Gutenberg Open Science (Univ. Mainz)
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Peer Teaching und fallbasiertes Simulationstraining – Ein Vergleich zweier Lehrmethoden im Bereich der Basiswiederbelebung
Get PDFXIV, 97 Seiten ; Illustrationen, Diagramm
Nivolumab plus ipilimumab versus lenvatinib or sorafenib as first-line treatment for unresectable hepatocellular carcinoma (CheckMate 9DW) : an open-label, randomised, phase 3 trial
Get PDFBackground:
Patients with unresectable hepatocellular carcinoma have a poor prognosis, and treatments with long-term benefits are needed. We report results from the preplanned interim analysis of the CheckMate 9DW trial assessing nivolumab plus ipilimumab versus lenvatinib or sorafenib for unresectable hepatocellular carcinoma in the first-line setting.
Methods:
This open-label, randomised, phase 3 trial enrolled patients aged 18 years or older with unresectable hepatocellular carcinoma without previous systemic therapy at 163 hospitals and cancer centres across 25 countries in Asia, Australia, Europe, North America, and South America. Patients had at least one measurable untreated lesion per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1, a Child–Pugh score of 5 or 6, and an Eastern Cooperative Oncology Group performance status of 0 or 1. Patients were randomly assigned (1:1) via an interactive response technology system to receive nivolumab (1 mg/kg) plus ipilimumab (3 mg/kg) intravenously every 3 weeks for up to four doses, followed by nivolumab 480 mg every 4 weeks or investigator's choice of either oral lenvatinib (8 mg or 12 mg mg daily depending on bodyweight) or oral sorafenib (400 mg twice daily). Randomisation was stratified by aetiology; the presence of macrovascular invasion, extrahepatic spread, or both; and baseline alpha-fetoprotein concentration. The primary endpoint was overall survival, which was assessed in all randomly assigned patients; safety was an exploratory endpoint and was assessed in all randomly assigned patients who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04039607 (ongoing).
Findings:
Between Jan 6, 2020, and Nov 8, 2021, 668 patients were randomly assigned to nivolumab plus ipilimumab (n=335) or lenvatinib or sorafenib (n=333). Early crossing of the overall survival Kaplan–Meier curves reflected a higher number of deaths during the first 6 months after randomisation with nivolumab plus ipilimumab (hazard ratio 1·65 [95% CI 1·12–2·43]) but was followed by a sustained separation of the curves thereafter in favour of nivolumab plus ipilimumab (0·61 [0·48–0·77]). After a median follow-up of 35·2 months (IQR 31·1–39·9), overall survival was significantly improved with nivolumab plus ipilimumab versus lenvatinib or sorafenib (median 23·7 months [95% CI 18·8–29·4] vs 20·6 months [17·5–22·5]; hazard ratio 0·79 [0·65–0·96]; two-sided stratified log-rank p=0·018); respective overall survival rates were 49% (95% CI 44–55) versus 39% (34–45) at 24 months and 38% (32–43) versus 24% (19–30) at 36 months. Overall, 137 (41%) of 332 patients receiving nivolumab plus ipilimumab and 138 (42%) of 325 patients receiving lenvatinib or sorafenib had grade 3–4 treatment-related adverse events. 12 deaths were attributed to treatment with nivolumab plus ipilimumab and three were attributed to treatment with lenvatinib or sorafenib.
Interpretation:
Nivolumab plus ipilimumab showed a significant overall survival benefit versus lenvatinib or sorafenib and manageable safety in patients with previously untreated unresectable hepatocellular carcinoma. These results support nivolumab plus ipilimumab as a first-line treatment in this setting.
Funding:
Bristol Myers Squibb
Biomarker combinations from different modalities predict early disability accumulation in multiple sclerosis
Get PDFObjective: Establishing biomarkers to predict multiple sclerosis (MS) disability accrual has been challenging using a single biomarker approach, likely due to the complex interplay of neuroinflammation and neurodegeneration. Here, we aimed to investigate the prognostic value of single and multimodal biomarker combinations to predict four-year disability progression in patients with MS.
