Extracellular Hsp90α stimulates a unique innate gene profile in microglial cells with simultaneous activation of Nrf2 and protection from oxidative stress.

Delivery of exogenous heat shock protein 90α (Hsp90α) and/or its induced expression in neural tissues has been suggested as a potential strategy to combat neurodegenerative disease. However, within a neurodegenerative context, a pro-inflammatory response to extracellular Hsp90α (eHsp90α) could undermine strategies to use it for therapeutic intervention. The aim of this study was to investigate the biological effects of eHsp90α on microglial cells, the primary mediators of inflammatory responses in the brain. Transcriptomic profiling by RNA-seq of primary microglia and the cultured EOC2 microglial cell line treated with eHsp90α showed the chaperone to stimulate activation of innate immune responses in microglia that were characterized by an increase in NF-kB-regulated genes. Further characterization showed this response to be substantially lower in amplitude than the effects of other inflammatory stimuli such as fibrillar amyloid-ß (fAß) or lipopolysaccharide (LPS). Additionally, the toxicity of conditioned media obtained from microglia treated with fAß was attenuated by addition of eHsp90α. Using a co-culture system of microglia and hippocampal neuronal cell line HT22 cells separated by a chamber insert, the neurotoxicity of medium conditioned by microglia treated with fAß was reduced when eHsp90α was also added. Mechanistically, eHsp90α was shown to activate Nrf2, a response which attenuated fAß-induced nitric oxide production. The data thus suggested that eHsp90α protects against fAß-induced oxidative stress. We also report eHsp90α to induce expression of macrophage receptor with collagenous structure (Marco), which would permit receptor-mediated endocytosis of fAß.

Anastomotic leak after colorectal surgery: does timing affect failure to rescue?

BACKGROUND: Anastomotic leak (AL) is a common complication after colectomy with a relatively high failure to rescue rate (FTR), or death after major complications. There is emerging evidence to suggest an early AL may be associated with increased technical difficulty. Whether the timing of an AL is associated with higher FTR has not been established. METHODS: Patients who underwent a colectomy between 2012 and 2017 were identified from the American College of Surgeons National Quality Improvement Program (ACS NSQIP database). The primary outcome was FTR after AL. The predictor variable used was day of post-operative leak (POD) categorized into early (POD ≤ 3), intermediate (3 < POD ≤ 20) and late (20 < POD ≤ 30) AL. These POD groups were compared to generate hypotheses to explain any association observed between timing of AL and FTR. RESULTS: Of 135,539 identified patients, 4613 patients experienced an AL (3.4%) with an overall FTR of 6.4%. FTR differed by timing of AL: early AL was found to have a FTR of 28/195 (12.6%), with a FTR in intermediate AL of 152/2550 (5.6%) and 3/356 (0.8%) in late AL patients (p < 0.0001). When compared by timing of AL, patients differed by sex, pre-operative bowel preparation, de-functioning ostomy rates and re-operation rates (p < 0.05). Controlling for age, ASA, sex, emergency status, operative approach, indication, de-functioning ostomy, re-operation and concurrent procedure, an early AL was found to have a 2.3-fold increased risk of FTR (95% CI 1.38-3.84, p = 0.001), with a late AL having a 0.15-fold decreased risk (95% CI 0.04-0.49, p = 0.002), both compared to an intermediate AL. CONCLUSION: Early ALs, occurring within three days of surgery, may carry a significant risk of FTR. Given the findings identified here, this may support the use of early detection algorithms and interventions of AL to minimize the risk of FTR.

A novel inflatable device for perihepatic packing and hepatic hemorrhage control: A proof-of-concept study.

