CTLA-4 Checkpoint Inhibition Improves Sepsis Survival in Alcohol-Exposed Mice.

Chronic alcohol use increases morbidity and mortality in the setting of sepsis. Both chronic alcohol use and sepsis are characterized by immune dysregulation, including overexpression of T cell coinhibitory molecules. We sought to characterize the role of CTLA-4 during sepsis in the setting of chronic alcohol exposure using a murine model of chronic alcohol ingestion followed by cecal ligation and puncture. Results indicated that CTLA-4 expression is increased on CD4+ T cells isolated from alcohol-drinking septic mice as compared with either alcohol-drinking sham controls or water-drinking septic mice. Moreover, checkpoint inhibition of CTLA-4 improved sepsis survival in alcohol-drinking septic mice, but not water-drinking septic mice. Interrogation of the T cell compartments in these animals following pharmacologic CTLA-4 blockade, as well as following conditional Ctla4 deletion in CD4+ T cells, revealed that CTLA-4 deficiency promoted the activation and proliferation of effector regulatory T cells and the generation of conventional effector memory CD4+ T cells. These data highlight an important role for CTLA-4 in mediating mortality during sepsis in the setting of chronic alcohol exposure and may inform future approaches to develop targeted therapies for this patient population.

Impact of chronic alcohol exposure on conventional and regulatory murine T cell subsets.

Introduction: Chronic alcohol use poses significant negative consequences to public health and, among its many biologic effects, is associated with significant T cell dysregulation within the adaptive immune system that has yet to be fully characterized. Novel, automated strategies for high dimensional flow cytometric analysis of the immune system are rapidly improving researchers' ability to detect and characterize rare cell types. Methods: Using a murine model of chronic alcohol ingestion in conjunction with viSNE and CITRUS analysis tools, we performed a machine-driven, exploratory analysis comparing rare splenic subpopulations within the conventional CD4+, regulatory CD4+ and CD8+ T cell compartments between alcohol- and water-fed animals. Results: While there were no differences in the absolute numbers of bulk CD3+ T cells, bulk CD4+ T cells, bulk CD8+ T cells, Foxp3- CD4+ conventional T cells (Tconv) or Foxp3+ CD4+ regulatory T cells (Treg), we identified populations of naïve Helios+ CD4+Tconv and naïve CD103+ CD8+ splenic T cells that were decreased in chronically alcohol exposed mice versus water-fed controls. In addition, we identified increased CD69+ Treg and decreased CD103+ effector regulatory T cell (eTreg) subsets in conjunction with increased frequency of a population that may represent a transitional phenotype between central regulatory T cell (cTreg) and eTreg. Discussion: These data provide further resolution into the character of decreased naïve T cell populations known to be present in alcohol exposed mice, as well as describe alterations in effector regulatory T cell phenotypes associated with the pathogenesis of chronic alcohol-induced immune dysfunction.

National adherence to the ASGE-SAGES guidelines for managing suspected choledocholithiasis: An EAST multicenter study.

BACKGROUND: The American Society for Gastrointestinal Endoscopy and Society of American Gastrointestinal and Endoscopic Surgeons provide guidelines for managing suspected common bile duct (CBD) stones. We sought to evaluate adherence to the guidelines among patients with choledocholithiasis and/or acute biliary pancreatitis (ABP) and to evaluate the ability of these guidelines to predict choledocholithiasis. METHODS: We prospectively identified patients undergoing same-admission cholecystectomy for choledocholithiasis and/or ABP from 2016 to 2019 at 12 United States medical centers. Predictors of suspected CBD stones were very strong (CBD stone on ultrasound; bilirubin >4 mg/dL), strong (CBD > 6 mm; bilirubin ≥1.8 to ≤4 mg/dL), or moderate (abnormal liver function tests other than bilirubin; age >55 years; ABP). Patients were grouped by probability of CBD stones: high (any very strong or both strong predictors), low (no predictors), or intermediate (any other predictor combination). The management of each probability group was compared with the recommended management in the guidelines. RESULTS: The cohort was comprised of 844 patients. High-probability patients had 64.3% (n = 238/370) deviation from guidelines, intermediate-probability patients had 29% (n = 132/455) deviation, and low-probability patients had 78.9% (n = 15/19) deviation. Acute biliary pancreatitis increased the odds of deviation for the high- (odds ratio [OR], 1.71; 95% confidence interval [CI], 1.06-2.8; p = 0.03) and intermediate-probability groups (OR, 1.6; 95% CI, 1.07-2.42; p = 0.02). Age older than 55 years (OR, 2.19; 95% CI, 1.4-3.43; p < 0.001) also increased the odds of deviation for the intermediate group. A CBD greater than 6 mm predicted choledocholithiasis in the high (adjusted OR (aOR), 2.16; 95% CI, 1.17-3.97; p = 0.01) and intermediate group (aOR, 2.78; 95% CI, 1.59-4.86; p < 0.001). Any very strong predictor (aOR, 2.43; 95% CI, 1.76-3.37; p < 0.0001) and both strong predictors predicted choledocholithiasis (aOR, 2; 95% CI, 1.35-2.96; p < 0.001). CONCLUSION: Almost 45% of patients with suspected CBD stones were managed discordantly from the American Society for Gastrointestinal Endoscopy and Society of American Gastrointestinal and Endoscopic Surgeons guidelines. We believe these guidelines warrant revision to better reflect the ability of the clinical variables at predicting choledocholithiasis. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level IV.

