Guosheng Wu

Transplantation is the treatment of choice for patients with end-stage organ failure. Its success is limited by side effects of immunosuppressive drugs, such as inhibitors of the calcineurin pathway that prevent rejection by reducing synthesis of interleukin-2 by T cells. Moreover, none of the existing drugs efficiently prevent the eventual rejection of the organ. Blocking the CD28-mediated T cell costimulation pathway is a nontoxic alternative immunosuppression strategy that is now achieved by blockade of CD80/86, the receptor for CD28 on antigen-presenting cells. However, interaction of CD80/86 with cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is required for immune regulation. Therefore, CD28 blockade, instead of CD80/86 blockade, might preserve regulatory signals mediated by CTLA-4 and preserve immune regulation. By using monovalent antibodies, we identified true CD28 antagonists that induced CTLA-4-dependent decreased T cell function compatible with regulatory T (Treg) cell suppression. In transplantation experiments in primates, blocking CD28 augmented intragraft and peripheral blood Treg cells, induced molecular signatures of immune regulation, and prevented graft rejection and vasculopathy in synergy with calcineurin inhibition. These findings suggest that targeting costimulation blockade at CD28 preserves CTLA-4-dependent immune regulation and promotes allograft survival.

Introduction: The incidence of postoperative sepsis is continually increased, while few studies have specifically focused on the risk factors and clinical outcomes associated with the development of sepsis after surgical procedures. The present study aimed to develop a mathematical model for predicting the in-hospital mortality among patients with postoperative sepsis. Materials and Methods: Surgical patients in Medical Information Mart for Intensive Care (MIMIC-III) database who simultaneously fulfilled Sepsis 3.0 as well as Agency for Healthcare Research and Quality (AHRQ) criteria during ICU admission were incorporated. We employed both extreme gradient boosting (XGBoost) and stepwise logistic regression model to predict in-hospital mortality among included patients with postoperative sepsis. Consequently, model performance was assessed from the angles of discrimination and calibration. Results: We included 3713 patients who fulfilled our inclusion criteria, in which 397 (10.7%) patients died during hospitalization, while 3316 (89.3%) of them survived through discharge. Fluid-electrolyte disturbance, coagulopathy, renal replacement therapy (RRT), urine output, and cardiovascular surgery were important features related to the in-hospital mortality. The XGBoost model had a better performance in both discriminatory ability (c-statistics, 0.835 [95% CI, 0.786 to 0.877] vs. c-statistics, 0.737 [95% CI, 0.688 to 0.786]) and goodness of fit (visualized by calibration curve) compared to the stepwise logistic regression model. Conclusion: XGBoost model appears to be a better performance in predicting hospital mortality among postoperative septic patients compared to the conventional stepwise logistic regression model. Machine learning-based algorithm might have significant application in the development of early warning system for septic patients following major operations.

Sepsis is an intractable disorder, which is associated with high risk of organ dysfunction and even death, while its pathogenesis remains largely unclear. Our study aims to study the research trend on sepsis and host immune response, and compare the contribution of publications from different countries, institutions, journals and authors.

Pharmacologic antagonism of CCR5, a chemokine receptor expressed on macrophages and activated T cells, is an effective antiviral therapy in patients with macrophage-tropic HIV infection, but its efficacy in modulating inflammation and immunity is only just beginning to be investigated. In this regard, the recruitment of CCR5-bearing cells into clinical allografts is a hallmark of acute rejection and may anticipate chronic rejection, whereas conventionally immunosuppressed renal transplant patients homozygous for a nonfunctional Delta32 CCR5 receptor rarely exhibit late graft loss. Therefore, we explored the effects of a potent, highly selective CCR5 antagonist, Merck's compound 167 (CMPD 167), in an established cynomolgus monkey cardiac allograft model. Although perioperative stress responses (fever, diminished activity) and the recruitment of CCR5-bearing leukocytes into the graft were markedly attenuated, anti-CCR5 monotherapy only marginally prolonged allograft survival. In contrast, relative to cyclosporine A monotherapy, CMPD 167 with cyclosporine A delayed alloantibody production, suppressed cardiac allograft vasculopathy, and tended to further prolong graft survival. CCR5 therefore represents an attractive therapeutic target for attenuating postsurgical stress responses and favorably modulating pathogenic alloimmunity in primates, including man.

The monitoring and management of blood glucose concentration are standard practices in critical settings as hyperglycaemia has been shown close association with poorer outcomes. Several meta-analyses have revealed that intensive glucose control has no benefit in decreasing short-term mortality among critically ill patients, while the studies these meta-analyses have incorporated have been largely divergent. We aim to perform a more comprehensive meta-analysis addressing this problem to provide stronger evidence. Methods: We conducted comprehensive searches for relevant randomized controlled studies in online databases, including the Cochrane Library, EMBASE, and PubMed databases, up to September 1, 2018. The clinical data, which included all-cause mortality, severe hypoglycemia, need for RRT, infection resulting in sepsis, ICU mortality, 90-day mortality, 180-day mortality, and hospital and ICU lengths of stay, were screened and analyzed after data extraction. We applied odds ratios (ORs) to analyze dichotomous outcomes and mean differences for continuous outcomes with a random effects model. Results: A total of 57 RCTs involving a total of 21840 patients were finally included. Patients admitted to the ICU who underwent intensive glucose control showed significantly reduced all-cause mortality (OR: 0.89; 95% CI: 0.80-1.00; P=0.04; I 2 =32%), reduced infection rate (OR: 0.65, 95% CI: 0.51-0.82, P=0.0002; I 2 =47%), a lower occurrence of acquired sepsis (OR: 0.80, 95% CI: 0.65-0.99, P=0.04; I 2 =0%) and shortened length of ICU stay (MD: -0.70, 95% CI: -1.21--0.19, P=0.007, I 2 =70%) when compared to the same parameters as those treated with the usual care strategy. However, patients in the intensive glucose control group presented with a significantly higher risk of severe hypoglycemia (OR: 5.63, 95% CI: 4.02-7.87, P<0.00001; I 2 =67%). Conclusions: Critically ill patients undergoing intensive glucose control showed significantly reduced all-cause mortality, length of ICU stay and incidence of acquired infection and sepsis compared to the same parameters in patients treated with the usual care strategy, while the intensive glucose control strategy was associated with higher occurrence of severe hypoglycemic events.