INTRODUCTION: Uncontrolled bleeding is the primary cause of death in complex liver trauma and perihepatic packing is regularly utilized for hemorrhage control. The purpose of this study was to investigate the effectiveness of a novel inflatable device (the airbag) for perihepatic packing using a validated liver injury damage control model in swine. MATERIAL AND METHODS: The image of the human liver was digitally isolated within an abdominal computerized tomography scan to produce a silicone model of the liver to mold the airbag. Two medical grade polyurethane sheets were thermal bonded to the configuration of the liver avoiding compression of the hepatic pedicle, hepatic veins, and the suprahepatic vena cava after inflation. Yorkshire pigs (n = 22) underwent controlled hemorrhagic shock (35% of the total blood volume), hypothermia, and fluid resuscitation to reproduce the indications for damage control surgery (coagulopathy, hypothermia, and acidosis) prior to a liver injury. A 3 × 10 cm rectangular segment of the left middle lobe of the liver was removed to create the injury. Subsequently, the animals were randomized into 4 groups for liver damage control (240 min), Sponge Pack (n = 6), Pressurized Airbag (n = 6), Vacuum Airbag (n = 6), and Uncontrolled (n = 4). Animals were monitored throughout the experiment and blood samples obtained. RESULTS: Perihepatic packing with the pressurized airbag led to significantly higher mean arterial pressure during the liver damage control phase compared to sponge pack and vacuum airbag 52 mmHg (SD 2.3), 44.9 mmHg (SD 2.1), and 32 mmHg (SD 2.3), respectively (p < 0.0001), ejection fraction was also higher in that group. Hepatic hemorrhage was significantly lower in the pressurized airbag group compared to sponge pack, vacuum airbag, and uncontrolled groups; respectively 225 ml (SD 160), 611 ml (SD 123), 991 ml (SD 385), 1162 ml (SD 137) (p < 0001). Rebleeding after perihepatic packing removal was also significantly lower in the pressurized airbag group; respectively 32 ml (SD 47), 630 ml (SD 185), 513 ml (SD 303), (p = 0.0004). Intra-abdominal pressure remained similar to baseline, 1.9 mmHg (SD 1), (p = 0.297). Histopathology showed less necrosis at the border of the liver injury site with the pressurized airbag. CONCLUSION: The pressurized airbag was significantly more effective at controlling hepatic hemorrhage and improving hemodynamics than the traditional sponge pack technique. Rebleeding after perihepatic packing removal was negligible with the pressurized airbag and it did not provoke hepatic injury.

Neoadjuvant therapy versus direct to surgery for T4 colon cancer: meta-analysis.

BACKGROUND: Despite persistently poor oncological outcomes, approaches to the management of T4 colonic cancer remain variable, with the role of neoadjuvant therapy unclear. The aim of this review was to compare oncological outcomes between direct-to-surgery and neoadjuvant therapy approaches to T4 colon cancer. METHODS: A librarian-led systematic search of MEDLINE, Embase, the Cochrane Library, Web of Science, and CINAHL up to 11 February 2020 was performed. Inclusion criteria were primary research articles comparing oncological outcomes between neoadjuvant therapies or direct to surgery for primary T4 colonic cancer. Based on PRISMA guidelines, screening and data abstraction were undertaken in duplicate. Quality assessment was carried out using Cochrane risk-of-bias tools. Random-effects models were used to pool effect estimates. This study compared pathological resection margins, postoperative morbidity, and oncological outcomes of cancer recurrence and overall survival. RESULTS: Four studies with a total of 43 063 patients met the inclusion criteria. Compared with direct to surgery, neoadjuvant therapy was associated with increased rates of margin-negative resection (odds ratio (OR) 2.60, 95 per cent c.i. 1.12 to 6.02; n = 15 487) and 5-year overall survival (pooled hazard ratio 1.42, 1.10 to 1.82, I2 = 0 per cent; n = 15 338). No difference was observed in rates of cancer recurrence (OR 0.42, 0.15 to 1.22; n = 131), 30-day minor (OR 1.12, 0.68 to 1.84; n = 15 488) or major (OR 0.62, 0.27 to 1.44; n = 15 488) morbidity, or rates of treatment-related adverse effects. CONCLUSION: Compared with direct to surgery, neoadjuvant therapy improves margin-negative resection rates and overall survival.

Interventions and Outcomes for Neoadjuvant Treatment of T4 Colon Cancer: A Scoping Review.

