IL-10 promotes endothelial progenitor cell infiltration and wound healing via STAT3.

Endothelial progenitor cells (EPCs) contribute to de novo angiogenesis, tissue regeneration, and remodeling. Interleukin 10 (IL-10), an anti-inflammatory cytokine that primarily signals via STAT3, has been shown to drive EPC recruitment to injured tissues. Our previous work demonstrated that overexpression of IL-10 in dermal wounds promotes regenerative tissue repair via STAT3-dependent regulation of fibroblast-specific hyaluronan synthesis. However, IL-10's role and specific mode of action on EPC recruitment, particularly in dermal wound healing and neovascularization in both normal and diabetic wounds, remain to be defined. Therefore, inducible skin-specific STAT3 knockdown mice were studied to determine IL-10's impact on EPCs, dermal wound neovascularization and healing, and whether it is STAT3-dependent. We show that IL-10 overexpression significantly elevated EPC counts in the granulating wound bed, which was associated with robust capillary lumen density and enhanced re-epithelialization of both control and diabetic (db/db) wounds at day 7. We noted increased VEGF and high C-X-C motif chemokine 12 (CXCL12) levels in wounds and a favorable CXCL12 gradient at day 3 that may support EPC mobilization and infiltration from bone marrow to wounds, an effect that was abrogated in STAT3 knockdown wounds. These findings were supported in vitro. IL-10 promoted VEGF and CXCL12 synthesis in primary murine dermal fibroblasts, with blunted VEGF expression upon blocking CXCL12 in the media by antibody binding. IL-10-conditioned fibroblast media also significantly promoted endothelial sprouting and network formation. In conclusion, these studies demonstrate that overexpression of IL-10 in dermal wounds recruits EPCs and leads to increased vascular structures and faster re-epithelialization.

Missed Opportunities to Promptly Diagnose and Treat Adrenal Tumors.

INTRODUCTION: Adrenal mass management guidelines are insufficiently applied, and timeliness of treatment is unknown. We evaluated missed opportunities to promptly diagnose and treat adrenal tumors that ultimately required adrenalectomy. METHODS: From the Veterans Affairs Corporate Data Warehouse, we identified patients who underwent adrenalectomy (2010-2016) in the South-Central Veterans Affairs HealthCare Network and reviewed their records. Diagnostic timeliness was assessed by the interval between initial (index) imaging with adrenal abnormality and the next diagnostic step. Workup was defined as early (interval ≤6 mo) or late (>6 mo). Adrenalectomy was considered prompt when the interval between index imaging and adrenalectomy was ≤12 mo and delayed when this was >12 mo. We quantified diagnostic and treatment delays and assessed factors associated with delayed adrenalectomy. RESULTS: During the study period, 84 patients underwent adrenalectomy: male (86.9%), White (57.1%), with a mean age of 58.7 y (±8.8). Of those, 25 (29.8%) had late workup, and 36 (42.9%) had delayed surgery (median interval: 44 mo, range 14-282). Late hormonal workup occurred in 24 of 36 (66.7%) patients with delayed surgery, compared with one of 48 (2.1%, P < 0.001) with prompt surgery. CONCLUSIONS: Missed opportunities in prompt diagnosis and treatment were common in patients with adrenal masses ultimately requiring adrenalectomy. Late hormonal workup is associated with delayed adrenalectomy. Interventions are needed to aid clinicians to recognize the presence, promptly evaluate, and make guideline-informed decisions on the management of an adrenal mass.

Skin-specific knockdown of hyaluronan in mice by an optimized topical 4-methylumbelliferone formulation.

