Age-related epithelial defects limit thymic function and regeneration.

The thymus is essential for establishing adaptive immunity yet undergoes age-related involution that leads to compromised immune responsiveness. The thymus is also extremely sensitive to acute insult and although capable of regeneration, this capacity declines with age for unknown reasons. We applied single-cell and spatial transcriptomics, lineage-tracing and advanced imaging to define age-related changes in nonhematopoietic stromal cells and discovered the emergence of two atypical thymic epithelial cell (TEC) states. These age-associated TECs (aaTECs) formed high-density peri-medullary epithelial clusters that were devoid of thymocytes; an accretion of nonproductive thymic tissue that worsened with age, exhibited features of epithelial-to-mesenchymal transition and was associated with downregulation of FOXN1. Interaction analysis revealed that the emergence of aaTECs drew tonic signals from other functional TEC populations at baseline acting as a sink for TEC growth factors. Following acute injury, aaTECs expanded substantially, further perturbing trophic regeneration pathways and correlating with defective repair of the involuted thymus. These findings therefore define a unique feature of thymic involution linked to immune aging and could have implications for developing immune-boosting therapies in older individuals.

Endovascular Management of Non-Cirrhotic Acute Portomesenteric Venous Thrombosis.

Acute portomesenteric venous thrombosis (PVT) is a rare but potentially life-threatening condition in individuals without cirrhosis. Initial management typically involves anticoagulation therapy, but the optimal approach to interventional treatment remains a topic of ongoing research. This article explores both traditional and emerging endovascular techniques, providing an overview of the existing evidence supporting their use. Additionally, it delves into the significance of acute PVT in the context of contemporary pathologies, notably COVID-19 infection, vaccine-induced immune thrombotic thrombocytopenia, and liver transplantation.

Accuracy of augmented reality-assisted pedicle screw placement: a systematic review.

OBJECTIVE: Conventional freehand methods of pedicle screw placement are associated with significant complications due to close proximity to neural and vascular structures. Recent advances in augmented reality surgical navigation (ARSN) have led to its adoption into spine surgery. However, little is known regarding its overall accuracy. The purpose of this study is to delineate the overall accuracy of ARSN pedicle screw placement across various models. METHODS: A systematic review was conducted of Medline/PubMed, Cochrane and Embase Library databases according to the PRISMA guidelines. Relevant data extracted included reports of pedicle screw placement accuracy and breaches, as defined by the Gertzbein-Robbins classification, in addition to deviation from pre-planned trajectory and entry point. Accuracy was defined as the summation of grade 0 and grade 1 events per the Gertzbein-Robbins classification. RESULTS: Twenty studies reported clinically accurate placed screws. The range of clinically accurate placed screws was 26.3-100%, with 2095 screws (93.1%) being deemed clinically accurate. Furthermore, 5.4% (112/2088) of screws were reported as grade two breaches, 1.6% (33/2088) grade 3 breaches, 3.1% (29/926) medial breaches and 2.3% (21/926) lateral breaches. Mean linear deviation ranged from 1.3 to 5.99 mm, while mean angular/trajectory deviation ranged 1.6°-5.88°. CONCLUSION: The results of this study highlight the overall accuracy of ARSN pedicle screw placement. However, further robust prospective studies are needed to accurately compare to conventional methods of pedicle screw placement.

Nrf2 regulates CD4+ T cell-induced acute graft-versus-host disease in mice.

Nuclear factor erythroid-derived 2-like 2 (Nrf2) is a ubiquitously expressed transcription factor that is well known for its role in regulating the cellular redox pathway. Although there is mounting evidence suggesting a critical role for Nrf2 in hematopoietic stem cells and innate leukocytes, little is known about its involvement in T-cell biology. In this study, we identified a novel role for Nrf2 in regulating alloreactive T-cell function during allogeneic hematopoietic cell transplantation (allo-HCT). We observed increased expression and nuclear translocation of Nrf2 upon T-cell activation in vitro, especially in CD4+ donor T cells after allo-HCT. Allo-HCT recipients of Nrf2 -/- donor T cells had significantly less acute graft-versus-host disease (GVHD)-induced mortality, morbidity, and pathology. This reduction in GVHD was associated with the persistence of Helios+ donor regulatory T cells in the allograft, as well as defective upregulation of the gut-homing receptor LPAM-1 on alloreactive CD8+ T cells. Additionally, Nrf2 -/- donor CD8+ T cells demonstrated intact cytotoxicity against allogeneic target cells. Tumor-bearing allo-HCT recipients of Nrf2 -/- donor T cells had overall improved survival as a result of preserved graft-versus-tumor activity and reduced GVHD activity. Our findings characterized a previously unrecognized role for Nrf2 in T-cell function, as well as revealed a novel therapeutic target to improve the outcomes of allo-HCT.

Robust patient-derived xenografts of MDS/MPN overlap syndromes capture the unique characteristics of CMML and JMML.

