Benefits of Aerosolized, Point-of-care, Autologous Skin Cell Suspension (ASCS) for the Closure of full Thickness Wounds from Thermal and Non-Thermal Causes: Learning Curves from the first 50 Consecutive cases at an Urban, Level 1 Trauma Center.

OBJECTIVE: To determine the utility of Autologous Skin Cell Suspension (ASCS) in closing full-thickness (FT) defects from injury and infection. SUMMARY BACKGROUND DATA: Although ASCS has documented success in closing partial-thickness burns, far less is known about the efficacy of ASCS in FT defects. METHODS: Fifty consecutive patients with FT defects (burn 17, necrotizing infection 13, crush 7, degloving 5, other 8) underwent closure with the bilayer technique of 3:1 widely-meshed, thin, split-thickness skin graft and 80:1 expanded ASCS. End points were limb salvage rate, donor site reduction, operative and hospital throughput, incidence of complications, and re-epithelialization by 4, 8, and 12 weeks. RESULTS: Definitive wound closure was achieved in 76%, 94%, and 98% of patients, at 4, 8, and 12 weeks, respectively. Limb salvage occurred in 42/43 patients (10 upper, 33 lower extremities). Mean area grafted was 435 cm2; donor site size was 212 cm2, representing a potential reduction of 50%. Mean surgical time was 71 minutes; total OR time was 124 minutes. Mean length-of-stay was 26.4 days; time from grafting to discharge was 11.2 days. 4/50 patients (8%) required 6 reoperations for bleeding (1), breakdown (4), and amputation (1). 4/50 patients (8%) developed hypertrophic scarring, which responded to silicone sheeting (2) and laser resurfacing (2). Mean follow-up was 92.7 days. CONCLUSION: When used for closure of FT wounds, point-of-care ASCS is effective and safe. Benefits include rapid re-epithelialization, high rate of limb salvage, reduction of donor site size and morbidity, and low incidence of hypertrophic scarring.

Cues to care: Chronic disease diagnosis in young adult trauma patients.

BACKGROUND: Prevention of chronic disease necessitates early diagnosis and intervention. In young adults, a trauma admission may be an early contact with the health care system, representing an opportunity for screening and intervention. This study estimates the prevalence of previously diagnosed disease and undiagnosed disease (UD)-diabetes mellitus, hypertension, obesity, and alcohol and substance use-in a young adult trauma population. We determine factors associated with UD and examine outcomes in patients with UD. METHODS: This is a multicenter, retrospective cohort study of adult trauma patients 18 to 40 years old admitted to participating Level I trauma centers between January 2018 and December 2020. Three Level 1 trauma centers in a single state participated in the study. Trauma registry data and chart review were examined for evidence of previously diagnosed disease or UD. Patient demographics and outcomes were compared between cohorts. Multivariable regression modeling was performed to assess risk factors associated with any UD. RESULTS: The analysis included 6,307 admitted patients. Of these, 4,843 (76.8%) had evidence of at least 1 UD, most commonly hypertension and obesity. In multivariable models, factors most associated with risk of UD were age (adjusted odds ratio [aOR], 0.98; 95% confidence interval [CI], 0.98-0.99), male sex (aOR, 1.43; 95% CI, 1.25-1.63), and uninsured status (aOR, 1.57; 95% CI, 1.38-1.80). Only 24.5% of patients had evidence of a primary care provider (PCP), which was not associated with decreased odds of UD. Clinical outcomes were significantly associated with the presence of chronic disease. Of those with UD and no PCP, only 11.2% were given a referral at discharge. CONCLUSION: In the young adult trauma population, the UD burden is high, especially among patients with traditional sociodemographic risk factors and even in patients with a PCP. Because of short hospital stays in this population, the full impact of UD may not be visible during a trauma admission. Early chronic disease diagnosis in this population will require rigorous, standard screening measures initiated within trauma centers. LEVEL OF EVIDENCE: Prognostic and Epidemiological; Level IV.

The Role of Diversion During Ileal Pouch Anal Anastomosis (IPAA) Creation in Pediatric Ulcerative Colitis.

