| 1. |
- Poli, Sven, et al.
(författare)
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Penumbral Rescue by normobaric O?=?O administration in patients with ischemic stroke and target mismatch proFile (PROOF): Study protocol of a phase IIb trial
- 2024
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Ingår i: INTERNATIONAL JOURNAL OF STROKE. - 1747-4930 .- 1747-4949. ; 19:1, s. 120-126
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Tidskriftsartikel (refereegranskat)abstract
- Rationale: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs.Aims: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion.Methods and design: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial.Study outcomes: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted.Sample size: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation.Discussion: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia.
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| 2. |
- Tull, Thomas J, et al.
(författare)
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Human marginal zone B cell development from early T2 progenitors.
- 2021
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Ingår i: The Journal of experimental medicine. - 1540-9538. ; 218:4
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Tidskriftsartikel (refereegranskat)abstract
- B cells emerge from the bone marrow as transitional (TS) B cells that differentiate through T1, T2, and T3 stages to become naive B cells. We have identified a bifurcation of human B cell maturation from the T1 stage forming IgMhi and IgMlo developmental trajectories. IgMhi T2 cells have higher expression of α4β7 integrin and lower expression of IL-4 receptor (IL4R) compared with the IgMlo branch and are selectively recruited into gut-associated lymphoid tissue. IgMhi T2 cells also share transcriptomic features with marginal zone B cells (MZBs). Lineage progression from T1 cells to MZBs via an IgMhi trajectory is identified by pseudotime analysis of scRNA-sequencing data. Reduced frequency of IgMhi gut-homing T2 cells is observed in severe SLE and is associated with reduction of MZBs and their putative IgMhi precursors. The collapse of the gut-associated MZB maturational axis in severe SLE affirms its existence in health.
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| 3. |
- Zhao, Yuan, et al.
(författare)
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Spatiotemporal segregation of human marginal zone and memory B cell populations in lymphoid tissue.
- 2018
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Human memory B cells and marginal zone (MZ) B cells share common features such as the expression of CD27 and somatic mutations in their IGHV and BCL6 genes, but the relationship between them is controversial. Here, we show phenotypic progression within lymphoid tissues as MZ B cells emerge from the mature naïve B cell pool via a precursor CD27-CD45RBMEM55+ population distant from memory cells. By imaging mass cytometry, we find that MZ B cells and memory B cells occupy different microanatomical niches in organised gut lymphoid tissues. Both populations disseminate widely between distant lymphoid tissues and blood, and both diversify their IGHV repertoire in gut germinal centres (GC), but nevertheless remain largely clonally separate. MZ B cells are therefore not developmentally contiguous with or analogous to classical memory B cells despite their shared ability to transit through GC, where somatic mutations are acquired.
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