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Analysis of 1386 epileptogenic brain lesions reveals association with DYRK1A and EGFR
Get PDFLesional focal epilepsy (LFE) is a common and severe seizure disorder caused by epileptogenic lesions, including malformations of cortical development (MCD) and low-grade epilepsy-associated tumors (LEAT). Understanding the genetic etiology of these lesions can inform medical and surgical treatment. We conducted a somatic variant enrichment mega-analysis in brain tissue from 1386 individuals who underwent epilepsy surgery, including 599 previously unpublished individuals with ultra-deep ( > 1600x) targeted panel sequencing. Here we confirm four known associations ( BRAF, SLC35A2, MTOR, PTPN11 ), support eight associations without prior statistical support ( FGFR1, PIK3CA, AKT3, NF1, PTEN, RHEB, KRAS, NRAS ), and identify novel associations for two genes, DYRK1A and EGFR . Both novel genes show specific histopathological phenotypes, interact with LFE genes and pathways, and may represent promising candidates as biomarkers and potentially druggable targets.Somatic variants in certain genes can cause lesional focal epilepsy. Here the authors perform the largest somatic variant detection study in epilepsy to date, finding statistical support for 8 known and 2 novel genes, DYRK1A and EGFR, which may be potential biomarkers and druggable targets.U.S. Department of Health & Human Services | NIH | National Institute of Neurological Disorders and Stroke (NINDS)https://doi.org/10.13039/100000065Programme d’Investissements d’Avenir - ANR-18-RHUS-00
Calcified Amorphous Tumor and Granulomatosis with Polyangiitis—Case Report and Systematic Review of the Literature
Get PDFBackground: Calcified amorphous tumor (CAT) is a rare, mostly incidental tumor-like cardiac lesion of unknown histogenesis. Current imaging modalities do not differentiate between CAT and other masses. As it can be a source for embolization, surgical excision of CAT is mandatory. CAT in patients with Granulomatosis with polyangiitis (GPA) is exceedingly rare. Methods: This systematic literature review was prompted by the case of a CAT in a patient with GPA. The search of all types of studies in two databases (PubMed and Scopus) was conducted through November 2024 to identify the relevant studies. Results: Nine studies were included describing cases of patients being diagnosed with GPA and a cardiac mass. All included patients had a histopathological examination of the either biopsied or surgically resected mass. Only one case reported a CAT. In our case, the patient was diagnosed with GPA through a kidney biopsy, whereas a cardiac mass in the right atrium was diagnosed by echocardiography during evaluation for possible kidney transplantation. One year later a progression was observed, and the mass was resected. The histopathological examination revealed a CAT. The patient could be successfully discharged in a good clinical condition. Conclusions: This systematic literature search and case report highlight the importance of regular echocardiographic examination in patients with GPA. Moreover, surgical excision is crucial for the diagnosis and for further therapy planning, regardless of whether the mass is neoplastic or not.This research received no external funding
Caspase-8 promotes scramblase-mediated phosphatidylserine exposure and fusion of osteoclast precursors
Get PDFEfficient cellular fusion of mononuclear precursors is the prerequisite for the generation of fully functional multinucleated bone-resorbing osteoclasts. However, the exact molecular factors and mechanisms controlling osteoclast fusion remain incompletely understood. Here we identify RANKL-mediated activation of caspase-8 as early key event during osteoclast fusion. Single cell RNA sequencing-based analyses suggested that activation of parts of the apoptotic machinery accompanied the differentiation of osteoclast precursors into mature multinucleated osteoclasts. A subsequent characterization of osteoclast precursors confirmed that RANKL-mediated activation of caspase-8 promoted the non-apoptotic cleavage and activation of downstream effector caspases that translocated to the plasma membrane where they triggered activation of the phospholipid scramblase Xkr8. Xkr8-mediated exposure of phosphatidylserine, in turn, aided cellular fusion of osteoclast precursors and thereby allowed generation of functional multinucleated osteoclast syncytia and