INTRODUCTION: In pediatric ulcerative colitis (UC), surgery is often postponed until disease is life-threatening or refractory to immune suppression. In these settings, diverting ileostomy (DI) is theorized to have a protective effect on the new anastomosis. However, analyses have been performed only in single-institution series and the true impact of performing DI at the time of IPAA on postoperative outcomes is unclear. METHODS: We performed a retrospective cohort study using claims data from the International Business Machines (IBM) MarketScan® database. Patients were sorted to the DI group if they carried a CPT code for ostomy closure within 6 months of index procedure. We examined demographics, preoperative risk factors, and performed regression analysis to compare 30-day postoperative outcomes between groups. RESULTS: We identified 317 patients ≤18yo that underwent IPAA procedure and met inclusion criteria from 2000 to 2019. Of these, 238 patients were assigned to the IPAA + DI cohort and 79 patients were assigned to the IPAA cohort. Adverse outcomes were comparable between cohorts. Surgical site infection (SSI) rates between IPAA and IPAA + DI were 10.1 vs. 11.3% (p = 0.67). Rates of intra-abdominal drainage procedures were 3.8 vs. 2.1% (p = 0.39). The rates of 30-day readmissions were 16.5 vs. 19.3% (p = 0.39). Creation of a DI was not associated with higher odds of 30-day readmission (OR = 1.4, p = 0.31). CONCLUSION: Creating a DI necessitates an additional surgery for closure and is not associated with decreased adverse outcomes. There is still a role for multicenter studies to define which patient populations may benefit from diversion. LEVEL OF EVIDENCE: Retrospective comparative study. TYPE OF STUDY: Level III.

The Effect of Area Social Deprivation on Health Behavior and Health Care Utilization in an Adult Trauma Population.

Social determinants of health may mediate health disparities, but these variables are not routinely measured in clinical practice. This is a retrospective, single-institution study that evaluates the effect of area deprivation on outcomes after trauma admission. Adult trauma patients 18 years and older were eligible. Patients were stratified into high-area (HSD) or low-area (LSD) social deprivation cohorts using zip code of residence. Regression modeling was used to explain the association between HSD, sociodemographic characteristics, and clinical outcomes. Patients who resided in HSD areas made up 29.5% of the study population, were more likely to be younger, male, and identify as a non-White race. Patients in the HSD cohort were also less likely to be admitted to the ICU (OR 0.84, CI 0.71-0.98) and discharged with additional services (OR 0.73, CI 0.57-0.94). We found that independently, area social deprivation affects trauma outcomes and the resources a patient is provided after discharge.

Nonoperative Management Versus Laparoscopic Appendectomy in Children: A Cost-Effectiveness Analysis.

INTRODUCTION: Nonoperative management (NOM) of acute appendicitis in the pediatric population is highly debated with uncertain cost-effectiveness. We performed a decision tree cost-effectiveness analysis of NOM versus early laparoscopic appendectomy (LA) for acute appendicitis in children. METHODS: We created a decision tree model for a simulated cohort of 49,000 patients, the number of uncomplicated appendectomies performed annually, comparing NOM and LA. We included postoperative complications, recurrent appendicitis, and antibiotic-related complications. We used the payer perspective with a 1-year time horizon. Model uncertainty was analyzed using a probabilistic sensitivity analysis. Event probabilities, health-state utilities, and costs were obtained from literature review, Healthcare Cost and Utilization Project, and Medicare fee schedules. RESULTS: In the base-case analysis, NOM costs $6530/patient and LA costs $9278/patient on average at 1 y. Quality-adjusted life year (QALY) differences minimally favored NOM compared to LA with 0.997 versus 0.996 QALYs/patient. The incremental cost-effectiveness ratio for NOM over LA was $4,791,149.52/QALY. NOM was dominant in 97.4% of simulations, outperforming in cost and QALYs. A probabilistic sensitivity analysis showed NOM was 99.6% likely to be cost-effective at a willingness-to-pay threshold of $100,000/QALY. CONCLUSIONS: Our model demonstrates that NOM is a dominant strategy to LA over a 1-year horizon. We use recent trial data demonstrating higher rates of early and late NOM failures. However, we also incorporate a shorter length of index hospitalizations with NOM, reflecting a contemporary approach to NOM and ultimately driving cost-effectiveness. Long-term follow-up data are needed in this population to assess the cost-effectiveness of NOM over longer time horizons, where healthcare utilization and recurrence rates may be higher.

The Use of Sequential Surveys to Shorten Implementation Time for Healthcare System-Level Enhanced Recovery After Surgery (ERAS) Pathways.