While adjuvant treatment of colon cancers that penetrate the serosa (T4) have been well-established, neoadjuvant strategies have yet to be formally evaluated. Our objective was to perform a scoping review of eligibility criteria, treatment regimens, and primary outcomes for neoadjuvant approaches to T4 colon cancer. A librarian-led, systematic search of MEDLINE, Embase, Cochrane Library, Web of Science, and CINAHL up to 11 February 2020 was performed. Primary research evaluating neoadjuvant treatment in T4 colon cancer were included. Screening and data abstraction were performed in duplicate; analyses were descriptive or thematic. A total of twenty studies were included, most of which were single-arm, single-center, and retrospective. The primary objectives of the literature to date has been to evaluate treatment feasibility, tumor response, disease-free survival, and overall survival in healthy patients. Conventional XELOX and FOLFOX chemotherapy were the most commonly administered interventions. Rationale for selecting a specific regimen and for treatment eligibility criteria were poorly documented across studies. The current literature on neoadjuvant strategies for T4 colon cancer is overrepresented by single-center, retrospective studies that evaluate treatment feasibility and efficacy in healthy patients. Future studies should prioritize evaluating clear selection criteria and rationale for specific neoadjuvant strategies. Validation of outcomes in multi-center, randomized trials for XELOX and FOLFOX have the most to contribute to the growing evidence for this poorly managed disease.

Will My Patient Survive an Anastomotic Leak? Predicting Failure to Rescue Using the Modified Frailty Index.

IMPORTANCE: Failure to rescue (FTR), or death after major complications, has emerged as a marker of hospital-level quality of care. OBJECTIVE: To evaluate the predictive performance of the ACS-NSQIP modified frailty index (mFI) in determining FTR following an anastomotic leak (AL) after a colectomy for colorectal cancer. DESIGN: Retrospective cohort study. SETTING: Multicenter interrogation of the 2012-2016 American College of Surgeons (ACS) colectomy procedure targeted National Surgical Quality Improvement Program (NSQIP) database. PATIENTS AND METHODS: A total of 50,944 patients who underwent colectomy for colorectal cancer. EXPOSURE: Frailty as measured by: (1) Age, ASA, and emergency status (model 1), (2) Age, ASA, emergency status, and mFI (model 2), (3) ACS-NSQIP mortality prediction (model 3). MAIN OUTCOME AND MEASURE: Primary outcome was FTR after AL. RESULTS: A total of 1755 patients experienced an AL (3.46%) with a FTR rate of 6.44%. The mean age was 65.6 years (95% CI 65.28-65.58 years), median ASA was 3 (IQR 2-3), 51 patients (2.92%) were partially or totally dependent, 366 (20.86%) were diabetic, 105 (5.98%) had a history of chronic obstructive pulmonary disease (COPD), 32 (1.82%) had a history of congestive heart disease (CHD), and 966 (55.04%) were on hypertensive treatment. The performance of model 1 (AUROC 0.77; 95% CI 0.72-0.81), model 2 (AUROC 0.77; 95% CI 0.73-0.82), and model 3 (AUROC 0.79; 95% CI 0.75-0.83) to predict FTR was not different (p = 0.44). CONCLUSIONS AND RELEVANCE: Age and ASA remain the most reliable predictors of failure to rescue anastomotic leak after colectomy for colorectal cancer. Addition of the modified frailty index, or all variables collected by NSQIP, did not significantly improve predictive performance.

In situ simulation and its effects on patient outcomes: a systematic review.

Background: The use of in situ simulation has previously been shown to increase confidence, teamwork and practical skills of trained professionals. However, a direct benefit to patient outcomes has not been sufficiently explored. This review focuses on the effect of in situ simulation training in a hospital setting on morbidity or mortality. Methods: A combined search was conducted in PUBMED, OVID, WEB OF SCIENCE, CINAHL, SCOPUS and EMBASE. 478 studies were screened with nine articles published between 2011 and 2017 meeting the inclusion criteria for analysis. Results: This review selected eight prospective studies and one prospective-retrospective study. Three studies isolated in situ simulation as an experimental variable while the remaining studies implemented in situ programmes as a component of larger quality improvement initiatives. Seven studies demonstrated a significant improvement in morbidity and/or mortality outcomes following integrated in situ simulation training. Conclusion: Existing literature, albeit limited, demonstrates that in situ training improves patient outcomes either in isolation or within a larger quality improvement programme. However, existing evidence contains difficulties such as isolating the impact of in situ training from various potential confounding factors and potential for publication bias.

