Extracellular vesicles from differentiated stem cells contain novel proangiogenic miRNAs and induce angiogenic responses at low doses.

Extracellular vesicles (EVs) released from healthy endothelial cells (ECs) have shown potential for promoting angiogenesis, but their therapeutic efficacy remains poorly understood. We have previously shown that transplantation of a human embryonic stem cell-derived endothelial cell product (hESC-ECP), promotes new vessel formation in acute ischemic disease in mice, likely via paracrine mechanism(s). Here, we demonstrated that EVs from hESC-ECPs (hESC-eEVs) significantly increased EC tube formation and wound closure in vitro at ultralow doses, whereas higher doses were ineffective. More important, EVs isolated from the mesodermal stage of the differentiation (hESC-mEVs) had no effect. Small RNA sequencing revealed that hESC-eEVs have a unique transcriptomic profile and are enriched in known proangiogenic microRNAs (miRNAs, miRs). Moreover, an in silico analysis identified three novel hESC-eEV-miRNAs with potential proangiogenic function. Differential expression analysis suggested that two of those, miR-4496 and miR-4691-5p, are highly enriched in hESC-eEVs. Overexpression of miR-4496 or miR-4691-5p resulted in increased EC tube formation and wound closure in vitro, validating the novel proangiogenic function of these miRNAs. In summary, we demonstrated that hESC-eEVs are potent inducers of EC angiogenic response at ultralow doses and contain a unique EV-associated miRNA repertoire, including miR-4496 and miR-4691-5p, with novel proangiogenic function.

Implementation of an opioid reduction toolkit in pancreatectomy patients significantly increases patient awareness of safe practice and decreases amount prescribed and consumed.

BACKGROUND: Postoperative opioid abuse following surgery is a major concern. This study sought to create an opioid reduction toolkit to reduce the number of narcotics prescribed and consumed while increasing awareness of safe disposal in pancreatectomy patients. METHODS: Prescription, consumption, and refill request data for postoperative opioids were collected from patients receiving an open pancreatectomy before and after the implementation of an opioid reduction toolkit. Outcomes included safe disposal practice awareness for unused medication. RESULTS: 159 patients were included in the study: 24 in the pre-intervention and 135 in the post-intervention group. No significant demographic or clinical differences existed between groups. Median morphine milliequivalents (MMEs) prescribed were significantly reduced from 225 (225-310) to 75 (75-113) in the post-intervention group (p < 0.0001). Median MMEs consumed were significantly reduced from 109 (111-207) to 15 (0-75), p < 0.0001), as well. Refill request rates remained equivalent during the study (Pre: 17% v Post: 13%, p = 0.9) while patient awareness of safe disposal increased (Pre: 25% v Post: 62%, p < 0.0001). DISCUSSION: An opioid reduction toolkit significantly reduced the number of postoperative opioids prescribed and consumed after open pancreatectomy, while refill request rates remained the same and patients' awareness of safe disposal increased.

Preoperative Opioid and Benzodiazepine Use: Influence on Abdominal Surgical Outcomes.

BACKGROUND: Preoperative opioid use has shown association with worse outcomes after surgery. However, little is known about the effect of preoperative benzodiazepines with and without opioids. The aim of this study was to determine the influence of preoperative substance use on outcomes after abdominal surgery. STUDY DESIGN: Patients undergoing abdominal operations including ventral hernia, colectomy, hysterectomy, cholecystectomy, appendectomy, nephrectomy, and hiatal hernia were identified in an opioid surgical steward program by a regional NSQIP consortium between 2019 and 2021. American College of Surgeons NSQIP data were linked with custom substance use variables created by the collaborative. Univariable and multivariable analyses were performed for 30-day outcomes. RESULTS: Of 4,439 patients, 64% (n = 2,847) were women, with a median age of 56 years. The most common operations performed were hysterectomy (22%), ventral hernia repair (22%), and colectomy (21%). Preoperative opioid use was present in 11% of patients (n = 472), 10% (n = 449) were on benzodiazepines, and 2.3% (n = 104) were on both. Serious morbidity was significantly (p < 0.001) increased in patients on preoperative opioids (16% vs 7.9%) and benzodiazepines (14% vs 8.3%) compared with their naïve counterpart and this effect was amplified in patients on both substances (20% vs 7.5%). Multivariable regression analyses reveal that preoperative substance use is an independent risk factor (p < 0.01) for overall morbidity and serious morbidity. CONCLUSIONS: Preoperative opioid and benzodiazepine use are independent risk factors that contribute to postoperative morbidity. This influence on surgical outcomes is exacerbated when patients are on both substances.

