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In a phase 3 trial (PANAMO, NCT04333420), vilobelimab, a complement 5a (C5a) inhibitor, reduced 28-day mortality in mechanically ventilated COVID-19 patients. This post hoc analysis of 368 patients aimed to explore treatment heterogeneity through unsupervised learning. All available clinical variables at baseline were used as input. Treatment heterogeneity was assessed using latent class analysis (LCA), Ward's hierarchical clustering (HC) and the adjudication to previously described clinical sepsis phenotypes. The primary outcome was 28-day mortality. For LCA, a 2-class latent model was deemed most suitable. In the LCA model, 82 (22%) patients were assigned to class 1 and 286 (78%) to class 2. Class 1 was defined by more severely ill patients with significantly higher mortality. In an adjusted logistic regression, no heterogeneity of treatment effect (HTE) between classes was observed (p = 0.998). For HC, no significant classes were found (p = 0.669). Using the previously described clinical sepsis subtypes, 41 patients (11%) were adjudicated subtype alpha (α), 17 (5%) beta (β), 112 (30%) delta (δ) and 198 (54%) gamma (γ). HTE was observed between clinical subtypes (p = 0.001) with improved 28-day mortality after treatment with vilobelimab for the δ subtype (OR = 0.17, 95% CI 0.07-0.40, p < 0.001). No signal for harm of treatment with vilobelimab was observed in any class or clinical subtype. Overall, treatment effect with vilobelimab was consistent across different classes and subtypes, except for the δ subtype, suggesting potential additional benefit for the most severely ill patients., (© 2024. The Author(s).)

Background: Diaphragm ultrasonography is rapidly evolving in both critical care and research. Nevertheless, methodologically robust guidelines on its methodology and acquiring expertise do not, or only partially, exist. Therefore, we set out to provide consensus-based statements towards a universal measurement protocol for diaphragm ultrasonography and establish key areas for research., Methods: To formulate a robust expert consensus statement, between November 2020 and May 2021, a two-round, anonymous and online survey-based Delphi study among experts in the field was performed. Based on the literature review, the following domains were chosen: "Anatomy and physiology", "Transducer Settings", "Ventilator Impact", "Learning and expertise", "Daily practice" and "Future directions". Agreement of ≥ 68% (≥ 10 panelists) was needed to reach consensus on a question., Results: Of 18 panelists invited, 14 agreed to participate in the survey. After two rounds, the survey included 117 questions of which 42 questions were designed to collect arguments and opinions and 75 questions aimed at reaching consensus. Of these, 46 (61%) consensus was reached. In both rounds, the response rate was 100%. Among others, there was agreement on measuring thickness between the pleura and peritoneum, using > 10% decrease in thickness as cut-off for atrophy and using 40 examinations as minimum training to use diaphragm ultrasonography in clinical practice. In addition, key areas for research were established., Conclusion: This expert consensus statement presents the first set of consensus-based statements on diaphragm ultrasonography methodology. They serve to ensure high-quality and homogenous measurements in daily clinical practice and in research. In addition, important gaps in current knowledge and thereby key areas for research are established. Trial registration The study was pre-registered on the Open Science Framework with registration digital object identifier https://doi.org/10.17605/OSF.IO/HM8UG ., (© 2022. The Author(s).)