Methods: In total, 111 MS patients were followed up for four years to track disability accumulation based on the Expanded Disability Status Scale (EDSS). Three clinically relevant modalities (MRI, OCT and blood serum) served as sources of potential predictors for disease worsening. Two key measures from each modality were determined and related to subsequent disability progression: lesion volume (LV), gray matter volume (GMV), retinal nerve fiber layer, ganglion cell-inner plexiform layer, serum neurofilament light chain (sNfL) and serum glial fibrillary acidic protein. First, receiver operator characteristic (ROC) analyses were performed to identify the discriminative power of individual biomarkers and their combinations. Second, we applied structural equation modeling (SEM) to the single biomarkers in order to determine their causal inter-relationships.
Results: Baseline GMV on its own allowed identification of subsequent EDSS progression based on ROC analysis. All other individual baseline biomarkers were unable to discriminate between progressive and non-progressive patients on their own. When comparing all possible biomarker combinations, the tripartite combination of MRI, OCT and blood biomarkers achieved the highest discriminative accuracy. Finally, predictive causal modeling identified that LV mediates significant parts of the effect of GMV and sNfL on disability progression.
Conclusion: Multimodal biomarkers, i.e. different major surrogates for pathology derived from MRI, OCT and blood, inform about different parts of the disease pathology leading to clinical progression
Non-commutative K-Theory of Lattice-Aperiodic Multi-q Magnetic Systems
Get PDFNon-collinear magnetic structures provide a promising platform for energy-efficient carriers of information. Periodic non-collinear spin arrangements generated as the interference pattern of spin waves are an extensive subclass known as multi- magnets. The study of their electronic properties is of central importance for the implementation in future technology. As the length scale of a multi- spin texture approaches the lattice constant of its host material, gapped topological states may form in the associated electronic system, similar to the formation of Landau levels in the presence of magnetic fields. Given that the textures at these length scales are discrete and lattice incommensurate, we challenge the prevailing notion that their description relies on emergent magnetic fields. Instead, we adopt a -algebraic viewpoint that harmonises with these properties and facilitates the computation of invariants associated with the topology of the electronic states. We implement a computational programme of non-commutative -theory to compute all Chern numbers associated with real, momentum and mixed space. As a central application, we tune texture parameters to create discontinuous jumps in the real space winding number of skyrmionic textures and observe the relation to the Chern numbers. We find a peculiar discrepancy between the behaviour of the momentum space Chern number and the winding number, and identify a single energy level that contributes to the real space Chern number. The non-commutative framework also provides access to the computation of the orbital magnetisation in accordance with modern theory even in the presence of finite magnetic flux. This allows us to compare the orbital magnetisation with the texture and electronic state topology and investigate the scaling behaviour with respect to the texture length scale and magnetic flux.iv, 263 Seiten ; Illustrationen, Diagramm
Anti-inflammatory properties of yellow passion fruit bagasse extract and its potential role in periodontal wound healing in vitro
Get PDFBackground/Objectives: Periodontal disease involves chronic immunoinflammatory processes and microbial dysbiosis, making phytochemicals with anti-inflammatory properties potential therapeutic agents. This study aimed to assess the modulatory effects of yellow passion fruit bagasse extract (PFBE) on periodontal cells under microbial condition. Methods: A human periodontal ligament (PDL) cell line was exposed to F. nucleatum ATCC 25586 to simulate a microbial environment in vitro in the presence and absence of PFBE containing three different concentrations (0.25, 0.50, and 1.00 µg/mL) of piceatannol. Pro-inflammatory markers (TNF-α, IL-8, CCL2), the antioxidant enzyme SOD2, and the protease marker MMP-1 were analyzed by real-time PCR. Protein levels were assessed via ELISA and NF-κB nuclear translocation by immunofluorescence. Cell viability was investigated using live/dead and alamarBlue assays, and in vitro wound healing was evaluated by an automated scratch assay. Results: PDL cells exposed to F. nucleatum significantly increased the gene and protein expression of all inflammatory markers. The stimulatory effects of F. nucleatum were significantly reduced when PDL cells were simultaneously exposed to PFBE. F. nucleatum triggered the NF-κB nuclear translocation while PFBE abrogated the F. nucleatum-stimulated NF-κB nuclear translocation at 60 min. Viability assays demonstrated that neither PFBE nor F. nucleatum were toxic or significantly affected PDL cell viability. In vitro wound closure was improved by the addition of PFBE to F. nucleatum. Conclusions: PFBE exhibited anti-inflammatory and anti-proteolytic effects while improving in vitro wound healing, suggesting a potential modulatory role of PFBE in periodontal disease prevention and treatment