Broad vs Narrow Spectrum Antibiotics in Common Bile Duct Stones: A Post Hoc Analysis of an Eastern Association for the Surgery of Trauma Multicenter Study.

BACKGROUND: Antimicrobial guidance for common bile duct stones during the perioperative period is limited. We sought to examine the effect of broad-spectrum (BS) vs narrow-spectrum (NS) antibiotics on surgical site infections (SSIs) in patients with common bile duct stones undergoing same-admission cholecystectomy. STUDY DESIGN: We performed a post hoc analysis of a prospective, observational, multicenter study of patients undergoing same-admission cholecystectomy for choledocholithiasis and/or acute biliary pancreatitis between 2016 and 2019. We excluded patients with cholangitis, perforated cholecystitis, and nonbiliary infections on admission. Patients were divided based on receipt of BS or NS antibiotics. Our primary outcome was the incidence of SSIs, and secondary outcomes included hospital length of stay, acute kidney injury (AKI), and 30-day readmission for SSI. RESULTS: The cohort had 891 patients: 51.7% (n= 461) received BS antibiotics and 48.3% (n = 430) received NS antibiotics. Overall antibiotic duration was longer in the BS group than in the NS group (6 vs 4 d, p = 0.01); however, there was no difference in rates of SSI (0.9% vs 0.5%, p = 0.7) or 30-day readmission for SSI (1.1% vs 1.2%, p = 1.0). Hospital length of stay was significantly longer in the BS group (p < 0.001) as were rates of AKI (5% vs 1.4%, p = 0.001). On multivariable regression, BS antibiotic use was a risk factor for AKI (adjusted odds ratio 2.8, 95% CI 1.16 to 7.82, p = 0.02). CONCLUSION: The incidence of SSI and 30-day readmission for SSI was similar between antibiotic groups. However, BS antibiotic use was associated with a longer hospitalization and greater likelihood of AKI.

Outcomes of same admission cholecystectomy and endoscopic retrograde cholangiopancreatography for common bile duct stones: A post hoc analysis of an Eastern Association for the Surgery of Trauma multicenter study.

BACKGROUND: The optimal timing for cholecystectomy after endoscopic retrograde cholangiopancreatography (ERCP) for common bile duct (CBD) stones is unknown. We hypothesized that a delay between procedures would correlate with more biliary complications and longer hospitalizations. METHODS: We prospectively identified patients who underwent same admission cholecystectomy after ERCP for CBD stones from 2016 to 2019 at 12 US medical centers. The cohort was stratified by time between ERCP and cholecystectomy: ≤24 hours (immediate), >24 to ≤72 hours (early), and >72 hours (late). Primary outcomes included operative duration, postoperative length of stay, (LOS), and hospital LOS. Secondary outcomes included rates of open conversion, CBD explorations, biliary complications, and in-hospital complications. RESULTS: For the 349 patients comprising the study cohort, 33.8% (n = 118) were categorized as immediate, 50.4% (n = 176) as early, and 15.8% (n = 55) as late. Rates of CBD explorations were lower in the immediate group compared with the late group (0.9% vs. 9.1%, p = 0.01). Rates of open conversion were lower in the immediate group compared with the early group (0.9% vs. 10.8%, p < 0.01) and in the immediate group compared with the late group (0.9% vs. 10.9%, p < 0.001). On a mixed-model regression analysis, an immediate cholecystectomy was associated with a significant reduction in postoperative LOS (ß = 0.79; 95% confidence interval, 0.65-0.96; p = 0.02) and hospital LOS (ß = 0.68; 95% confidence interval, 0.62-0.75; p < 0.0001). CONCLUSION: An immediate cholecystectomy following ERCP correlates with a shorter postoperative LOS and hospital LOS. Rates of CBD explorations and conversion to open appear more common after 24 hours. LEVEL OF EVIDENCE: Therapeutic, level III.

Ovariectomy induces bone loss via microbial-dependent trafficking of intestinal TNF+ T cells and Th17 cells.