Extracorporeal life support and cardiopulmonary bypass for central airway surgery: A systematic review.

BACKGROUND: Major airway surgery can pose a complex problem to perioperative central airway management. Adjuncts to advanced ventilation strategies have included cardiopulmonary bypass, veno-arterial, or veno-venous extracorporeal life support. We performed a systematic review to assess the existing evidence utilizing these strategies. METHODS: An electronic search was conducted to identify studies written in English reporting the use of extracorporeal life support (ECLS) during central airway surgery. Thirty-six articles consisting of 78 patients were selected and patient-level data were analyzed. RESULTS: Median patient age was 47 [IQR: 34-53] and 59.0% (46/78) were male. Indications for surgery included central airway or mediastinal cancer in 57.7% (45/78), lesion or injury in 15.4% (12/78), and stenosis in 12.8% (10/78). Support was initiated pre-operatively in 9.9% (7/71) and at the time of induction in 55.3% (42/76). It was most commonly used at the time of tracheal resection/repair [93.2% (68/73)], intubation of the tracheal stump [94.4% (68/72)], and re-anastomosis [94.2% (65/69)]; 13.7% (10/73) patients were supported post-operatively. The most commonly performed surgery was tracheal repair or resection in 70.3% (52/74). Median hospital stay was 12 [8, 25] days and in-hospital mortality was 7.9% (6/76). There was no significant difference in survival between the three groups (p = .54). CONCLUSIONS: Extracorporeal membrane oxygenation offers versatility in timing, surgical approach, and ECLS runtime that makes it a viable addition to the surgical armamentarium for treating complex central airway pathologies.

Stereotactic body radiation therapy (SBRT) for patients with stage I non-small cell lung cancer is applicable to more tumors than sublobar resection.

BACKGROUND: Virtually all patients with medically inoperable stage I non-small cell lung cancer (NSCLC) can receive stereotactic body radiation therapy. However, the percentage of such patients in whom sublobar resection is technically feasible is unknown. This discrepancy can confound clinical trial eligibility and designs comparing stereotactic body radiation therapy vs. sublobar resection. METHODS: A total of 137 patients treated with stereotactic body radiation therapy for lung lesions (3/2013-11/2017) underwent retrospective review. Diagnostic CT chest and PET/CT images, stereotactic body radiation therapy dates, and demographic data were collected on 100 of 137 patients. Two experienced board-certified thoracic surgeons independently reviewed anonymized patients' pre-stereotactic body radiation therapy diagnostic imaging and completed a custom survey about the technical feasibility of sublobar resection for each patient. Interrater agreement was measured using Cohen's kappa coefficient by bootstrap methodology. Summary statistics were performed for baseline demographics and tumor characteristics. RESULTS: Of the 100 patients, 57% were female, with median age of 75 years (range, 52-95 years) and Karnofsky Performance Status of 80 (range, 40-100). Most patients (61%) had Stage IA1, T1a tumors. For interrater agreement analysis, one patient was removed from each cohort due to inability to locate tumor on images, leaving 98 patients analyzed. Comparing Surgeon #1 vs. Surgeon #2, 64 (65.3%) vs. 69 (70.3%) of tumors were thought eligible for sublobar resection, respectively (κ=0.414). CONCLUSIONS: Stereotactic body radiation therapy for stage I NSCLC is applicable to more tumors than sublobar resection, with ~30-35% of stereotactic body radiation therapy patients unable to undergo sublobar resection assessed by pretreatment diagnostic imaging based on technical grounds. This study illustrates that clinical trials comparing stereotactic body radiation therapy vs. sublobar resection are limited to only a subpopulation of patients with stage I NSCLC.

