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.

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.

Wound Healing and Wound Care in Neonates: Current Therapies and Novel Options.

GENERAL PURPOSE: To provide wound care information that considers the specific physiology of neonates. TARGET AUDIENCE: This continuing education activity is intended for physicians, physician assistants, nurse practitioners, and nurses with an interest in skin and wound care. LEARNING OBJECTIVES/OUTCOMES: After participating in this educational activity, the participant will:1. Differentiate the use of hydrocolloids, hydrogels, foam dressings, and barrier creams in the neonatal population.2. Identify issues related to the use of solvents, alginates, collagen dressings, and negative-pressure wound therapy in neonates. ABSTRACT: OBJECTIVETo discuss what is known about the wound milieu in premature and full-term neonates, including the unique challenges pediatric clinicians face, the therapies that have proven effective, and the therapies contraindicated for use in neonatal wound healing to guide treatment that accounts for the specific physiological characteristics of this often overlooked population. DATA SOURCES: Data were collected on neonatal wound healing from a wide variety of sources, including PubMed, Google Scholar, journals, and textbooks. STUDY SELECTION: Selection criteria included publications focused on the differences and nuances of wound healing in neonates in comparison with all other age groups. DATA EXTRACTION: Data were extracted based on articles covering wound healing therapies with proven effectiveness in neonates. Terms for neonatal wound care were compiled, and then a comprehensive literature search was performed by the authors. DATA SYNTHESIS: Although many therapies are safe for treatment of older children and adolescents, most have not been explicitly tested for neonatal use. This article reviews therapies with proven effectiveness and/or specific concerns in the neonatal population. CONCLUSION: This review sheds light on the advantages and disadvantages of current standards of care regarding wound healing for neonates to direct researchers and clinicians toward developing treatments specifically for this delicate population.

To discuss what is known about the wound milieu in premature and full-term neonates, including the unique challenges pediatric clinicians face, the therapies that have proven effective, and the therapies contraindicated for use in neonatal wound healing to guide treatment that accounts for the specific physiological characteristics of this often overlooked population. Data were collected on neonatal wound healing from a wide variety of sources, including PubMed, Google Scholar, journals, and textbooks. Selection criteria included publications focused on the differences and nuances of wound healing in neonates in comparison with all other age groups. Data were extracted based on articles covering wound healing therapies with proven effectiveness in neonates. Terms for neonatal wound care were compiled, and then a comprehensive literature search was performed by the authors. Although many therapies are safe for treatment of older children and adolescents, most have not been explicitly tested for neonatal use. This article reviews therapies with proven effectiveness and/or specific concerns in the neonatal population. This review sheds light on the advantages and disadvantages of current standards of care regarding wound healing for neonates to direct researchers and clinicians toward developing treatments specifically for this delicate population.

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.

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.

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.

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 Role of the Anti-Inflammatory Cytokine Interleukin-10 in Tissue Fibrosis.

Significance: Fibrosis is the endpoint of chronic disease in multiple organs, including the skin, heart, lungs, intestine, liver, and kidneys. Pathologic accumulation of fibrotic tissue results in a loss of structural integrity and function, with resultant increases in morbidity and mortality. Understanding the pathways governing fibrosis and identifying therapeutic targets within those pathways is necessary to develop novel antifibrotic therapies for fibrotic disease. Recent Advances: Given the connection between inflammation and fibrogenesis, Interleukin-10 (IL-10) has been a focus of potential antifibrotic therapies because of its well-known role as an anti-inflammatory mediator. Despite the apparent dissimilarity of diseases associated with fibrotic progression, pathways involving IL-10 appear to be a conserved molecular theme. More recently, many groups have worked to develop novel delivery tools for recombinant IL-10, such as hydrogels, and cell-based therapies, such as ex vivo activated macrophages, to directly or indirectly modulate IL-10 signaling. Critical Issues: Some efforts in this area, however, have been stymied by IL-10's pleiotropic and sometimes conflicting effects. A deeper, contextual understanding of IL-10 signaling and its interaction with effector cells, particularly immune cells, will be critical to future studies in the field. Future Directions: IL-10 is clearly a gatekeeper of fibrotic/antifibrotic signaling. The development of novel therapeutics and cell-based therapies that capitalize on targets within the IL-10 signaling pathway could have far-reaching implications for patients suffering from the consequences of organ fibrosis.

High-molecular weight hyaluronan attenuates tubulointerstitial scarring in kidney injury.

Renal fibrosis features exaggerated inflammation, extracellular matrix (ECM) deposition, and peritubular capillary loss. We previously showed that IL-10 stimulates high-molecular weight hyaluronan (HMW-HA) expression by fibroblasts, and we hypothesize that HMW-HA attenuates renal fibrosis by reducing inflammation and ECM remodeling. We studied the effects of IL-10 overexpression on HA production and scarring in mouse models of unilateral ureteral obstruction (UUO) and ischemia/reperfusion (I/R) to investigate whether IL-10 antifibrotic effects are HA dependent. C57BL/6J mice were fed with the HA synthesis inhibitor, 4-methylumbelliferone (4-MU), before UUO. We observed that in vivo injury increased intratubular spaces, ECM deposition, and HA expression at day 7 and onward. IL-10 overexpression reduced renal fibrosis in both models, promoted HMW-HA synthesis and stability in UUO, and regulated cell proliferation in I/R. 4-MU inhibited IL-10-driven antifibrotic effects, indicating that HMW-HA is necessary for cytokine-mediated reduction of fibrosis. We also found that IL-10 induces in vitro HMW-HA production by renal fibroblasts via STAT3-dependent upregulation of HA synthase 2. We propose that IL-10-induced HMW-HA synthesis plays cytoprotective and antifibrotic roles in kidney injury, thereby revealing an effective strategy to attenuate renal fibrosis in obstructive and ischemic pathologies.

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.

T Lymphocytes Attenuate Dermal Scarring by Regulating Inflammation, Neovascularization, and Extracellular Matrix Remodeling.

Objective: While tissue injury and repair are known to involve adaptive immunity, the profile of lymphocytes involved and their contribution to dermal scarring remain unclear. We hypothesized that restoration of T cell deficiency attenuates dermal scarring. Approach: We assessed the temporal-spatial distribution of T lymphocytes and their subtypes during the physiological dermal wound repair process in mice. Also, we compared the scarring outcomes between wild-type (WT) and severe combined immunodeficient (SCID) mice, which are lymphocyte deficient. Complementary gain-of-function experiments were performed by adoptively transferring lymphocyte subsets to validate their contribution to tissue repair in wounded SCID mice. Results: CD4+ T lymphocytes were present within dermal wounds of WT mice beginning on day 1 and remained through day 30. Wounds of SCID mice exhibited accelerated closure, increased inflammation, limited neovascularization, and exacerbated scarring compared with WT mice. Conversely, transfer of either mixed B and T lymphocytes or CD4+ lymphocytes alone into SCID mice resulted in moderated healing with less inflammation, collagen deposition, and scarring than control SCID wounds. In contrast, transfer of other lymphocyte subsets, including helper T lymphocytes (CD3+CD4+CD25-), CD8+ T cells and B cells, or regulatory T lymphocytes (CD4+CD25+CD127low), did not reduce scar. Innovation: The finding that lymphocytes delay wound healing but reduce scar is novel and provides new insights into how dermal scarring is regulated. Conclusion: Our data support a suppressive role for CD4+ T cells against inflammation and collagen deposition, with protective effects in early-stage dermal wound healing. These data implicate adaptive immunity in the regulation of scarring phenotypes.