BACKGROUND: Enhanced Recovery After Surgery (ERAS) pathways improve healthcare quality, safety, and cost-effectiveness. We hypothesized that the RAND Method (a hybrid Delphi approach), involving anonymous sequential surveys and face-to-face meetings, would allow for more rapid agreement and initiation of new ERAS pathways. METHODS: Using the ERAS Society guidelines for cesarean section as a baseline, our institution's ERAS Leadership Team (ELT) compiled published literature and institutional practices to design a 32-component survey that was sent to obstetricians, nurse midwives, anesthesiologists, pharmacists, and nurses. Components that did not reach 90% consensus were included in a second survey the following week, and meetings were held to review results. At the conclusion of this process, time to agreement was retrospectively compared to the colorectal ERAS pathway process at this institution. RESULTS: ERAS pathway components were compiled and reviewed by 121 stakeholders at 7 hospitals using iterative surveys with review meetings over a 13-week period. Survey response rates were 61% and 50% in the initial and follow-up surveys, respectively. There was agreement on 28/32 and 32/32 items on the initial and follow-up surveys. Using the RAND Method, time to agreement decreased by 54.1% (24 vs 13 weeks) compared to prior system-wide efforts to standardize the colorectal surgery ERAS pathway. DISCUSSION: With rapidly expanding healthcare systems, effective methods to gain consensus and adopt ERAS pathways are critical to implementation of ERAS guidelines. We demonstrate that the RAND Method allows for a transparent and efficient means of agreement across a diverse group of clinicians practicing in several settings.

Same-Day Surgery Clinic: A model for improving access to care at academic medical centers.

BACKGROUND: Best-practice models delivering surgical care in the preoperative setting are unknown. In April 2018, we established a Same-Day Clinic (SDC) to increase the access and efficiency of general surgical care delivery. METHODS: This is a single-institution retrospective cohort study. We included patients who underwent elective laparoscopic cholecystectomy, inguinal or umbilical hernia repair. 112 patients were seen in the year prior to clinic creation; 84 were seen in the year following clinic creation. RESULTS: After clinic creation, the percentage of patients referred following an emergency department encounter decreased from 33.4 to 17.9%. Patients referred from primary care encounters increased from 28.6 to 44%. Patients who underwent pre-referral imaging decreased from 58.9% to 44%. The SDC cohort was seen 11 days sooner (40 vs. 29d). CONCLUSION: The SDC increases access and decreases wait times to surgical treatment. It strengthens referral networks for traditionally underserved populations and reduces the burden of non-necessary preoperative imaging.

Blood Utilization and Thresholds for Mortality Following Major Trauma.

INTRODUCTION: Blood loss is a hallmark of traumatic injury. Massive transfusion, historically defined as the replacement by transfusion of 10 units of packed red blood cells (PRBCs) in 4 h, is a response to uncontrolled hemorrhage. We sought to identify blood transfusion thresholds in which predicted mortality exceeds 50%. METHODS: We analyzed the 2017-2019 National Trauma Database. Inclusion criteria included patients ≥18 y who received ≥1 unit of PRBCs. Statistical analysis included bivariate analysis, logistic regression for mortality, and adjusted predicted probability modeling was utilized. RESULTS: We identified 61,676 patients for analysis. The 50% predicted mortality for all patients was 31 PRBC units. The 50% predicted mortality was 6 units of PRBCs for elderly trauma patients 80 y and older. CONCLUSIONS: Blood remains as scarce resource in hospitals especially with trauma. Patients receiving a massive transfusion over a short period of time may exhaust blood bank supply with diminishing survival benefit. Surgeons should be judicious regarding continued blood usage once the 50% predicted mortality threshold is reached.

Surgical patient values frame and modify the impact of risk factors for non-routine postdischarge care: A mixed-methods study.