Homeostatic artificial cells enable self-protection in prototissue spheroids
Get PDFPrototissues made from artificial cells (ACs) aim to replicate the behaviors of living tissues, such as communication, collective behavior, and homeostasis. Despite progress in developing diverse AC types, building prototissues and achieving effective communication as well as collective behavior in such prototissues remain challenging. We introduce ACs with an intrinsic homeostatic pH control mechanism that can be organized into prototissues to collectively maintain a stable microenvironment and protect cargo from environmental pH fluctuations. These ACs contain pH-modulating enzymes within a pH-sensitive membrane, allowing for self-regulation through chemo-structural feedback. They adjust pH by importing substrates within a specific pH range and self-regulate to control substrate influx. This enables them to modulate local pH, manage cargo release, and facilitate interactive communication in organized spheroids. Our findings demonstrate the potential of homeostatic ACs to create advanced synthetic tissue mimics, replicating protective and communicative functions of living tissues for biomedical and tissue engineering applications
Der Fascia-Iliaca-Compartment-Block im Rahmen anästhesiologischer Konzepte zur postoperativen Analgesie bei Patienten zur Hüfttotalendoprothese
Get PDFIV, 71 Seiten ; Diagramm
Extra-anatomic left subclavian artery bypass patency in frozen elephant trunk surgery
Get PDFObjective:
To explore the advantages and consequences of using an extra-anatomic Dacron bypass in frozen elephant trunk surgery for fast and secure left subclavian artery (LSA) reimplantation.
Methods:
Between June 2017 and June 2023, 195 patients were treated using an LSA bypass. All postoperative imaging was reviewed to assess the patency of the bypass grafts. If the LSA bypass was not patent, symptoms of complications and their management were evaluated. Time-to-event analysis was performed to assess bypass patency and time to thrombosis.
Results:
Out of 195 LSA bypasses, 183 remained patent during follow-up, for a 5-year patency rate of 91.4%. Prolonged cardiopulmonary bypass duration was associated with poorer graft patency. Eight of the 12 patients with a thrombosed LSA bypass were asymptomatic. The most common complication of thrombosed bypass was subclavian steal syndrome. Surgical revision was necessary in 2 of the 4 symptomatic patients. All cases of thrombosed LSA bypass occurred within the first 15 months.
Conclusions:
LSA bypass in frozen elephant trunk surgery is a fast and safe technique for supra-aortic artery reimplantation. Bypass thrombosis is rare and often does not require surgical intervention
Glial fibrillary acid protein reflects disease activity in autoimmune encephalitis
Get PDFBackground and Purpose:
Management of autoimmune encephalitis (AE) is challenging due to a lack of reliable biomarkers. We here assess the combination of glial fibrillary acid protein (GFAP) and neurofilament (NfL) as biomarkers for diagnosis and disease monitoring of AE.
Methods:
GFAP and NfL CSF levels (cGFAP, cNfL) of 42 AE patients were correlated with CSF markers of neuroinflammation. NfL/GFAP ratios were compared between patients with stable and active AE, stable and active multiple sclerosis (MS), and patients undergoing diagnostic lumbar puncture without evident pathological alterations (controls).
Results:
In patients with AE, cGFAP levels showed strong correlations with albumin and IgG quotients and moderate correlations with CSF cell count; cNfL levels showed weak correlations with albumin quotients. cGFAP and cNfL levels showed no significant differences between patients with and without epileptic activity or inflammatory MRI lesions. Both sNfL and sGFAP correlated with the Clinical Assessment Scale in Autoimmune Encephalitis. Compared to NfL or GFAP alone, the NfL/GFAP ratio from CSF or serum led to a clearer separation of AE from MS patients and controls. Furthermore, serum NfL/GFAP ratios better discriminated active from stable AE.
Conclusion:
cGFAP levels indicate intrathecal inflammatory processes in patients with active AE to a stronger degree than cNfL levels. Serum NfL/GFAP ratios recognize active AE, suggesting this ratio identifies AE patients with CNS-compartmentalized neuronal injury (autoantibody-mediated or cytotoxic) behind a relatively intact blood–brain barrier. Our findings indicate that the NfL/GFAP ratio can function as a blood-based biomarker, aiding clinicians with diagnosis and disease management of AE