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Data Pharmacokinetics Meloxicam Mouse
No full textData concerning the following project/manuscript: Suitability of prolonged meloxicam treatment in mice seems limited due to unfavorable pharmacokinetics, side effects, and impact on home-cage behaviors Aylina Glasenapp, Jens P. Bankstahl, Heike Bähre, Jana Hauser, Amisha R. Parmar, Andrey V. Kozlov, Silke Glage, Rupert Palme, Marion Bankstahl Meloxicam is commonly used for analgesia, but no preparation approved for mice. Here, we determined plasma concentrations, safety, anti-nociceptive activity and impact on home-cage behaviors for subcutaneous injection (5 mg/kg) and oral self-intake (sweetened drinking water, 20 mg/kg/24h, 5 days) for C57BL/6J mice (n=21/sex). After injection, plasma concentrations measured by LC-MS/MS were higher in females (2h) and remained within an estimated therapeutic range (390–911ng/mL) for up to 6h. T1/2 was 2.32 h. Despite acceptance, plasma levels fluctuated strongly during oral self-intake. No anti-nociceptive effect was found (tail-immersion test). Side effects comprised reduced grip strength and increased vocalization (Irwin test), increased clinical score values (females, oral treatment) with two individuals reaching humane endpoint, increase in body temperature, body weight drop, decreased wheel-running activity, increased burrowing latency (males), and prolonged grooming activity (females). Grimace scale, nesting activity and plasma corticosterone remained unaffected. Red blood profile parameters and ALT were decreased and Ca2+ and Cl- concentrations elevated. Histopathological analysis revealed inflammatory cells and hyperplasia in stomach and jejunum. In view of the unfavorable pharmacokinetics, meloxicam treatment via the drinking water is unsuitable in mice. The limited tolerability and the lack of anti-nociceptive effect make prolonged treatment with the doses studied appear inappropriate. Data were aquired at MHH by Aylina Glasenapp et al
Exploring the Transitivity Assumption in Network Meta-Analysis: A Novel Approach and Its Implications.
Get PDFThe feasibility of network meta-analysis depends on several factors, one of which is the validity of the transitivity assumption that posits no systematic differences in the distribution of effect modifiers across treatment comparisons within a connected network. However, evaluating transitivity is complex for relying on epidemiological grounds. Therefore, establishing a methodological framework to evaluate this assumption is challenging. We propose a novel approach, which involves calculating dissimilarities between treatment comparisons based on study-level aggregate participant and methodological characteristics reported across studies and applying hierarchical clustering to cluster similar comparisons. This approach detects "hot spots" of potential intransitivity in the network, enabling empirical exploration of transitivity and semi-objective judgments. Our approach quantifies clinical and methodological (non-statistical) heterogeneity within and between treatment comparisons by computing the dissimilarities across studies in key characteristics acting as effect modifiers. The investigated networks showed varying between-comparison dissimilarities, indicating variability in the clinical and methodological heterogeneity of the networks. Several pairs of treatment comparisons with "likely concerning" non-statistical heterogeneity were identified, and some studies were organized into several clusters, suggesting potential intransitivity in the networks. These findings necessitate a closer examination of the evidence base, and such scrutiny becomes pivotal in determining whether concerns about the feasibility of network meta-analysis are justified. Similar to statistical heterogeneity, heterogeneity in clinical and methodological characteristics of the collected studies should be expected and appropriately assessed. Our proposed approach facilitates the evaluation of transitivity using well-established methods and can be applied to newly planned and published systematic reviews
Statistical Heterogeneity in Oral Health Meta-Analyses.
Get PDFProviding the summary effect size and its uncertainty, a prediction interval, and a measure of statistical heterogeneity constitute good reporting practices in meta-analyses. Popular statistical heterogeneity measures comprise the τ2 and I2 statistics. However, researchers often rely unduly on the I2 statistic, using naive categorizations to gauge the extent of heterogeneity, leading to misuses of the meta-analysis models, deficiencies in reporting, and misleading conclusions. The present study aimed to provide empirical evidence on the reporting and interpretation of statistical heterogeneity in systematic reviews of oral health published between 2021 and 2023 in 21 leading specialty and general dental journals. Systematic reviews with at least 1 meta-analysis on binary or continuous outcomes with the most studies were identified. Characteristics were extracted at the systematic review and meta-analysis levels. In total, 313 systematic reviews with meta-analyses were analyzed. Within this cohort of meta-analyses, the random-effects model (89%, n = 278) was frequently applied. Almost all meta-analyses (98%, n = 308) reported the I2 value, and 51% (n = 160) reported the τ2 value. For this sample, the median I2 was 76% (range: 0%-100%), and the median τ2 was 0.29 (range: 0-2,632), with 13% (n = 20/160) of these meta-analyses reporting zero τ2. Most of the meta-analyses (96%, n = 299) based the heterogeneity interpretation on I2 and only 21 (7%) on τ2. Although 49% (n = 152) of the meta-analyses chose the meta-analysis model a priori, only 41% (n = 63/152) justified this choice. Furthermore, 42% (n = 131) of the 313 meta-analyses chose the meta-analysis model based on the I2. Within oral health meta-analyses, there is evidence of overreliance on I2 when reporting and interpreting statistical heterogeneity and selecting the meta-analysis model. The inappropriate use of I2 in meta-analysis model selection and interpretation of statistical heterogeneity may have implications for the quality of conclusions delivered to the end users of systematic reviews
