Development and validation of a novel nomogram model predicting the unfavorable outcome based on NAR and collaterals status for patients with AIS.

INTRODUCTION: Stroke is a leading cause of disability and mortality globally. This study aimed to develop a prognostic nomogram based on neutrophil-to-albumin ratio (NAR) and collateral status in acute ischemic stroke (AIS) patients with anterior large vessel occlusion (LVO). MATERIAL & METHOD: 590 AIS patients with LVO assessed for regional leptomeningeal collateral (rLMC) were retrospectively enrolled, and randomly divided into a training set (n = 414) and a testing set (n = 176). Unfavorable functional outcome was defined as a modified Rankin scale (mRS) score of 3 to 6 at 3 months. We assessed the accuracy and clinical utility of the nomogram using calibration plots, area under the curve (AUC), decision curve analysis (DCA), net reclassification index (NRI), and integrated discrimination improvement (IDI). RESULTS: Both NAR and rLMC were independently associated with unfavorable outcome at 3 months (OR=8.96, p=0.0341; OR=0.89, p=0.0002, respectively). The developed nomogram (akaike information criterion (AIC)=398.77), which included NAR, rLMC and other factors, showed good performance (the AUC for the development and validation cohorts was 0.848 and 0.840 respectively) and improved the predictive value compared to a model without NAR and rLMC, according to an overall NRI of 3.27% (p=0.2401), overall IDI of 3.27% (p=0.2414), and a higher AUC (0.848 vs 0.831). CONCLUSIONS: NAR can serve as an independent predictor in AIS patients with anterior LVO, and the nomogram incorporating NAR and rLMC is reliable in predicting unfavorable outcome. Further studies with larger sample sizes are needed to validate and extend these findings.

Influence of immunosuppressive drugs on natural killer cells in therapeutic drug exposure in liver transplantation.

Background: Natural killer (NK) cells are enriched in the liver and are the main regulators in liver transplantation regarding rejection or tolerance, viral infection, or tumor recurrence. Immunosuppression consists of a triple drug standard regimen comprising tacrolimus (TAC) and corticosteroids (CS) with either mycophenolate mofetil (MMF) or sirolimus (SIR)/everolimus (EVE). The aim of this study was to evaluate the impact of trough levels of these regimens under clinical conditions and exposure on human NK-cell activity and function in order to better understand the antiviral and anti-tumor effects of mammalian target of rapamycin inhibitor (mTORI). Methods: Peripheral blood mononuclear cells (PBMCs) were collected from liver transplant recipients and healthy controls. Number and phenotypes of NK cells in vivo were analyzed by flow cytometry. In this study we simulated the immunosuppressive microenvironment in vitro. PBMCs were cultured at the clinically effective plasma concentration of drugs for 3 d to detect the effect of immunosuppressants on NK cells. Drug type and concentration: single drug [EVE, 5 ng/mL; SIR, 5 ng/mL; TAC, 5 ng/mL; cyclosporine A (CSA), 125 ng/mL; MMF, 15 µg/mL; CS, 0.5 µg/mL] and combined immunosuppressants (Group 1: TAC, 5 ng/mL + MMF, 15 µg/mL + CS, 0.5 µg/mL; Group 2: TAC, 5 ng/mL + SIR, 5 ng/mL + CS, 0.5 µg/mL; Group 3: TAC, 5 ng/mL + EVE, 5 ng/mL + CS, 0.5 µg/mL). In addition, NK cells were sorted from PBMCs and treated under the above conditions to detect NK cell killing function and RNA transcription characteristics. Results: CS significantly impaired the cytolytic activity of NK cells, followed by MMF and SIR/EVE. CS and TAC/CSA significantly decreased the secretion of IFN-γ and CD107a. NK cell function in liver transplant recipients was most pronouncedly inhibited by a triple immunosuppressive regimen, with CS playing the most prominent role compared with the other drugs. The MMF-containing regimen demonstrated a significant increase in the expression of suppressive genes, especially of the Siglec7/9 family. The SIR group had stronger NK cell activity compared with that of the MMF group, although liver transplantation patients have lower NK cell activity and function. Conclusions: Despite an overall comparable immunosuppressive efficiency in terms of prevention of acute rejection, a mTORIs-including regimen might be considered as having less impact on NK cell function.

Postmortem high-dimensional immune profiling of severe COVID-19 patients reveals distinct patterns of immunosuppression and immunoactivation.

A complete diagnostic autopsy is the gold-standard to gain insight into Coronavirus disease 2019 (COVID-19) pathogenesis. To delineate the in situ immune responses to SARS-CoV-2 viral infection, here we perform comprehensive high-dimensional transcriptional and spatial immune profiling in 22 COVID-19 decedents from Wuhan, China. We find TIM-3-mediated and PD-1-mediated immunosuppression as a hallmark of severe COVID-19, particularly in men, with PD-1+ cells being proximal rather than distal to TIM-3+ cells. Concurrently, lymphocytes are distal, while activated myeloid cells are proximal, to SARS-CoV-2 viral antigens, consistent with prevalent SARS-CoV-2 infection of myeloid cells in multiple organs. Finally, viral load positively correlates with specific immunosuppression and dendritic cell markers. In summary, our data show that SARS-CoV-2 viral infection induces lymphocyte suppression yet myeloid activation in severe COVID-19, so these two cell types likely have distinct functions in severe COVID-19 disease progression, and should be targeted differently for therapy.