal depression after sexual abuse in childhood increasing the risk for HPT axis disorders and elevated thyroid autoantibodies four-fold. In addition, psychological illnesses influence thyroid function. In the future, laboratory studies with standardized induction of various stress forms are warranted to better understand stress-induced effects on the HPT axis and their corresponding mechanisms.