Hyaluronan (HA) is abundant in the skin; while HA can be synthesized by the synthases (HAS1-3), HAS2 is the leading contributor. Dysregulation and accumulation of HA is implicated in the pathogenesis of diseases such as keloid scarring, lymphedema and metastatic melanoma. To understand how HA synthesis contributes to skin physiology, and pathologic and fibrotic disorders, we propose the development of skin-specific HA inhibition model, which tests an optimal delivery system of topical 4-methylumbelliferone (4-MU). A design-of-experiments (DOE) approach was employed to develop an optimal 4-MU skin-delivery formulation comprising propylene glycol, ethanol, and water, topically applied to dorsal skin in male and female C57BL/6J wildtype mice to determine the effect on HAS gene expression and HA inhibition. Serum and skin samples were analyzed for HA content along with analysis of expression of HAS1-3, hyaluronidases (HYAL 1-2), and KIAA1199. Using results from DOE and response surface methodology with genetic algorithm optimization, we developed an optimal topical 4-MU formulation to result in ∼70% reduction of HA in dorsal skin, with validation demonstrating ∼50% reduction in HA in dorsal skin. 4-MU topical application resulted in significant decrease in skin HAS2 expression in female mice only. Histology showed thicker dermis in male mice, whereas female mice had thinner dermal layer with more adiposity; and staining for HA-binding protein showed that topical 4-MU resulted in breakdown in HA. Our data suggest a topical 4-MU formulation-based dermal HA inhibition model that would enable elucidating the skin-specific effects of HA in normal and pathologic states.

Broad Utility of a Minimally Invasive Technique for Pediatric Wound Care: Simple and Effective.

OBJECTIVE: Infected or contaminated wound sites have historically been managed with incision and drainage. Here, the authors review their experience with skin closure over vessel loops and assess the results of this technique in a variety of clinical situations, hypothesizing that minimally invasive drainage strategies are associated with a decrease in common postoperative complications. METHODS: Investigators retrospectively reviewed the data of all children with infected or contaminated wound sites operated on by a single surgeon with skin closure over vessel loops from September 2016 to September 2018. Demographics, indications for surgery, complications, and follow-up were assessed. RESULTS: Over a 2-year period, 33 children underwent skin closure over vessel loops. The majority were female (82%), Hispanic/Latino (40%), and younger than 5 years (58%; range, 4 months to 16 years). One-third were obese. Reasons for intervention included skin and soft tissue infection (64%), trauma (15%), and ostomy closure (6%). Median postoperative length of stay was 1 day. Three-quarters (76%) of the patients returned to the clinic for follow-up and/or vessel loop removal. At 30 days after operation, no patients in this cohort returned to the ED with recurrent infection or wound dehiscence. CONCLUSIONS: This minimally invasive technique for contaminated wound management demonstrates no evidence of subsequent infection in standard follow-up. These results are indicative of specific advantages related to vessel loop drainage, including shorter lengths of stay and ease of wound maintenance, in a variety of challenging clinical scenarios.

Prenatal Imaging to Predict Need for Urgent Perinatal Surgery in Congenital Lung Lesions.

BACKGROUND: Congenital lung malformations (CLMs) have a variable natural history: some patients require urgent perinatal surgical intervention (UPSI) and others remain asymptomatic. These lesions have potential growth until 26-28 wk gestation. CLM volume ratio (CVR) has been shown to predict the risk of hydrops in CLMs. However, no criteria exist to delineate lesions requiring urgent surgical intervention in the perinatal period. Our goal was to determine prenatal diagnostic features that predict the need for UPSI in patients diagnosed with CLM. METHODS: Records and imaging features of all fetuses evaluated by our fetal center between May 2015 and December 2018 were retrospectively reviewed. Data included demographics, fetal ultrasound and magnetic resonance imaging, CVR, surgical treatment, and outcome. Features were analyzed for their ability to predict the need for UPSI. RESULTS: Sixty-four patients were referred for CLM, with 48 patients serially followed. Nine (18.8%) patients were followed nonoperatively, 35 (72.9%) underwent resection, and four (8.3%) were lost to follow-up. Of the patients who underwent resection, 24 (68.5%) were electively resected and 11 were urgently resected. Five (14.3%) patients underwent ex utero intrapartum treatment resection, and six (17.1%) were urgently resected for symptomatic CLM. There were no cases of UPSI with final CVR <1.1. Of the patients with final CVR 1.1-1.7, 43% required urgent resection. CVR ≥1.1 has 100% sensitivity and 87.8% specificity to predict patients requiring UPSI (area under the curve of 0.98). CONCLUSIONS: A final CVR ≥1.1 is highly predictive for UPSI. Patients with a final CVR ≥1.1 should be referred for delivery at centers with pediatric surgeons equipped for potential UPSI for CLM.