initiation of bone resorption. Pharmacological blockage or genetic deletion of caspase-8 accordingly interfered with fusion of osteoclasts and bone resorption resulting in increased bone mass in mice carrying a conditional deletion of caspase-8 in mononuclear osteoclast precursors. These data identify a novel pathway controlling osteoclast biology and bone turnover with the potential to serve as target for therapeutic intervention during diseases characterized by pathologic osteoclast-mediated bone loss. Proposed model of osteoclast fusion regulated by caspase-8 activation and PS exposure . RANK/RANK-L interaction. Activation of procaspase-8 into caspase-8. Caspase-8 activates caspase-3. Active capase-3 cleaves Xkr8. Local PS exposure is induced. Exposed PS is recognized by the fusion partner. FUSION. PS is re-internalized.Bayerische Forschungsstiftung (Bavarian Research Foundation)https://doi.org/10.13039/501100002745RCUK | Biotechnology and Biological Sciences Research Council (BBSRC)https://doi.org/10.13039/501100000268Wellcome Trust (Wellcome)https://doi.org/10.13039/100004440Deutsche Forschungsgemeinschaft (German Research Foundation)https://doi.org/10.13039/50110000165
Fostering self-efficacy through usability and emotional product design? An explorative study
Get PDFRaising the user’s self-confidence is a promising strategy to reduce product-related user stigma. In the context of product usage, the commonly used term self-confidence refers to the psychological construct of self-efficacy. To strengthen a user’s self-efficacy through product design, providing both good usability and emotionality in a product seems to be a reasonable starting point. However, their suitability and validity for this purpose has not yet been sufficiently assessed. This paper examines whether self-efficacy would be associated with perceptions of a product’s usability and emotionality. By conducting an online survey ( n = 105; stigma-sensitive product demonstrator: walker), it was confirmed that the perception of good usability and emotionality of walkers were positively associated with the user’s perceived self-efficacy. Moreover, a negative interaction effect was identified showing that the association between emotionality and self-efficacy increased with lower levels of perceived usability and vice versa. This may indicate that emotions can compensate the importance of usability at least to some extent.Open Access funding enabled and organized by Projekt DEAL.Deutsche Forschungsgemeinschafthttp://dx.doi.org/10.13039/501100001659Friedrich-Alexander-Universität Erlangen-Nürnberg (1041
The Value of a Modified Posterior Thigh Flap with Z-Plasty for Reconstruction of Ischial Tuberosity Pressure Ulcers: A Retrospective Single Center Analysis
Get PDFPressure ulcers are a persistent and growing challenge in modern medicine, with prevalence rates ranging from 3.4% to 32.4% globally. Demographic changes suggest an increasing number of patients at risk, emphasizing the need for effective prevention and advanced treatment strategies. These ulcers, particularly stages III and IV, often require surgical intervention due to severe tissue damage. Among the surgical options, the Posterior Thigh Flap has emerged as a reliable fasciocutaneous flap, frequently referred to as a “work-horse flap”, for defect coverage in the ischial region. To improve outcomes and minimize recurrences in weight-bearing areas, our clinic combined this flap technique with a Z-plasty modification to achieve redistribution of scar tissue to reduce localized pressure. In this retrospective study, six patients with seven ischial pressure ulcers were treated between 2003 and 2024 using this approach. Following debridement and wound conditioning with negative pressure therapy, defect coverage was performed. The results show clinically acceptable complication rates (42.9%) and a low recurrence rate (14.3%), with recurrences occurring no earlier than 12 months post-treatment. The Z-plasty effectively shifted scar zones away from high-pressure areas, reducing tension and recurrence risk. This study highlights the potential benefits of combining fasciocutaneous flaps with scar management techniques to improve long-term outcomes for ischial pressure ulcers and provides an innovative approach to treating ischial pressure ulcers.This research received no external funding
Mental health in the workplace – What role do socioeconomic-, gender-, and migration-related inequalities play?