Development and Validation of a Prediction Model for Stroke, Cardiac, and Mortality Risk After Non-Cardiac Surgery.

Background Commonly used cardiovascular risk calculators do not provide risk estimation of stroke, a major postoperative complication with high morbidity and mortality. We developed and validated an accurate cardiovascular risk prediction tool for stroke, major cardiac complications (myocardial infarction or cardiac arrest), and mortality after non-cardiac surgery. Methods and Results This retrospective cohort study included 1 165 750 surgical patients over a 4-year period (2007-2010) from the American College of Surgeons National Surgical Quality Improvement Program Database. A predictive model was developed with the following preoperative conditions: age, history of coronary artery disease, history of stroke, emergency surgery, preoperative serum sodium (≤130 mEq/L, >146 mEq/L), creatinine >1.8 mg/dL, hematocrit ≤27%, American Society of Anesthesiologists physical status class, and type of surgery. The model was trained using American College of Surgeons National Surgical Quality Improvement Program data from 2007 to 2009 (n=809 880) and tested using data from 2010 (n=355 870). Risk models were developed using multivariate logistic regression. The outcomes were postoperative 30-day stroke, major cardiovascular events (myocardial infarction, cardiac arrest, or stroke), and 30-day mortality. Major cardiac complications occurred in 0.66% (n=5332) of patients (myocardial infarction, 0.28%; cardiac arrest, 0.41%), postoperative stroke in 0.25% (n=2005); 30-day mortality was 1.66% (n=13 484). The risk prediction model had high predictive accuracy with area under the receiver operating characteristic curve for stroke (training cohort=0.869, validation cohort=0.876), major cardiovascular events (training cohort=0.871, validation cohort=0.868), and 30-day mortality (training cohort=0.922, validation cohort=0.925). Surgery types, history of stroke, and coronary artery disease are significant risk factors for stroke and major cardiac complications. Conclusions Postoperative stroke, major cardiac complications, and 30-day mortality can be predicted with high accuracy using this web-based predictive model.

Postoperative Telehealth Visits Reduce Emergency Department Visits and 30-Day Readmissions in Elective Thoracic Surgery Patients.

BACKGROUND: Preventing postoperative 30-day readmissions requires an investment in patient care. The use of postdischarge telehealth visits to prevent potential adverse events or hospital visits has been shown in previous studies. PURPOSE: We aim to determine the impact of postoperative telehealth visits (PTV) on reducing emergency department visits (EDV) and readmissions within 30 days postdischarge (30DR). METHODS: All elective thoracic surgery patients opted-in or opted-out of PTV. Postoperative telehealth visits assessed patients' overall health status and addressed patient concerns. Patients were also seen at their postoperative clinic follow-up. Emergency department visits and 30DR were recorded. RESULTS: Three hundred fourty-one patients were included-295 and 46 patients opted-in and opted-out of PTV. Opting-out of PTV, being discharged with chest tubes or drains, and the inability to perform activities of daily living at their postoperative follow-up were associated with increased EDV (OR = 8.7, 5.3, 6.3; p ≤ .05) and 30DR (OR = 5.1, 6.3, 7.1; p ≤ .05). CONCLUSION: Postoperative telehealth visits were able to reduce EDV and 30DR in our study, although further studies establishing the range of interventions that can be feasibly provided remotely should be performed to identify limitations of these PTV. IMPLICATIONS: Telehealth could be used postoperatively to reduce EDV and 30DR, improving quality and cost-effectiveness of healthcare delivery to patients.

Debility Risk Model as a Predictor for Postsurgical Outcomes.