The Use of a Fixation Dressing to Reduce Complications After Neonatal Gastrostomy Tube Placement.

Objective: Gastrostomy tubes (GTs) are one of the most common procedures in neonatal surgery, and their malfunction represents one of the most common complaints in the emergency room and clinic. Complications can occur in up to one-third of patients and include pain, peristomal leak, and infection, but can range in severity. We hypothesize that a preventative strategy employing a GT fixation dressing at the time of operation minimizes these postoperative complications in neonates. Approach: All patients less than 1 year of age who underwent laparoscopic GT placement by a single surgeon in the study period were reviewed. All tubes were secured in place on the external abdominal wall for 2 weeks postoperatively. Demographics and outcomes were evaluated. Results: Fifty-three percent of our cohort were male, and 47% were premature. The most common indication for placement was failure to thrive (59%), and common comorbid conditions were characterized as neurologic (71%), and cardiac (59%). The dressing did not prevent hypertrophic granulation tissue formation, but no patient experienced surgical site infection or device-related pressure injury at 30 and 120 days postoperatively. No patient required reoperation or readmission. Innovation: This simple, one-time, cost-effective fixation dressing has the potential to reduce some of the most common postoperative surgical issues in neonatal patients and can be applied in almost any health care setting. Conclusions: A dressing aimed at tube fixation and immobilization for the first two postoperative weeks averts some of the major complications of GT placement over a standard follow-up period as compared with the literature.

The Pediatric Surgeon-Scientist: Succeeding in Today's Academic Environment.

BACKGROUND: Pediatric surgeons have long been advocates of basic science research. However, new challenges facing the scientific community have threatened the success of academic surgeons pursuing basic science careers. The purpose of this study was to compare academic pediatric surgeons' perceptions of their ability to effectively conduct basic science research to those of other surgical subspecialties. METHODS: An online survey was distributed to all members of the Association for Academic Surgery and Society of University Surgeons. A total of 1033 members (41%) responded, and 137 (13.3%) were pediatric surgeons. Comparisons were made between the five most-represented surgical subspecialties. Data are presented as reporting percentage and P values by Student's t-test. RESULTS: Among the specialists studied, pediatric surgeons are those most likely to believe that surgeons can succeed as basic scientists in today's research environment. Pediatric surgery reported the highest rates of National Institutes of Health funding of all surgical specialties and the lowest rates of perceived external pressures related to clinical demands, hospital administrative duties, and work-life balance concerns than their surgical peers. CONCLUSIONS: Pediatric surgeons have a more optimistic perspective on the state of basic science research in surgery while exhibiting an enhanced ability to overcome the challenges that surgeon-scientists currently face. Our findings suggest that pediatric surgery may provide a model for succeeding in basic science in today's challenging surgical research environment.

Central Venous Catheter-Related Deep Vein Thrombosis in the Pediatric Cardiac Intensive Care Unit.

