Bariatric surgery: trends in utilization, complications, conversions and revisions.

BACKGROUND: Sleeve gastrectomy (SG) increased in popularity after 2010 but recent data suggest it has concerning rates of gastroesophageal reflux and need for conversions. This study aims to evaluate recent trends in the utilization of bariatric procedures, associated complications, and conversions using an administrative claims database in the United States. METHODS: We included adults who had bariatric procedures from 2000 to 2020 with continuous enrollment for at least 6 months in the MarketScan Commercial Claims and Encounters database. Index bariatric procedures and subsequent revisions or conversions were identified using CPT codes. Baseline comorbidities and postoperative complications were identified with ICD-9-CM and ICD-10 codes. Cumulative incidences of complications were estimated at 30-days, 6-months, and 1-year and compared with stabilized inverse probability of treatment weighted Kaplan-Meier analysis. RESULTS: We identified 349,411 bariatric procedures and 5521 conversions or revisions. The sampled SG volume appeared to begin declining in 2018 while Roux-en-Y gastric bypass (RYGB) remained steady. Compared to RYGB, SG was associated with lower 1-year incidence [aHR, (95% CIs)] for 30-days readmission [0.65, (0.64-0.68)], dehydration [0.75, (0.73-0.78)], nausea or vomiting [0.70, (0.69-0.72)], dysphagia [0.55, (0.53-0.57)], and gastrointestinal hemorrhage [0.43, (0.40-0.46)]. Compared to RYGB, SG was associated with higher 1-year incidence [aHR, (95% CIs)] of esophagogastroduodenoscopy [1.13, (1.11-1.15)], heartburn [1.38, (1.28-1.49)], gastritis [4.28, (4.14-4.44)], portal vein thrombosis [3.93, (2.82-5.48)], and hernias of all types [1.36, (1.34-1.39)]. There were more conversions from SG to RYGB than re-sleeving procedures. SG had a significantly lower 1-year incidence of other non-revisional surgical interventions when compared to RYGB. CONCLUSIONS: The overall volume of bariatric procedures within the claims database appeared to be declining over the last 10 years. The decreasing proportion of SG and the increasing proportion of RYGB suggest the specific complications of SG may be driving this trend. Clearly, RYGB should remain an important tool in the bariatric surgeon's armamentarium.

Abnormal response after multiple rapid swallow provocation is not predictive of post-operative dysphagia following a tailored fundoplication approach.

INTRODUCTION: The aim was to evaluate the clinical significance of multiple rapid swallows (MRS) during high-resolution manometry (HRM) prior to fundoplication. Despite pre-operative HRM, up to 38% of patients report post-fundoplication dysphagia. Suggestion that MRS improves prediction of dysphagia after fundoplication has not been investigated when using a tailored approach. We hypothesize response to MRS is predictive of dysphagia after tailored fundoplication. METHODS: A retrospective cohort study was performed on patients undergoing HRM with MRS provocation 5/2019-7/2021 at a single institution. Patients who underwent subsequent index laparoscopic fundoplication, without peptic stricture or achalasia, were included. After performing standard 10-swallow HRM, MRS provocation was performed. Patient-reported dysphagia frequency scores were collected at initial consultation and post-operative follow-up. At least weekly symptoms were considered clinically significant. Normal MRS response was defined as adequate deglutitive inhibition and MRS contractile response. Fundoplications were tailored based on standard HRM values. RESULTS: HRM was performed in 1201 patients, 220 met inclusion criteria. Clinically significant pre-operative dysphagia was reported by 85 (38.6%). Patients undergoing partial fundoplication (n = 123, 55.9%) had lower mean distal contractile integer, distal esophageal contraction amplitude, and percent peristalsis (p < 0.005). Post-operatively, 120 (54.5%) were without dysphagia, 59 (26.8%) had improved dysphagia, 26 (11.8%) had unchanged dysphagia, and 15 (6.8%) reported new dysphagia. There was no statistical difference in early or late dysphagia outcome between tailored fundoplication groups (p = 0.69). On univariate and multivariate analysis, neither MRS response, nor standard HRM metrics were significantly associated with post-operative dysphagia. Younger age (OR 0.96, 95% CI 0.94-0.986, p = 0.042) and the presence of pre-operative dysphagia (OR 2.54, 95% CI 1.17-5.65, p = 0.015) were significant predictors of post-operative dysphagia. CONCLUSION: The risk of clinically significant dysphagia post-fundoplication is low when using a tailored approach based on standard HRM metrics. Additional data provided by MRS does not add to surgical decision-making using the investigated approach.