BACKGROUND: Decreased patient functional status is associated with higher rates of postoperative morbidity and mortality. The Vizient program recently implemented a debility risk model to identify patients with impaired functional status. We examined the relationship between this novel model and inpatient postsurgical outcomes in a large urban tertiary care center. METHODS: The Vizient database was accessed to compare surgical outcomes between patients coded with debility and patients without debility between January 2017 and December 2018. Data for each surgical specialty were obtained, and a chi-squared analysis was used to detect differences in readmission rates, mortality, and postoperative complications (defined by Vizient). These complications include pneumonia, postoperative infection, anesthesia complications, and shock. RESULTS: We found patients with debility have a higher mortality rate (3%) than patients without debility (2%) across all surgical specialties (P = .0103). Patients with debility have a higher 30-day readmission rate (16%) than those without debility (8%) across all specialties (P < .0001). Patients with debility had a higher rate of inpatient complications for neurosurgery (12.11% vs. 8%, P = .008), trauma surgery (11.9% vs. 6%, P =.025), general surgery (17.67% vs. 7%, P = .013), and cardiac surgery (47.06% vs. 18%, P =.0025). CONCLUSIONS: Our study supports the use of the Vizient debility code to predict postsurgical outcomes and risk stratify patients. By extension, functional status assessments in preoperative evaluation of patients remain important. Further, studies can build upon this data to measure the impact of preoperative, outpatient debility assessments in surgical patients.

Racial Disparities in Rates of Surgery for Esophageal Cancer: a Study from the National Cancer Database.

BACKGROUND: Treatment guidelines for stage I-III esophageal cancer indicate that management should include surgery in appropriate patients. Variations in utilization of surgery may contribute to racial differences observed in survival. We sought to identify factors associated with racial disparities in surgical resection of esophageal cancer and evaluate associated survival differences. METHODS: Patients diagnosed with stage I-III esophageal cancer from 2004 to 2015 were identified using the National Cancer Database. Matched patient cohorts were created to reduce confounding. Multivariate logistic regression was used to identify factors associated with receipt of surgery. Multi-level modeling was performed to control for random effects of individual hospitals on surgical utilization. RESULTS: A total of 60,041 patients were included (4402 black; 55,639 white). After 1:1 matching, there were 5858 patients evenly distributed across race. For all stages, significantly fewer black than white patients received surgery. Black race independently conferred lower likelihood of receiving surgery in single-level multivariable analysis (OR (95% CI); stage I, 0.67 (0.48-0.94); stage II, 0.76 (0.60-0.96); stage III, 0.62 (0.50-0.76)) and after controlling for hospital random effects. Hospital-level random effects accounted for one third of the unexplained variance in receipt of surgery. Risk-adjusted 1-, 3-, and 5-year mortality was higher for patients who did not undergo surgery. CONCLUSION: Black patients with esophageal cancer are at higher risk of mortality compared to white patients. This increased risk may be influenced by decreased likelihood of receiving surgical intervention for resectable disease, in part because of between-hospital differences. Improving access to surgical care may improve disparities in esophageal cancer survival.

Development and Validation of a Web-Based Prediction Model for AKI after Surgery.

Background: AKI after surgery is associated with high mortality and morbidity. The purpose of this study is to develop and validate a risk prediction tool for the occurrence of postoperative AKI requiring RRT (AKI-dialysis). Methods: This retrospective cohort study had 2,299,502 surgical patients over 2015-2017 from the American College of Surgeons National Surgical Quality Improvement Program Database (ACS NSQIP). Eleven predictors were selected for the predictive model: age, history of congestive heart failure, diabetes, ascites, emergency surgery, hypertension requiring medication, preoperative serum creatinine, hematocrit, sodium, preoperative sepsis, and surgery type. The predictive model was trained using 2015-2016 data (n=1,487,724) and further tested using 2017 data (n=811,778). A risk model was developed using multivariable logistic regression. Results: AKI-dialysis occurred in 0.3% (n=6853) of patients. The unadjusted 30-day postoperative mortality rate associated with AKI-dialysis was 37.5%. The AKI risk prediction model had high area under the receiver operating characteristic curve (AUC; training cohort: 0.89, test cohort: 0.90) for postoperative AKI-dialysis. Conclusions: This model provides a clinically useful bedside predictive tool for postoperative AKI requiring dialysis.

The Pathway to Low Outlier Status in Venous Thromboembolism Events: An Analysis of Pancreatic Surgery in the National Surgical Quality Improvement Program.

