Zusammenhang zwischen krankheitsspezifischem Wissen und Lebensqualität bei Patienten mit idiopathischer Skoliose und Korsetttherapie

Einleitung Die Idiopathische Adoleszentenskoliose trifft die Jugendlichen inmitten ihrer Pubertät. Bekanntermaßen benötigt eine erfolgreiche konservative Korsettbehandlung ein hohes Maß an Compliance. Ebenso weiß man, dass krankheitsspezifisches Wissen das Therapieergebnis beeinflusst. Daher wurde in dieser Studie das Patientenwissen analysiert und mit der Lebensqualität in Zusammenhang gebracht. Methoden Diese Studie schließt 67 Patienten ein, die alle mit einem Chêneau-Korsett behandelt wurden. Ein Fragebogen mit Fragen zu krankheitsspezifischem Wissen wurde entwickelt. Patienten sollten anonym den Fragebogen beantworten, der wiederum mit dem persönlichen Arztgespräch und den Untersuchungen in der Skolioseambulanz in Bad Abbach verglichen wurde. Der SRS-22r wurde ausgewertet, um die Lebensqualität der Patienten zu beurteilen. Ergebnisse Die behandelnden Ärzte stehen als Informationsquelle immer noch an erster Stelle für die jungen Patienten, gefolgt vom Internet. Die Mehrheit gibt an verstanden zu haben, was Skoliose ist. Beim genaueren Auswerten des Fragebogens fielen jedoch größere Wissenslücken auf, insbesondere im Bereich der Behandlungsmöglichkeiten, Korsetttragezeiten und Ätiologie der Skoliose. Patienten mit einer hohen Compliance zeigten eine höhere Lebensqualität. Der Wunsch nach einem geraden Rücken mithilfe der Skoliosetherapie korrelierte signifikant mit der Lebensqualität. Zusammenfassung Diese Studie deckt große Wissenslücken der Patienten im Bereich des Krankheitsspezifischen Wissens über Skoliose auf, insbesondere in den Behandlungsmöglichkeiten, in der Korsetttragezeit und Ätiologie der Skoliose. Hohe Lebensqualität geht signifikant mit einem hohen krankheitsspezifischen Wissen einher

Probing the dynamic nature of self-assembling cyclic peptide-polymer nanotubes in solution and in mammalian cells

Self-assembling cyclic peptide–polymer nanotubes have emerged as a fascinating supramolecular system, well suited for a diverse range of biomedical applications. Due to their well-defined diameter, tunable peptide anatomy, and ability to disassemble in situ, they have been investigated as promising materials for numerous applications including biosensors, antimicrobials, and drug delivery. Despite this continuous effort, the underlying mechanisms of assembly and disassembly are still not fully understood. In particular, the exchange of units between individual assembled nanotubes has been overlooked so far, despite its knowledge being essential for understanding their behavior in different environments. To investigate the dynamic nature of these systems, cyclic peptide–polymer nanotubes are synthesized, conjugated with complementary dyes, which undergo a Förster resonance energy transfer (FRET) in close proximity. Model conjugates enable to demonstrate not only that their self-assembly is highly dynamic and not kinetically trapped, but also that the self-assembly of the conjugates is strongly influenced by both solvent and concentration. Additionally, the versatility of the FRET system allows studying the dynamic exchange of these systems in mammalian cells in vitro using confocal microscopy, demonstrating the exchange of subunits between assembled nanotubes in the highly complex environment of a cell

KL-VS heterozygosity is associated with lower amyloid-dependent tau accumulation and memory impairment in Alzheimer's disease

Klotho-VS heterozygosity (KL-VShet) is associated with reduced risk of Alzheimer's disease (AD). However, whether KL-VShet is associated with lower levels of pathologic tau, i.e., the key AD pathology driving neurodegeneration and cognitive decline, is unknown. Here, we assessed the interaction between KL-VShet and levels of beta-amyloid, a key driver of tau pathology, on the levels of PET-assessed neurofibrillary tau in 551 controls and patients across the AD continuum. KL-VShet showed lower cross-sectional and longitudinal increase in tau-PET per unit increase in amyloid-PET when compared to that of non-carriers. This association of KL-VShet on tau-PET was stronger in Klotho mRNA-expressing brain regions mapped onto a gene expression atlas. KL-VShet was related to better memory functions in amyloid-positive participants and this association was mediated by lower tau-PET. Amyloid-PET levels did not differ between KL-VShet carriers versus non-carriers. Together, our findings provide evidence to suggest a protective role of KL-VShet against amyloid-related tau pathology and tau-related memory impairments in elderly humans at risk of AD dementia

