Acute graft-versus-host disease (GVHD) considerably limits wider usage of allogeneic hematopoietic cell transplantation (allo-HCT). Antigen-presenting cells and T cells are populations customarily associated with GVHD pathogenesis. Of note, neutrophils are the largest human white blood cell population. The cells cleave chemokines and produce reactive oxygen species, thereby promoting T cell activation. Therefore, during an allogeneic immune response, neutrophils could amplify tissue damage caused by conditioning regimens. We analyzed neutrophil infiltration of the mouse ileum after allo-HCT by in vivo myeloperoxidase imaging and found that infiltration levels were dependent on the local microbial flora and were not detectable under germ-free conditions. Physical or genetic depletion of neutrophils reduced GVHD-related mortality. The contribution of neutrophils to GVHD severity required reactive oxygen species (ROS) because selective Cybb (encoding cytochrome b-245, beta polypeptide, also known as NOX2) deficiency in neutrophils impairing ROS production led to lower levels of tissue damage, GVHD-related mortality and effector phenotype T cells. Enhanced survival of Bcl-xL transgenic neutrophils increased GVHD severity. In contrast, when we transferred neutrophils lacking Toll-like receptor-2 (TLR2), TLR3, TLR4, TLR7 and TLR9, which are normally less strongly activated by translocating bacteria, into wild-type C57BL/6 mice, GVHD severity was reduced. In humans, severity of intestinal GVHD strongly correlated with levels of neutrophils present in GVHD lesions. This study describes a new potential role for neutrophils in the pathogenesis of GVHD in both mice and humans.

BACKGROUND The Timed Up and Go Test (TUG Test) has previously been described as a reliable tool to evaluate objective functional impairment in patients with degenerative disc disease. OBJECTIVE The aim of this study was to assess the minimum clinically important difference (MCID) of the TUG Test. METHODS The TUG Test (measured in seconds) was correlated with validated patient-reported outcome measures (PROs) of pain intensity (Visual Analog Scale for back and leg pain), functional impairment (Oswestry Disability Index, Roland Morris Disability Index), and health-related quality of life measures (Short Form-12 and EuroQol 5D). Three established methods were used to establish anchor-based MCID values using responders of the following PROs (Visual Analog Scale back and leg pain, Oswestry Disability Index, Roland Morris Disability Index, EuroQol 5D index, and Short Form-12 Physical Component Summary) as anchors: (1) average change, (2) minimum detectable change, and (3) change difference approach. RESULTS One hundred patients with a mean ± SD age of 56.2 ± 16.1 years, 57 (57%) male, 45 patients undergoing microdiscectomy, 35 undergoing lumbar decompression, and 20 undergoing fusion surgery were studied. The 3 MCID computation methods revealed a range of MCID values according to the PRO used from 0.9 s (Oswestry Disability Index based on the change difference approach) to 6.0 s (EuroQol 5D index based on the minimum detectable change approach), with a mean MCID of 3.4 s for all measured PROs. CONCLUSION The MCID for the TUG Test time is highly variable depending on the computation technique used. The average TUG Test MCID was 3.4 s using all 3 methods and all anchors. ABBREVIATIONS D3, day 3DDD, degenerative disc diseaseEQ5D, EuroQol 5DFU, follow-upHRQoL, health-related quality of lifeMCID, minimum clinically important differenceODI, Oswestry Disability IndexOFI, objective functional impairmentPCS, Physical Component SummaryPRO, patient-reported outcome measureRMDI, Roland-Morris Disability IndexSF-12, Short Form 12TUG Test, Time Up and Go TestVAS, Visual Analog Scale.