Purpose: Our institution's hepatopancreaticobiliary surgery service (HPBS) has demonstrated low rates of venous thromboembolism (VTE). We sought to determine whether the HPBS's regimented multimodal VTE prophylaxis pathway, which includes the use of mechanical prophylaxis, pharmacological prophylaxis, and ambulation, plays a role in achieving low VTE rates. Methods: We compared pancreatic surgeries in the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) participant user file with our institution's data from 2011 to 2016 using univariate, multivariate, and matching statistics. Results: Among 36,435 NSQIP operations, 850 (2.3%) underwent surgery by the HPBS. The HPBS achieved lower VTE rates than the national cohort (2.0% vs. 3.5%, p = 0.018). Upon multivariate analysis, having an operation performed by the HPBS independently conferred lower odds of VTE incidence in the matched cohort (odds ratio = 0.530, p = 0.041). Conclusions: We identified an independent correlation between the HPBS and decreased VTE incidence, which we believe to be due to strict adherence to and team participation in a high risk VTE prophylaxis pathway, including inpatient pharmacological prophylaxis, thromboembolic deterrent stockings, sequential compression devices, and mandatory ambulation.

Asymptomatic Trauma Patients Screened for Venous Thromboembolism Have a Higher Risk Profile with Lower Rate of Pulmonary Embolism: A Five-Year Single-Institution Experience.

Deep vein thrombosis (DVT) is linked to reimbursements and publicly reported metrics. Some hospitals discourage venous duplex ultrasound (VDUS) screening in asymptomatic trauma patients because they often find higher rates of DVT. We aim to evaluate the association between lower extremity (LE) VDUS screening and pulmonary embolism (PE) in trauma patients. Trauma patients admitted to an urban Level-1 trauma center between 2010 and 2015 were retrospectively analyzed. We characterized the association of asymptomatic LE VDUSs with PE, upper extremity DVT, proximal LE DVT, and distal LE DVT by univariate and multivariable logistic regression controlling for confounders. Of the 3959 trauma patients included in our study-after adjusting for covariates related to patient demographics, injury, and procedures-there was a significantly lower likelihood of PE in screened patients (odds ratio (OR) = 0.02, P < 0.001) and a higher rate of distal LE DVT (OR 11.1, P = 0.004). Screening was not associated with higher rates of proximal LE DVT after adjustment for covariates (OR = 1.8, P = 0.193). PE was associated with patient transfer status, pelvis fracture, and spinal procedures in unscreened patients. After adjusting for covariates, we have shown that LE VDUS asymptomatic screening is associated with lower rates of PE in trauma patients and not associated with higher rates of proximal LE DVT. Our detailed institutional review of a large cohort of trauma patients over five years provides support for ongoing asymptomatic screening and better characterizes venous thromboembolism outcomes than similarly sized purely administrative data reviews. As a retrospective cohort study with a large sample size, no loss to follow-up, and a population with low heterogeneity, this study should be considered as level III evidence for care management.

Early Discharge Does Not Increase Readmission Rates After Minimally Invasive Anatomic Lung Resection.

OBJECTIVE: Enhanced recovery pathways reduce length of stay and costs following lung resection. However, many fear that early discharge may lead to increased hospital readmissions. In this study, we aimed to determine whether early discharge was associated with increased readmission following anatomic lung resection. METHODS: Using the lung resection database approved by our institutional review board, we identified all patients undergoing minimally invasive lobectomy and segmentectomy between January 2010 and March 2017 at our institution, where an enhanced recovery pathway is well established. Thirty-day readmissions were compared between patients with short- and average length of stay, defined as 1 to 2 days and 3 to 5 days, respectively. Multivariable logistic regression analysis of patients matched by propensity scores was performed to determine odds of 30-day readmission for each group. Significance was set at P < 0.05. RESULTS: A total of 296 patients met inclusion criteria. Unadjusted analysis revealed a 3-fold increased rate of readmission in the group with average length of stay (9%, n = 12) versus the group with short length of stay (3%, n = 5; P < 0.01). At baseline, patients with average length of stay had increased rates of preoperative chemotherapy (13%, n = 18 vs. 4%, n = 6; P < 0.01) and radiation (12%, n = 16 vs. 3%, n = 5). Patients with average length of stay also had higher rates of lobectomy (95%, n = 127 vs. 86%, n = 140; P = 0.02) and postoperative complications (31%, n = 41 vs. 4%, n = 7; P < 0.01). On multivariable analysis, patients with average length of stay had a 2.3-fold greater odds of readmission, which was not statistically significant (OR = 2.33; 95% CI, 0.60 to 9.02; P = 0.22). CONCLUSIONS: Early discharge following minimally invasive anatomic lung resection does not increase the risk of hospital readmission in patients treated within an enhanced recovery pathway.

