ABSTRACT
The liver is an organ that, when dysfunctional in a septic patient, is strongly associated with morbidity and mortality. Understanding the pathophysiology of liver failure during sepsis may lead to improved diagnostics and potential therapeutic targets. Historically, programmed cell death receptor (PD) ligand 1 (PD-L1) has been considered the primary ligand for its checkpoint molecule counterpart, PD-1, with PD-L2 rarely in the immunopathological spotlight. PD-1 and PD-L1 contribute to liver dysfunction in a murine cecal ligation and puncture (CLP) model of sepsis, but virtually nothing is known about PD-L2's role in sepsis. Therefore, our central hypothesis was that sepsis-induced changes in hepatic PD-L2 expression contributed to worsened liver function and, subsequently, more pronounced morbidity and mortality. We found that although PD-L1 gene deficiency attenuated the hepatic dysfunction seen in wild-type mice after CLP, the loss of PD-L2 appeared to actually worsen indices of liver function along with a trend toward higher liver tissue vascular permeability. Conversely, some protective effects of PD-L2 gene deletion were noted, such as reduced liver/peritoneal bacterial load and reduced IL-6, IL-10, and macrophage inflammatory protein 2 levels following CLP. These diverse actions, as well as the unique expression pattern of PD-L2, may explain why no overt survival advantage could be witnessed in the septic PD-L2-/- mice. Taken together, these data suggest that although PD-L2 has some selective effects on the hepatic response seen in the septic mouse, these factors are not sufficient to alter septic mortality in this adult murine model. NEW & NOTEWORTHY Our study shows not only that ligands of the checkpoint protein PD-1 respond inversely to a stressor such as septic challenge (PD-L2 declines, whereas PD-L1 rises) but also that aspects of liver dysfunction increase in septic mice lacking the PD-L2 gene. Furthermore, these differences in PD-L2 gene-deficient animals culminated in the abrogation of the survival advantage seen in the septic PD-L1-knockout mice, suggesting that PD-L2 may have roles beyond a simple immune tolerogen.
Subject(s)
Liver Diseases/metabolism , Programmed Cell Death 1 Ligand 2 Protein/genetics , Programmed Cell Death 1 Receptor/genetics , Sepsis/immunology , Animals , Apoptosis/genetics , Cecum/metabolism , Disease Models, Animal , Liver/metabolism , Liver Diseases/etiology , Liver Diseases/genetics , Mice, Inbred C57BL , Sepsis/complications , Sepsis/geneticsSubject(s)
Carcinoma, Basal Cell , Carcinoma, Squamous Cell , Skin Neoplasms , Aged , Aged, 80 and over , Female , Humans , Male , Middle Aged , Carcinoma, Basal Cell/surgery , Carcinoma, Basal Cell/pathology , Carcinoma, Squamous Cell/surgery , Carcinoma, Squamous Cell/pathology , Mohs Surgery , Prospective Studies , Skin Neoplasms/surgery , Skin Neoplasms/pathology , Skin Pigmentation , Treatment OutcomeSubject(s)
Mohs Surgery , Scalp , Humans , Mohs Surgery/adverse effects , Scalp/surgery , Surgical Tape , Suture Techniques , SuturesABSTRACT
Importance: It has been suggested that Mohs surgery for skin cancer among individuals with limited life expectancy may be associated with needless risk and discomfort, along with increased health care costs. Objective: To investigate patient- and tumor-specific indications considered by clinicians for treatment of nonmelanoma skin cancer in older individuals. Design, Setting, and Participants: This multicenter, prospective cohort study was conducted using data from US private practice and academic centers. Included patients were those older than age 85 years presenting for skin cancer surgery and referred for Mohs surgery, with reference groups of those younger than age 85 years receiving Mohs surgery and those older than age 85 years not receiving Mohs surgery. Data were analyzed from November 2018 through January 2019. Exposures: Mohs surgery for nonmelanoma skin cancer. Main Outcomes and Measures: Reason for treatment selection. Results: Among 1181 patients older than age 85 years referred for Mohs surgery (724 [61.9%] men among 1169 patients with sex data; 681 individuals aged >85 to 88 years [57.9%] among 1176 patients with age data) treated at 22 sites, 1078 patients (91.3%) were treated by Mohs surgery, and 103 patients (8.7%) received alternate treatment. Patients receiving Mohs surgery were more likely to have tumors on the face (738 patients [68.5%] vs 26 patients [25.2%]; P < .001) and nearly 4-fold more likely to have high functional status (614 patients [57.0%] vs 16 patients [15.5%]; P < .001). Of 15 distinct reasons provided by surgeons for opting to proceed with Mohs surgery, the most common were patient desire for treatment with a high cure rate (712 patients [66.0%]), good or excellent patient functional status for age (614 patients [57.0%]), and high risk associated with the tumor based on histology (433 patients [40.2%]). Conclusions and Relevance: This study found that older patients who received Mohs surgery often had high functional status, high-risk tumors, and tumors located on the face. These findings suggest that timely surgical treatment may be appropriate in older patients given that their tumors may be aggressive, painful, disfiguring, and anxiety provoking.
Subject(s)
Carcinoma, Basal Cell , Skin Neoplasms , Aged , Carcinoma, Basal Cell/pathology , Carcinoma, Basal Cell/surgery , Female , Humans , Male , Mohs Surgery , Private Practice , Prospective Studies , Skin/pathology , Skin Neoplasms/pathology , Skin Neoplasms/surgeryABSTRACT
BACKGROUND: Cardiac surgeons have a significant history of participating in humanitarian work; however, the outcomes in this arena are not well delineated. We sought to define and describe failure to rescue (FTR) in this setting by analyzing the outcomes of the International Children's Heart Foundation. METHODS: From 2008 to 2017, 3009 patients underwent operations during the course of an International Children's Heart Foundation mission. Of these, 1165 patients had at least one complication. These patients were divided into those who ultimately died (FTR group, n = 107) and those who survived (survivor group, n = 1058). Clinical presentation and outcomes were compared. RESULTS: The overall FTR rate was 10%. Patients in the FTR group were significantly younger, weighed less, and were shorter. Children who required a preoperative admission to the intensive care unit were more likely to be in the FTR group. Intraoperative data demonstrated significantly longer cardiopulmonary bypass time among FTR patients, with similar use of intraoperative blood product. Postoperatively, patients in the FTR group had more reintubations than survivors. Cardiopulmonary bypass and intensive care unit times were shown to be significant predictors of FTR. There was a trend between program volume and FTR rate. Program volume appeared to be correlated with FTR. CONCLUSIONS: Failure to rescue occurs at a rate of 10% in the humanitarian congenital cardiac surgery setting. The FTR patients were younger, required more intubations, and had significantly more diagnoses of transposition of the great arteries. Longer cardiopulmonary bypass time and intensive care unit admission were associated with increased risk of FTR.