BACKGROUND: Adult colorectal surgery patients continue to have high rates of readmissions, despite known risk factors for non-routine postdischarge care (emergency department (ED) visit or rehospitalization) and countless interventions to address these. It is unclear how the difficult-to-quantify patient perspective frames and modifies the impact of these quantifiable risk factors. STUDY DESIGN: We identified consecutive adult inpatient colorectal surgery patients from 2017 to 2018. This mixed methods study merged data from electronic health records and in-depth patient interviews. RESULTS: We enrolled 258 participants, surveyed 167, and interviewed 18. Depressive symptoms represent one of many risk factors confirmed to increase non-routine healthcare utilization (RR 1.85, 95% CI 1.02-3.37), though the patient perspective explained why these symptoms seemed to greatly impact some patients more than others. Additionally, consistent with patient report, patients with non-routine postdischarge care (26%) were less likely to report communication with their surgical team (80% vs 97%, p < 0.001). CONCLUSION: Patient perspectives add depth and understanding of the impact of risk factors on non-routine post-discharge care. This expanded knowledge explains why one patient is more likely to visit an ED close to home whereas another patient might prefer to visit their surgeon's clinic directly. Effective strategies to reduce unplanned postdischarge care should be tailored.

Transition to multiple mini interview (MMI) interviewing for medical school admissions.

INTRODUCTION: The multiple mini interview (MMI) has been incorporated into the holistic review process in the selection of students to US medical schools. The MMI has been used to evaluate interpersonal and intrapersonal attributes which are deemed as necessary for future physicians. We hypothesized that there would be little difference in overall MMI evaluation data compared with traditional interview ratings. METHODS: The University of North Carolina School of Medicine developed an interview process that included a traditional interview and MMI format during the 2019 admissions cycle. Evaluation data along with key demographic variables for 608 MD program applicants were analyzed using descriptive and inferential statistical analyses. RESULTS: The MMI format slightly favored female over male applicants (p = 0.002) but did not select for or against applicants based on age, race/ethnicity, underserved/rural area upbringing, or indicators of disadvantage. Out of 608 applicants, 356 (59%) completed a post-interview survey in which the experience was positively rated. DISCUSSION: Based on our experience, the use of a hybrid model of traditional interviews complemented with MMI stations provided greater details in the assessment of medical school applicants while obtaining equivalent data and acceptability amongst applicants.

E2F transcription factor 1 regulates cellular and organismal senescence by inhibiting Forkhead box O transcription factors.

E2F1 and FOXO3 are two transcription factors that have been shown to participate in cellular senescence. Previous report reveals that E2F1 enhanced cellular senescence in human fibroblast cells, while FOXO transcription factors play against senescence by regulation reactive oxygen species scavenging proteins. However, their functional interplay has been unclear. Here we use E2F1 knock-out murine Embryonic fibroblasts (MEFs), knockdown RNAi constructs, and ectopic expression of E2F1 to show that it functions by negatively regulating FOXO3. E2F1 attenuates FOXO3-mediated expression of MnSOD and Catalase without affecting FOXO3 protein stability, subcellular localization, or phosphorylation by Akt. We mapped the interaction between E2F1 and FOXO3 to a region including the DNA binding domain of E2F1 and the C-terminal transcription-activation domain of FOXO3. We propose that E2F1 inhibits FOXO3-dependent transcription by directly binding FOXO3 in the nucleus and preventing activation of its target genes. Moreover, knockdown of the Caenorhabditis elegans E2F1 ortholog efl-1 significantly extends lifespan in a manner that requires the activity of the C. elegans FOXO gene daf-16. We conclude that there is an evolutionarily conserved signaling connection between E2F1 and FOXO3, which regulates cellular senescence and aging by regulating the activity of FOXO3. We speculate that drugs and/or therapies that inhibit this physical interaction might be good candidates for reducing cellular senescence and increasing longevity.

YAP/TEAD-mediated transcription controls cellular senescence.

Transcription coactivator Yes-associated protein (YAP) plays an important role in the regulation of cell proliferation and apoptosis. Here, we identify a new role of YAP in the regulation of cellular senescence. We find that the expression levels of YAP proteins decrease following the replication-induced cellular senescence in IMR90 cells. Silencing of YAP inhibits cell proliferation and induces premature senescence. In additional experiments, we observe that cellular senescence induced by YAP deficiency is TEAD- and Rb/p16/p53-dependent. Furthermore, we show that Cdk6 is a direct downstream target gene of YAP in the regulation of cellular senescence, and the expression of Cdk6 is through the YAP-TEAD complex. Ectopic expression of Cdk6 rescued YAP knockdown-induced senescence. Finally, we find that downregulation of YAP in tumor cells increases senescence in response to chemotherapeutic agents, and YAP or Cdk6 expression rescues cellular senescence. Taken together, our findings define the critical role of YAP in the regulation of cellular senescence and provide a novel insight into a potential chemotherapeutic avenue for tumor suppression.