BACKGROUND: Central venous catheter (CVC) use is common in the management of critically ill children, especially those with congenital heart disease. CVCs are known to augment the risk of deep vein thrombosis (DVT), but data on CVC-associated DVTs in the pediatric cardiac intensive care unit (CICU) are limited. In this study, we aim to identify the incidence of and risk factors for CVC-related DVT in this high-risk population, as its complications are highly morbid. MATERIALS AND METHODS: The PC4 database and a radiologic imaging database were retrospectively reviewed for the demographics and outcomes of patients admitted to the Texas Children's Hospital CICU requiring CVC placement, as well as the incidence of DVT and its complications. RESULTS: Between January 2017 and December 2017, 1215 central lines were placed over 851 admissions. DVT was diagnosed in 8% of admissions with a CVC, 29% of which demonstrated thrombus in the inferior vena cava. The risk factors significantly associated with DVT included the presence of >1 line, higher total line hours, longer intubation times, and extended CICU stay. A diagnosis of low cardiac output syndrome, sepsis, central line-associated bloodstream infection, and cardiac catheterization were also significant risk factors. Interestingly, cardiac surgery with cardiopulmonary bypass appeared to be protective of clot development. DVT was a highly significant risk factor for mortality in these patients. CONCLUSIONS: CVC-related DVTs in critically ill children with congenital heart disease are associated with higher risks of morbidity and mortality, highlighting the need for well-designed studies to determine the best preventative and treatment strategies and to establish guidelines for appropriate monitoring and follow-up of these patients.

Congenital diaphragmatic hernia repair in patients on extracorporeal membrane oxygenation: How early can we repair?

BACKGROUND: The benefits to early repair (<72 h postcannulation) of infants with congenital diaphragmatic hernia (CDH) on extracorporeal membrane oxygenation (ECMO) are increasingly recognized. Yet it is not known if even earlier repair (<24 h) results in comparable or improved patient outcomes. The goal of this study was to compare "super-early" (<24 h) to early repair (24-72 h) of CDH patients on ECMO. METHODS: A retrospective review of infants with CDH placed on ECMO (2004-2017; n = 72) was performed. Data collected on the patients repaired while on ECMO within 72 h of cannulation (n = 33) included pre- and postnatal disease severity stratification variables and postnatal outcomes. Comparison groups were those patients repaired within 24 h of cannulation (n = 14) and those repaired between 24 and 72 h postcannulation (n = 19). RESULTS: Patients undergoing "super-early" (<24 h) repair had an average survival of 71.4% compared to the average survival of 59.7% in the early repair group. Pre- and postnatal variables predicting disease severity were not significantly different between the groups. Mean hospital stays, ventilator days, and cannulation days were statistically similar between the groups. CONCLUSIONS: Repair of patients with CDH patients on ECMO at less than 24 h postcannulation achieves outcomes that are comparable to those of repair between 24 and 72 h. While the present data suggest that there is not a "too early" time point for CDH repair on ECMO, larger multicenter studies are needed to validate our findings and determine the overall benefits. TYPE OF STUDY: Retrospective comparative study. LEVEL OF EVIDENCE: Level III.

Sex-specific differences in primary neonatal murine lung fibroblasts exposed to hyperoxia in vitro: implications for bronchopulmonary dysplasia.

Bronchopulmonary dysplasia (BPD) is a chronic lung disease of the neonate characterized by impaired alveolarization and vascular growth. BPD is more common in premature male infants, but the reasons underlying sexually dimorphic outcomes are not known. It is thought that alterations in fibroblast phenotype in response to environmental stress such as hyperoxia contribute to BPD. Notch signaling creates a profibrotic environment in the lung. However, the role of hyperoxia on differential Notch pathway activation in male vs. female neonatal lung fibroblasts is not known. Primary murine lung fibroblasts from 10-day-old male and female mice were exposed to room air (21% O2, 5% CO2) or hyperoxia (95% O2, 5% CO2), and changes in cell proliferation, viability and expression of fibrosis-related genes and Notch pathway mediators were measured. Upon exposure to hyperoxia, cell proliferation was arrested in male and female fibroblasts, but cell viability was preserved. Increased Notch pathway activation was noted in male fibroblasts along with differential sex-specific modulation of key Notch pathway mediators in response to hyperoxia. α-Smooth muscle actin expression was increased in both male and female fibroblasts upon exposure to hyperoxia. Male and female fibroblasts further demonstrated distinct changes in expression of key fibrosis-related genes upon exposure to hyperoxia. Differential Notch pathway activation and distinct differences in the expression of key fibrosis-related genes might contribute to the sex-specific differences seen in hyperoxia-induced fibrosis and inhibition of lung development in BPD, with more severe implications in male neonates.