No full textZusammenfassung Hintergrund Risikofaktoren für die psychische Gesundheit sind häufig in sozioökonomischen, geschlechter- und migrationsspezifischen Ungleichheiten begründet. Diese sowie die Ausprägung der Depressivität, Ängstlichkeit und Somatisierung von Beschäftigten wurden in der vorliegenden Studie untersucht. Methoden Im Rahmen der friaa-Studie („Frühe Intervention am Arbeitsplatz“) wurden psychisch belastete Beschäftigte an 5 Standorten in Deutschland zu soziodemografischen, arbeits-, migrations- und gesundheitsbezogenen Inhalten befragt. Mittels Regressionsanalysen wurde der Zusammenhang dieser Faktoren mit Depressivität (Patient-Health-Questionnaire-9, PHQ-9), Ängstlichkeit (Generalized Anxiety Disorder-2, GAD-2) und Somatisierung (Somatic Symptom Scale-8, SSS-8) an der gesamten Stichprobe sowie bei Personen mit Migrationshintergrund (MH) untersucht. Bei Letzteren wurden zusätzlich die Akkulturation (Frankfurter Akkulturationsskala, FRAKK) und das Belastungsempfinden gegenüber Migrationsanforderungen (Demands of Immigration Scale, DIS) berücksichtigt. Ergebnisse Die 550 Beschäftigten (12 % mit MH) wiesen im Durchschnitt eine klinisch relevante Depressivität (M = 13,0, SD = 5,1) (PHQ-9 ≥ 10), Ängstlichkeit (M = 3,5, SD = 1,7) (GAD ≥ 3) sowie Somatisierung (M = 13,0, SD = 5,8) (SSS-8 ≥ 12) auf. Das weibliche Geschlecht war mit höheren Werten für Ängstlichkeit und Somatisierung assoziiert. Höheres Alter und Nachtschichtarbeit hingen mit stärkerer Somatisierung zusammen. Diskussion Die Ergebnisse bestätigen die hohe psychische Belastung der Beschäftigten in dieser Stichprobe aus Deutschland. Um deren psychische Gesundheit aufrechtzuerhalten, sollten Unterstützungsmaßnahmen insbesondere für vulnerable Gruppen wie Frauen, ältere Beschäftigte und Nachtschichtarbeitende angeboten werden.Background Risk factors for mental health can be found in socio-economic-, gender- and migration-specific inequalities. These factors and the extent of depression, anxiety, and somatization among employees were examined in the present study. Methods As part of the Early Intervention in the Workplace Study (friaa), mentally burdened employees at five locations in Germany were surveyed on socio-demographic-, work-, migration-, and health-related content. Regression analyses were used to examine the relationship between these factors and depression (Patient-Health-Questionnaire-9, PHQ-9), anxiety (Generalized Anxiety Disorder-2, GAD-2), and somatization (Somatic Symptom Scale-8, SSS-8) in the entire sample and in people with migration background (MB). For the latter, acculturation (Frankfurt Acculturation Scale, FRACC) and the perception of burden in terms of demands of immigration (Demands of Immigration Scale, DIS) were also taken into account. Results On average, the 550 employees (12% with MB) showed clinically relevant depression (M = 13.0, SD = 5.1) (PHQ-9 ≥ 10), anxiety (M = 3.5, SD = 1.7) (GAD ≥ 3) and somatization (M = 13.0, SD = 5.8) (SSS-8 ≥ 12). Female gender was associated with higher anxiety and somatization. Older age and night shift work were associated with higher somatization. Discussion The results confirm the high level of mental burden among this sample of employees in Germany. In order to maintain their mental health, support measures should be offered, especially for vulnerable groups such as women, older employees, and night shift workers.Open Access funding enabled and organized by Projekt DEAL.Friedrich-Alexander-Universität Erlangen-Nürnberg (1041
Effects of Ply Misalignment in Material Characterization of Composite Laminates
Get PDFCarbon fiber reinforced plastic (CFRP) parts find a rising number of applications as structural components. Therefore, new manufacturing technologies are developed, enabling high volume production of such parts. With those higher volumes, variation management during product design becomes more critical. While manufacturing variations in CFRP materials occur on different scales, detecting and considering those on the meso (ply) scale becomes more important. Thus, the question arises whether such variations can be detected with standardized testing methods. In this study, artificial fiber misalignment has been introduced into the outer plies of standardized tensile specimens to explore the influence of such variations on the mechanical properties. A simulation model was developed to identify these variations and the test results were used to calibrate and optimize the material parameters of the simulation model. The effects of the artificially induced variation were distinguishable in the test data as well as in the simulation models. Furthermore, the simulation models showed good agreement with the experimental data, which leads to the conclusion that the utilized measuring techniques are well suited to characterize the fiber misalignment. The developed simulation models can be used to investigate the effects of fiber misalignment within the product development process without the need for physical testing.This research was funded by Bayerische Forschungsstiftung within the program for the initiation of international cooperations BayIntAn, grant number Bay_Int_An_FAU_2022_88. The authors gratefully thank Bayerische Forschungsstiftung for the funding.Bayerische Forschungsstiftun
Efficacy of digital interventions on physical activity promotion in individuals with noncommunicable diseases: an overview of systematic reviews