Chronic myelomonocytic leukemia (CMML) and juvenile myelomonocytic leukemia (JMML) are myelodysplastic syndrome (MDS)/myeloproliferative neoplasm (MPN) overlap disorders characterized by monocytosis, myelodysplasia, and a characteristic hypersensitivity to granulocyte-macrophage colony-stimulating factor (GM-CSF). Currently, there are no available disease-modifying therapies for CMML, nor are there preclinical models that fully recapitulate the unique features of CMML. Through use of immunocompromised mice with transgenic expression of human GM-CSF, interleukin-3, and stem cell factor in a NOD/SCID-IL2Rγnull background (NSGS mice), we demonstrate remarkable engraftment of CMML and JMML providing the first examples of serially transplantable and genetically accurate models of CMML. Xenotransplantation of CD34+ cells (n = 8 patients) or unfractionated bone marrow (BM) or peripheral blood mononuclear cells (n = 10) resulted in robust engraftment of CMML in BM, spleen, liver, and lung of recipients (n = 82 total mice). Engrafted cells were myeloid-restricted and matched the immunophenotype, morphology, and genetic mutations of the corresponding patient. Similar levels of engraftment were seen upon serial transplantation of human CD34+ cells in secondary NSGS recipients (2/5 patients, 6/11 mice), demonstrating the durability of CMML grafts and functionally validating CD34+ cells as harboring the disease-initiating compartment in vivo. Successful engraftments of JMML primary samples were also achieved in all NSGS recipients (n = 4 patients, n = 12 mice). Engraftment of CMML and JMML resulted in overt phenotypic abnormalities and lethality in recipients, which facilitated evaluation of the JAK2/FLT3 inhibitor pacritinib in vivo. These data reveal that NSGS mice support the development of CMML and JMML disease-initiating and mature leukemic cells in vivo, allowing creation of genetically accurate preclinical models of these disorders.

The efficacy of anchored stand-alone spacers in comparison to conventional cage and plate in anterior cervical discectomy and fusion surgery: A meta-analysis of randomised controlled trials for clinical and radiological outcomes.

Introduction: Anterior cervical discectomy and fusion (ACDF) is commonly performed with cage and plate constructs to stabilise diseased or injured cervical segments. Despite it being a commonly performed procedure, there are notable rates of associated morbidity reported in the literature. Stand-alone spacers represent a novel form of instrumentation to conventional cage and plate constructs. Research question: Do stand-alone spacers have improved operative characteristics and postoperative outcomes in ACDF cohorts when compared to cage and plate constructs? Methods: A systematic review and meta-analysis was conducted of PubMed/Medline, Embase and Google Scholar databases per the Preferred Reporting Items for Systematic Reviews and Meta-Analyzes guidelines. Studies of interest included cage and plate instrumentation versus anchored stand-alone spacers for patients undergoing ACDF. Pre- and post-operative clinical and radiological outcomes were collated and compared for significance between cohorts. Results: 10 RCTs were identified and included with 779 patients total. Mean age of the entire cohort was 50.1 years. 62% (483/779) of the cohort were male. 384 patients underwent ACDF with stand-alone cage, while 395 had ACDF with conventional cage and plate. Stand-alone spacers significantly outperformed conventional instrumentation in terms of estimated blood loss (p < 0.01), total postoperative complications (p < 0.01), dysphagia rates (p = 0.04) and adjacent segment disease (p = 0.04). Non-inferiority was evident in both patient reported outcome measures and radiological outcomes. Conclusion: This meta-analysis highlights the efficacy of stand-alone spacers for the management of primarily cervical spondylitic disease for both single-level and multi-level pathology, and thus presents an attractive alternative to conventional instrumentation for patients undergoing ACDF surgery.

Quantitative differences in volumetric calculations for radiation dosimetry in segmental Y90 treatment planning using hybrid angiography-CT compared with anatomic segmentation.

OBJECTIVE: To compare treatment volumes reconstructed from hybrid Angio-CT catheter-directed infusion imaging and Couinaud anatomic model as well as the implied differences in Y-90 radiation dosimetry. METHODS: Patients who underwent transarterial radioembolization (TARE) using Y-90 glass microspheres with pretreatment CT or MRI imaging as well as intraprocedural angiography-CT (Angio-CT) were analysed. Treatment volumes were delineated using both tumoural angiosomes (derived from Angio-CT) and Couinaud anatomic landmarks. Segmental and lobar treatment volumes were calculated via semi-automated contouring software. Volume and dose differences were compared by the two-tailed Student t test or Wilcoxon signed-rank test. Factors affecting volume and dose differences were assessed via simple and/or multiple variable linear regression analysis. RESULTS: From September 2018 to March 2021, 44 patients underwent 45 lobar treatments and 38 patients received 56 segmental treatments. All target liver lobes and all tumours were completely included within the field-of-view by Angio-CT. Tumour sizes ranged between 1.1 and 19.5 cm in diameter. Segmental volumes and treatment doses were significantly different between the Couinaud and Angio-CT volumetry methods (316 vs 404 mL, P < .0001 and 253 vs 212 Gy, P < .01, respectively). Watershed tumours were significantly correlated with underestimated volumes by the Couinaud anatomic model (P < .001). There was a significant linear relationship between tumour diameter and percent volume difference (R2 = 0.44, P < .0001). The Couinaud model overestimated volumes for large tumours that exhibited central hypovascularity/necrosis and for superselected peripheral tumours. CONCLUSIONS: Angio-CT may confer advantages over the Couinaud anatomic model and enable more accurate, personalized dosimetry for TARE. ADVANCES IN KNOWLEDGE: Angio-CT may confer advantages over traditional cross-sectional and cone-beam CT imaging for selective internal radiation therapy planning.