Disparity in age at lung cancer diagnosis between current and former smokers.

PURPOSE: In a previous study of smoking cessation in veterans with lung cancer, we noted as an incidental finding that current smokers were much younger than former smokers at diagnosis. To confirm and extend this observation, we analyzed the association of smoking status with age at diagnosis and survival of lung cancer patients. METHODS: The Jefferson Cancer Registry collects information on all cancer patients registered at this hospital. Information on smoking status has been recorded since 1995. We determined age at diagnosis and survival of current and former smokers with lung cancer. RESULTS: 5111 lung cancer cases were identified in the registry from 1995 to 2011 inclusive. Smoking status was recorded in 4687 cases (91.7%). Of these, 1859 (39.7%) were current, 2423 (51.7%) were former, and 405 (8.6%) were never smokers. There was a 6-year difference in median age at lung cancer diagnosis between the current (63 years) and former smokers (69 years) (P < 0.0001). The median survival was 12.1 months for current versus 14.5 months for former smokers (P < 0.0001). CONCLUSIONS: These results confirm and extend our observation that among patients diagnosed with lung cancer, current smokers are younger than former smokers. The possible explanations include higher competing causes of death and increased risk of lung cancer among current smokers as well as increasing proportions of former smokers in older populations. Ongoing exposure to tobacco carcinogens may accelerate the development of lung cancer in continuing smokers. This provides more incentive for smokers to quit at the earliest age possible.

Dr. Orvar Swenson and the Pull-Through.

Dr. Orvar Swenson is best remembered for developing the Swenson pull-through, a technique he developed to treat Hirschsprung's disease. After graduating from Harvard Medical School and beginning his residency at Peter Bent Brigham Hospital, Dr. Swenson observed that patients with Hirschsprung's disease and toxic megacolon resumed normal bowel function after placement of transverse colostomies. His observation led to studying the patency of his patients' colons using barium enema contrast studies. At the collapsed portion of the colon, he performed rectal biopsies leading to the discovery that the cause of Hirschsprung's disease is that the collapsed portion of the colon lacks the Auerbach plexus. The Swenson pull-through removes this aganglionic portion of the colon and cures the patient. His career grew from there as he traveled to academic institutions teaching his technique. He is remembered fondly for his contributions to pediatric surgery through the restructuring of pediatric surgery departments, pediatric surgery research, and writing and editing multiple volumes of Pediatric Surgery, the standard textbook for pediatric surgeons. He died peacefully in 2012 at the age of 103 years.

Leveraging Structural Changes in an Electronic Health Record Tool to Standardize Written Handoff.

Miscommunications during patient handoff can lead to harm. The I-PASS bundle has been shown to improve safety outcomes. Although effective training reliably improves verbal handoffs, research has demonstrated a lack of effect on written handoffs. The objective was to compare written handoff before and after integration of a standardized electronic health record (EHR) tool. Interns at a large urban academic medical center underwent I-PASS handoff training. The EHR handoff tool was then revised to prompt the I-PASS components. Handoff documents were obtained before and after the intervention. More handoffs included Illness Severity (33% to 59%, P < .001) and Action List (65% to 83%, P = .005) after the intervention. There was no change in handoffs with miscommunications (12.5% to 10%, P = .566) or omissions (8% to 11%, P = .447). Handoffs including tangential or unrelated information decreased (20% to 4%, P = .001). A written handoff tool can reinforce the effect of training and increase adherence to I-PASS.