Implementation and validation of a novel instrument for the grading of unexpected events in paediatric surgery: Clavien–Madadi classification

Background: Inconsistent definitions of complications and unexpected events have limited accurate analysis of surgical outcomes. Perioperative outcome classifications currently used for adult patients have limitations when used for children./ Methods: A multidisciplinary group of experts modified the Clavien–Dindo classification to increase its utility and accuracy in paediatric surgery cohorts. Organizational and management errors were considered in the novel Clavien–Madadi classification, which focuses on procedural invasiveness rather than anaesthetic management. Unexpected events were prospectively documented in a paediatric surgery cohort. Results of the Clavien–Dindo and Clavien–Madadi classifications were compared and correlated with procedure complexity./ Results: Unexpected events were prospectively documented in a cohort of 17 502 children undergoing surgery between 2017 and 2021. The results of both classifications were highly correlated (ρ = 0.95), although the novel Clavien–Madadi classification identified 449 additional events (organizational and management errors) over the Clavien–Dindo classification, increasing the total number of events by 38 per cent (1605 versus 1158 events). The results of the novel system correlated significantly with the complexity of procedures in children (ρ = 0.756). Furthermore, grading of events > grade III according to the Clavien–Madadi classification showed a higher correlation with procedure complexity (ρ = 0.658) than the Clavien–Dindo classification (ρ = 0.198)./ Conclusion: The Clavien–Madadi classification is a tool for the detection of surgical and non-medical errors in paediatric surgery populations. Further validation in paediatric surgery populations is required before widespread use

Systematic study of the structural parameters affecting the self-assembly of cyclic peptide–poly(ethylene glycol) conjugates

Self-assembling cyclic peptides (CP) consisting of amino acids with alternating D- and L-chirality form nanotubes by hydrogen bonding, hydrophobic interactions, and π–π stacking in solution. These highly dynamic materials are emerging as promising supramolecular systems for a wide range of biomedical applications. Herein, we discuss how varying the polymer conformation (linear vs. brush), as well as the number of polymer arms per peptide unimer affects the self-assembly of PEGylated cyclic peptides in different solvents, using small angle neutron scattering. Using the derived information, strong correlations were drawn between the size of the aggregates, solvent polarity, and its ability to compete for hydrogen bonding interactions between the peptide unimers. Using these data, it could be possible to engineer cyclic peptide nanotubes of a controlled length

Dual self-assembly of supramolecular peptide nanotubes to provide stabilisation in water

Self-assembling peptides have the ability to spontaneously aggregate into large ordered structures. The reversibility of the peptide hydrogen bonded supramolecular assembly make them tunable to a host of different applications, although it leaves them highly dynamic and prone to disassembly at the low concentration needed for biological applications. Here we demonstrate that a secondary hydrophobic interaction, near the peptide core, can stabilise the highly dynamic peptide bonds, without losing the vital solubility of the systems in aqueous conditions. This hierarchical self-assembly process can be used to stabilise a range of different β-sheet hydrogen bonded architectures

Colon cancer cell-derived 12(S)-HETE induces the retraction of cancer-associated fibroblast via MLC2, RHO/ROCK and Ca2+ signalling