Estrogen deficiency causes a gut microbiome-dependent expansion of BM Th17 cells and TNF-α-producing T cells. The resulting increased BM levels of IL-17a (IL-17) and TNF stimulate RANKL expression and activity, causing bone loss. However, the origin of BM Th17 cells and TNF+ T cells is unknown. Here, we show that ovariectomy (ovx) expanded intestinal Th17 cells and TNF+ T cells, increased their S1P receptor 1-mediated (S1PR1-mediated) egress from the intestine, and enhanced their subsequent influx into the BM through CXCR3- and CCL20-mediated mechanisms. Demonstrating the functional relevance of T cell trafficking, blockade of Th17 cell and TNF+ T cell egress from the gut or their influx into the BM prevented ovx-induced bone loss. Therefore, intestinal T cells are a proximal target of sex steroid deficiency relevant for bone loss. Blockade of intestinal T cell migration may represent a therapeutic strategy for the treatment of postmenopausal bone loss.

The effect of prolonged antibiotics on postoperative complications for common bile duct stones: A post hoc analysis of an EAST multicenter study.

BACKGROUND: Antimicrobial guidance for common bile duct (CBD) stones is limited. We sought to examine the effect of antibiotic duration on infectious complications in patients with choledocholithiasis and/or gallstone pancreatitis. METHODS: We performed a post hoc analysis of a prospective, observational, multicenter study of patients undergoing same admission cholecystectomy for choledocholithiasis and gallstone pancreatitis between 2016 and 2019. We excluded patients with cholangitis and/or cholecystitis. Patients were divided into groups based on duration of antibiotics: prophylactic (<24 hours) or prolonged (≥24 hours). We analyzed these two groups in the preoperative and postoperative periods. Outcomes included infectious complications, acute kidney injury (AKI), and hospital length of stay (LOS). RESULTS: There were 755 patients in the cohort. Increasing age, CBD diameter, and a preoperative endoscopic retrograde cholangiopancreatography (odds ratio, 1.91; 95% confidence interval, 1.34-2.73; p < 0.001) significantly predicted prolonged preoperative antibiotic use. Increasing age, operative duration, and a postoperative endoscopic retrograde cholangiopancreatography (odds ratio, 4.8; 95% confidence interval, 1.85-13.65; p < 0.001) significantly predicted prolonged postoperative antibiotic use. Rates of infectious complications were similar between groups, but LOS was 2 days longer for patients receiving overall prolonged antibiotics (p < 0.0001). Patients with AKI received two more days of overall antibiotic therapy (p = 0.02) compared with those without AKI. CONCLUSION: Rates of postoperative infectious complications were similar among patients treated with a prolonged or prophylactic course of antibiotics. Prolonged antibiotic use was associated with a longer LOS and AKI. LEVEL OF EVIDENCE: Therapeutic, Level IV.

Breaking the bond between tetranectin and HMGB1 in sepsis.

The interaction between tetranectin and high-mobility group box-1 protein may be manipulated via monoclonal antibodies to improve survival in sepsis (Chen et al. same issue).

Risk factors for complications after cholecystectomy for common bile duct stones: An EAST multicenter study.

BACKGROUND: We sought to prospectively identify risk factors for biliary complications and 30-day readmission after cholecystectomy for choledocholithiasis and gallstone pancreatitis across multiple US hospitals. METHODS: We performed a prospective, observational study of patients who underwent same admission cholecystectomy for choledocholithiasis and gallstone pancreatitis between 2016 and 2019 at 12 US centers. Patients with prior history of endoscopic retrograde cholangiopancreatography or diagnosis of cholangitis were excluded. We used logistic regression to determine associations between preoperative demographics, labs, and imaging on primary outcomes: postoperative biliary complications and 30-day readmission. RESULTS: There were 989 patients in the cohort. There were 16 (1.6%) patients with postoperative biliary complications, including intra-abdominal abscesses, endoscopic retrograde cholangiopancreatography-induced pancreatitis, and biliary leaks. Increasing operative time (odds ratio 1.01, 95% confidence interval 1.00-1.01, P = .02), worsening leukocytosis (odds ratio 1.16, 95% confidence interval 1.07-1.25, P = .0002), and jaundice (odds ratio 3.25, 95% confidence interval 1.01-10.42, P = .04) were associated with postoperative biliary complications. There were 36 (3.6%) patients readmitted within 30 days owing to a surgical complication. A prior postoperative biliary complication (odds ratio 7.8, 95% confidence interval 1.63-37.27, P = .01), male sex (odds ratio 2.42, 95% confidence interval 1.2-4.87, P = .01), and index operative duration (odds ratio 1.01, 95% confidence interval 1.00-1.01, P = .03) were associated with 30-day readmission. CONCLUSION: Among patients undergoing cholecystectomy for common bile duct stones, jaundice, worsening leukocytosis, and longer operations are associated with postoperative biliary complications. A prior biliary complication is also predictive of a 30-day readmission. Surgeons should recognize these factors and avoid prematurely discharging at-risk patients given their propensity to develop complications and require readmission.