Entschlüsselung der Wirkung von Vitamin C und Vitamin D auf virusspezifische T-Zellen für die adoptive Immuntherapie
Get PDFReappraisal of IgG subclass deficiencies: a retrospective comparative cohort study
Get PDFObjective The aim of the present study was to investigate the clinical spectrum of IgG subclass deficiencies (IgGSDs) and assess the relative clinical significance of diagnosing each specific IgGSD disorder as compared to the common variable immunodeficiency (CVID). Methods The clinical spectrum and immunological findings from 96 patients, diagnosed with diverse IgGSDs, were retrospectively evaluated. Specific IgGSDs were compared with each other and a cohort of 270 patients with CVID. Results In comparison to CVID, recurrent lower respiratory tract infections (LRTIs) and bronchiectasis were rarer in IgGSDs, while recurrent mucocutaneous herpes simplex virus reactivations were more common. With respect to autoimmunity, IgGSDs were associated with arthritis, while autoimmune cytopenias were less frequently observed than in CVID. Among IgGSDs, herpes zoster was more common in IgG3SD. Arthritis was more prevalent in IgG1 + 3SD. Given its association with LRTI, splenomegaly, immune thrombocytopenic purpura, and the lower class-switched memory B-cell counts, IgG2 + 4SD is the IgGSD that rather resembles CVID. Conclusions Comparative evaluation of phenotypes and treatments of patients with IgGSDs and CVID reveals distinct features, suggesting the differential clinical significance of diagnosing IgGSDs. The differential clinical expressions of IgGSDs highlight the need for studying each IgGSD separately in order to optimize disorder-specific follow-up procedures and prophylactic anti-infective measures
Worse recovery from acute attacks and faster disability accumulation highlights the unmet need for improved treatment in patients with late-onset neuromyelitis optica spectrum disorders (COPTER-LO study)
Get PDFObjective This study analyzed clinical characteristics, attack recovery and long-term disability accumulation in late-onset (LO ≥ 50 years at onset) versus early-onset (EO < 50 years) NMOSD. Methods This multicenter cohort study included demographic and clinical data from 446 NMOSD patients collected from 35 German Neuromyelitis Optica Study Group (NEMOS) centers. Time to disability milestones was estimated through Kaplan-Meier analysis and Cox proportional hazard regression models adjusted for sex, year of onset, immunotherapy exposure and antibody status. Generalized estimating equations (GEE) were used to compare attack outcomes. Results Of the 446 NMOSD patients analyzed (83.4% female, 85.4% AQP4-IgG-positive, median age at disease onset = 43 years), 153 had a late-onset (34.3%). AQP4-IgG+ prevalence was higher in LO- than in EO-NMOSD (94.1% vs. 80.9%, p<0.001). Optic neuritis at onset was more frequent in EO-NMOSD (27.4% vs. 42.6%, p<0.002), whereas myelitis was more common in LO-NMOSD (58.4% vs. 37.9%, p<0.001). Both groups had similar annualized attack rates (AAR, 0.51 vs. 0.54, p=0.352), but attack recovery was poorer (complete remission in 15.6% vs. 27.4%, p<0.001) and relapse-associated worsening (RAW) was higher in LO-NMOSD (RAW: 3 vs. 0.5, p<0.001). Long-term immunotherapy use was comparable. LO-NMOSD exhibited faster progression to disability endpoints (EDSS 4: HR = 2.64, 95% CI=1.81-3.84). Interpretation LO-NMOSD patients presented more often with myelitis, experienced worse attack outcomes and faster disability accumulation, despite comparable AAR, acute attack treatment and long-term treatment regimens. Accordingly, therapeutic strategies for attack and prophylactic treatment in LO-NMOSD have to be improved
Retrospektive Analyse von Langzeitergebnissen nach operativer Therapie durch laterale Thorakotomie der unkomplexen Aortenisthmusstenose im Kindes- und Jugendalter in der Medizinischen Hochschule Hannover von 1972 – 2020
Get PDFLänger leben, länger arbeiten? Zeittrendanalysen der Lebensarbeitszeit aus gesundheitlicher Perspektive zwischen 2002 und 2018
Get PDFLentiviral-vermittelte Expression zytotoxischer Effektor-proteine zur Optimierung einer Makrophagen-basierten Anti-Tumor-Immuntherapie
Get PDFInvestigating plasticity within the interleukin-6 family with AlphaFold-Multimer
Get PDFCytokines are important soluble mediators that are involved in physiological and pathophysiological processes. Among them, members of the interleukin-6 (IL-6) family of cytokines have gained remarkable attention, because especially the name-giving cytokine IL-6 has been shown to be an excellent target to treat inflammatory and autoimmune diseases. The IL-6 family consists of nine members, which activate their target cells via combinations of non-signaling α- and/or signal-transducing β-receptors. While some receptor combinations are exclusively used by a single cytokine, other cytokine receptor combinations are used by multiple cytokines. Research in recent years unraveled another level of complexity: several cytokine cannot only signal via their canonical receptors, but can bind to and signal via additional α- and/or β-receptors, albeit with less affinity. While several examples of such cytokine plasticity have been reported, a systematic analysis of this phenomenon is lacking. The development of artificial intelligence programs like AlphaFold allows the computational analysis of protein complexes in a systematic manner. Here, we develop a analysis pipeline for cytokine:cytokine receptor interaction and show that AlphaFold-Multimer correctly predicts the canonical ligands of the IL-6 family. However, AlphaFold-Multimer does not provide sufficient insight to conclusively predict alternative, low-affinity ligands for receptors within the IL-6 family