Retraction of mesenchymal stromal cells supports the invasion of colorectal cancer cells (CRC) into the adjacent compartment. CRC-secreted 12(S)-HETE enhances the retraction of cancer-associated fibroblasts (CAFs) and therefore, 12(S)-HETE may enforce invasivity of CRC. Understanding the mechanisms of metastatic CRC is crucial for successful intervention. Therefore, we studied pro-invasive contributions of stromal cells in physiologically relevant three-dimensional in vitro assays consisting of CRC spheroids, CAFs, extracellular matrix and endothelial cells, as well as in reductionist models. In order to elucidate how CAFs support CRC invasion, tumour spheroid-induced CAF retraction and free intracellular Ca2+ levels were measured and pharmacological-or siRNA-based inhibition of selected signalling cascades was performed. CRC spheroids caused the retraction of CAFs, generating entry gates in the adjacent surrogate stroma. The responsible trigger factor 12(S)-HETE provoked a signal, which was transduced by PLC, IP3, free intracellular Ca2+, Ca(2+)calmodulin-kinase-II, RHO/ROCK and MYLK which led to the activation of myosin light chain 2, and subsequent CAF mobility. RHO activity was observed downstream as well as upstream of Ca2+ release. Thus, Ca2+ signalling served as central signal amplifier. Treatment with the FDA-approved drugs carbamazepine, cinnarizine, nifedipine and bepridil HCl, which reportedly interfere with cellular calcium availability, inhibited CAF-retraction. The elucidation of signalling pathways and identification of approved inhibitory drugs warrant development of intervention strategies targeting tumour-stroma interaction

Feasibility of radiomic feature harmonization for pooling of [18F]FET or [18F]GE-180 PET images of gliomas

Introduction: Large datasets are required to ensure reliable non-invasive glioma assessment with radiomics-based machine learning methods. This can often only be achieved by pooling images from different centers. Moreover, trained models should perform with high accuracy when applied to data from different centers. In this study, the impact of reconstruction settings and segmentation methods on radiomic features derived from amino acid and TSPO PET images of glioma patients was examined. Additionally, the ability to model and thus reduce feature differences was investigated.Methods: [(18)FJFET and [(18)FJGE-180 PET data were acquired from 19 glioma patients. For each acquisition, 10 reconstruction settings and 9 segmentation methods were included to emulate multicentric data. Statistical robustness measures were calculated before and after ComBat harmonization. Differences between features due to setting variations were assessed using Friedman test, coefficient of variation (CV) and inter-rater reliability measures, including intraclass and Spearman's rank correlation coefficients and Fleiss' Kappa.Results: According to Friedman analyses, most features (>60%) showed significant differences. Yet, CV and interrater reliability measures indicated higher robustness. ComBat resulted in almost complete harmonization (>87%) according to Friedman test and little to no improvement according to CV and inter-rater reliability measures. [(18)FJGE-180 features were more sensitive to reconstruction settings than [(18)FJFET features.Conclusions: According to Friedman test, feature distributions could be successfully aligned using ComBat. However, depending on settings, changes in patient ranks were observed for some features and could not be eliminated by harmo-nization. Thus, for clinical utilization it is recommended to exclude affected features

Developing a core outcome set for the health outcomes for children and adults with congenital oesophageal atresia and/or tracheo-oesophageal fistula: OCELOT task group study protocol

Introduction: Heterogeneity in reported outcomes of infants with oesophageal atresia (OA) with or without tracheo-oesophageal fistula (TOF) prevents effective data pooling. Core outcome sets (COS) have been developed for many conditions to standardise outcome reporting, facilitate meta-analysis and improve the relevance of research for patients and families. Our aim is to develop an internationally-agreed, comprehensive COS for OA-TOF, relevant from birth through to transition and adulthood. Methods and analysis: A long list of outcomes will be generated using (1) a systematic review of existing studies on OA-TOF and (2) qualitative research with children (patients), adults (patients) and families involving focus groups, semistructured interviews and self-reported outcome activity packs. A two-phase Delphi survey will then be completed by four key stakeholder groups: (1) patients (paediatric and adult); (2) families; (3) healthcare professionals; and (4) researchers. Phase I will include stakeholders individually rating the importance and relevance of each long-listed outcome using a 9-point Likert scale, with the option to suggest additional outcomes not already included. During phase II, stakeholders will review summarised results from phase I relative to their own initial score and then will be asked to rescore the outcome based on this information. Responses from phase II will be summarised using descriptive statistics and a predefined definition of consensus for inclusion or exclusion of outcomes. Following the Delphi process, stakeholder experts will be invited to review data at a consensus meeting and agree on a COS for OA-TOF. Ethics and dissemination: Ethical approval was sought through the Health Research Authority via the Integrated Research Application System, registration no. 297026. However, approval was deemed not to be required, so study sponsorship and oversight were provided by Alder Hey Children’s NHS Foundation Trust. The study has been prospectively registered with the COMET Initiative. The study will be published in an open access forum