Racial Disparities in Surgery: A Cross-Specialty Matched Comparison Between Black and White Patients.

Objective: To determine if Black race is associated with worse short-term postoperative morbidity and mortality when compared to White race in a contemporary, cross-specialty-matched cohort. Background: Growing evidence suggests poorer outcomes for Black patients undergoing surgery. Methods: A retrospective analysis was conducted comprising of all patients undergoing surgery in the National Surgical Quality Improvement Program dataset between 2012 and 2018. One-to-one coarsened exact matching was conducted between Black and White patients. Primary outcome was rate of 30-day morbidity and mortality. Results: After 1:1 matching, 615,118 patients were identified. Black race was associated with increased rate of all-cause morbidity (odds ratio [OR] = 1.10, 95% confidence interval [CI] 1.08-1.13, P < 0.001) and mortality (OR = 1.15, 95% CI 1.01-1.31, P = 0.039). Black race was associated with increased risk of re-intubation (OR = 1.33, 95% CI 1.21-1.48, P < 0.001), pulmonary embolism (OR = 1.55, 95% CI 1.40-1.71, P < 0.001), failure to wean from ventilator for >48 hours (OR = 1.14, 95% CI 1.02-1.29, P < 0.001), progressive renal insufficiency (OR = 1.63, 95% CI 1.43-1.86, P < 0.001), acute renal failure (OR = 1.39, 95% CI 1.16-1.66, P < 0.001), cardiac arrest (OR = 1.47, 95% CI 1.24-1.76 P < 0.001), bleeding requiring transfusion (OR = 1.39, 95% CI 1.34-1.43, P < 0.001), DVT/thrombophlebitis (OR = 1.24, 95% CI 1.14-1.35, P < 0.001), and sepsis/septic shock (OR = 1.09, 95% CI 1.03-1.15, P < 0.001). Black patients were also more likely to have a readmission (OR = 1.12, 95% CI 1.10-1.16, P < 0.001), discharge to a rehabilitation center (OR = 1.73, 95% CI 1.66-1.80, P < 0.001) or facility other than home (OR = 1.20, 95% CI 1.16-1.23, P < 0.001). Conclusion and Relevance: This contemporary matched analysis demonstrates an association with increased morbidity, mortality, and readmissions for Black patients across surgical procedures and specialties.

Genotoxic stress induces Sca-1-expressing metastatic mammary cancer cells.

We describe a cell damage-induced phenotype in mammary carcinoma cells involving acquisition of enhanced migratory and metastatic properties. Induction of this state by radiation required increased activity of the Ptgs2 gene product cyclooxygenase 2 (Cox2), secretion of its bioactive lipid product prostaglandin E2 (PGE2), and the activity of the PGE2 receptor EP4. Although largely transient, decaying to low levels in a few days to a week, this phenotype was cumulative with damage and levels of cell markers Sca-1 and ALDH1 increased with treatment dose. The Sca-1+ , metastatic phenotype was inhibited by both Cox2 inhibitors and PGE2 receptor antagonists, suggesting novel approaches to radiosensitization.

CARD 2017: expansion and model-centric curation of the comprehensive antibiotic resistance database.

The Comprehensive Antibiotic Resistance Database (CARD; http://arpcard.mcmaster.ca) is a manually curated resource containing high quality reference data on the molecular basis of antimicrobial resistance (AMR), with an emphasis on the genes, proteins and mutations involved in AMR. CARD is ontologically structured, model centric, and spans the breadth of AMR drug classes and resistance mechanisms, including intrinsic, mutation-driven and acquired resistance. It is built upon the Antibiotic Resistance Ontology (ARO), a custom built, interconnected and hierarchical controlled vocabulary allowing advanced data sharing and organization. Its design allows the development of novel genome analysis tools, such as the Resistance Gene Identifier (RGI) for resistome prediction from raw genome sequence. Recent improvements include extensive curation of additional reference sequences and mutations, development of a unique Model Ontology and accompanying AMR detection models to power sequence analysis, new visualization tools, and expansion of the RGI for detection of emergent AMR threats. CARD curation is updated monthly based on an interplay of manual literature curation, computational text mining, and genome analysis.