Get PDFBackground Physical inactivity is considered one of the main modifiable risk factors for noncommunicable diseases. It has been proven that an active lifestyle is an efficient means of preventing and managing noncommunicable diseases. Multiple barriers have been identified that hinder engagement in conventional physical activity programs and the achievement of physical activity recommendations. Digital interventions may expand opportunities to resolve these barriers and empower people with noncommunicable diseases to be physically active. This overview of systematic reviews aims to evaluate the efficacy of digital interventions on physical activity promotion among individuals with major noncommunicable diseases. Method A protocol was registered in the PROSPERO database (CRD42022364350). A qualitative synthesis method was applied to summarize the efficacy data. The assessment of methodological quality using AMSTAR-2 for each systematic review was performed by two independent reviewers. Results Searches in nine databases resulted in seven systematic reviews for inclusion. Most of the primary studies included in these seven reviews were conducted in high-income countries. The reviews addressed five populations: participants with cancers, cardiovascular diseases, chronic obstructive pulmonary disease, type 2 diabetes, and osteoarthritis. Digital interventions were classified into two categories: interventions based on digital activity trackers and remote interventions via digital facilities. Additional components were identified in both categories of interventions such as motivational content, counseling, goal setting, tailored feedback/reminders, and other behavioral change techniques. The overall quality of the reviews ranged from critically low to low. The findings provided some evidence that both categories of interventions were effective in promoting physical activity. Conclusion The findings of this overview suggest that some types of digital interventions, such as self-monitoring with digital activity trackers and remote interventions via digital facilities, may be effective means of promoting physical activity across major noncommunicable diseases. The findings should be interpreted cautiously since the methodological quality of the included reviews ranged from critically low to low, and there was no consistent assessment of the certainty of evidence. Further systematic reviews are required on efficacy of digital interventions with more rigorous conducting and reporting of systematic review methodologies.Open Access funding enabled and organized by Projekt DEAL.We acknowledge financial support by Deutsche Forschungsgemeinschaft and Friedrich-Alexander-Universität Erlangen-Nürnberg within the funding programme “Open Access Publication Funding”. The funding body did not play any role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.Friedrich-Alexander-Universität Erlangen-Nürnberg (1041
The influence of crack and interface oxidation on dwell fatigue crack propagation behavior of the nickel-base superalloy ATI A718Plus
Get PDFThe crack propagation properties are an important and often limiting factor for the commercial application of superalloys in aerospace applications where the oxidation ahead of the crack tip plays an important role. Previous research on the Ni-base superalloy A718Plus revealed that the orientation and the volume fraction of the high temperature grain boundary phases δ and η have a major influence on the dwell fatigue crack propagation rate at 650 °C in ambient air but not in vacuum. In this work, the effect of internal oxidation at the η / δ –matrix interface and its effect on dwell fatigue crack propagation and mechanical properties are examined by advanced microscopic methods and micro-cantilever testing. During crack propagation, the crack tip is exposed to air where a Nb-rich oxide layer forms and embrittles the η / δ –matrix interface causing the cracks to deflect and propagate along the oxidized interfaces. Micro-cantilever tests on the oxidized interface show that these oxide layers also significantly reduce the local strength and fracture toughness of the material. This proves that interfacial oxide layers are the underlying reason for the reduction of the dwell fatigue crack growth resistance at 650 °C, particularly in microstructures whose η / δ –matrix interfaces are oriented parallel to the crack growth direction. Graphical AbstractOpen Access funding enabled and organized by Projekt DEAL.Friedrich-Alexander-Universität Erlangen-Nürnberg (1041
Relationship of peak capillary blood lactate accumulation and body composition in determining the mechanical energy equivalent of lactate during sprint cycling
Get PDFAimA 15-s all-out sprint cycle test (i.e., νLamax-test) and the post-exercise change in capillary blood lactate concentration is an emerging diagnostic tool that is used to quantify the maximal glycolytic rate. The goal of this study was to determine the relation between 15 s-work, change in capillary blood lactate concentration (∆La) and body composition in a νLamax-test.MethodFifty cyclists performed a 15 s all-out sprint test on a Cyclus2 ergometer twice after a previous familiarization trial. Capillary blood was sampled before and every minute (for 8 min) after the sprint to determine ∆La. Body composition was determined employing InBody720 eight-electrode impedance analysis.ResultSimple regression models of fat-free mass (FFM) and also the product of FFM and ∆La showed similar ability to predict 15 s-work (R2 = 0.79; 0.82). Multiple regression combining both predictors explains 93% of variance between individuals. No differences between males and females were found regarding 15 s-work relative to the product of fat-free mass and ∆La. Considering pairs of similar FFM, a change 1 mmol/l of ∆La is estimated to be equal to 12 J/kg in 15 s-work (R2 = 0.85).DiscussionFifteen s-work is both closely related to FFM and also the product of ∆La and lactate-distribution space approximated by FFM. Differences in 15 s-work between males and females disappear when total lactate production is considered. Considering interindividual differences, the mechanical energy equivalent of blood lactate accumulation seems a robust parameter displaying a clear relationship between ∆La and 15 s-work relative to FFM