MOMS Plus: Single-Institution Review of Outcomes for Extended BMI Criteria for Open Fetal Repair of Myelomeningocele.

BACKGROUND: In utero repair has become an accepted therapy to decrease the rate of ventriculoperitoneal shunting and improve neurologic function in select cases of myelomeningocele. The Management of Myelomeningocele Study (MOMS) trial excluded patients with a BMI >35 due to concerns for increased maternal complications and preterm delivery, limiting the population that may benefit from this intervention. OBJECTIVES: The aim of this study was to evaluate outcomes associated with extending the maternal BMI criteria to 40 in open fetal repair of myelomeningocele. METHOD: Retrospective review of fetal closure of myelomeningocele at a quaternary referral center between 2013 and 2016 with maternal BMI ranging from 35 to 40. RESULTS: Eleven patients with a BMI >35 were identified. The average BMI was 37. The average maternal age at the time of evaluation was 27 years. The average gestational age at fetal surgery was 24 weeks. Gestational age at birth was an average of 32 weeks. There was one perinatal death immediately following the fetal intervention. The shunt rate at 1 year was 45% (5/11 patients). CONCLUSIONS: In this single-institution review of expanded BMI criteria for fetal repair of myelomeningocele, we did not observe any adverse maternal outcomes associated with maternal obesity; however, the gestational age at delivery was 2 weeks earlier compared to the MOMS trial.

Impact of Objective Echocardiographic Criteria for Timing of Congenital Diaphragmatic Hernia Repair.

OBJECTIVE: To assess the impact of specific echocardiographic criteria for timing of congenital diaphragmatic hernia repair on the incidence of acute postoperative clinical decompensation from pulmonary hypertensive crisis and/or acute respiratory decompensation, with secondary outcomes including survival to discharge, duration of ventilator support, and length of hospitalization. STUDY DESIGN: The multidisciplinary congenital diaphragmatic hernia management team instituted a protocol in 2012 requiring the specific criterion of echocardiogram-estimated pulmonary artery pressure ≤80% systemic blood pressure before repairing congenital diaphragmatic hernias. A retrospective review of 77 neonatal patients with Bochdalek hernias repaired between 2008 and 2015 were reviewed: group 1 included patients repaired before protocol implementation (n = 25) and group 2 included patients repaired after implementation (n = 52). RESULTS: The groups had similar baseline characteristics. Postoperative decompensation occurred less often in group 2 compared with group 1 (17% vs 48%, P = .01). Adjusted analysis accounting for repair type, liver herniation, and prematurity yielded similar results (15% vs 37%, P = .04). Group 2 displayed a trend toward improved survival to 30 days postoperatively, though this did not reach statistical significance (94% vs 80%, P = .06). Patient survival to discharge, duration of ventilator support, and length of hospitalization were not different between groups. CONCLUSIONS: The implementation of a protocol requiring echocardiogram-estimated pulmonary arterial pressure ≤80% of systemic pressure before congenital diaphragmatic hernia repair may reduce the incidence of acute postoperative decompensation, although there was no difference in longer-term secondary outcomes, including survival to discharge.

Mesenchymal stem cells correct impaired diabetic wound healing by decreasing ECM proteolysis.

Impaired diabetic wound healing is associated with a dermal extracellular matrix protein profile favoring proteolysis; within the healing diabetic wound, this is represented by an increase in activated matrix metalloproteinase (MMPs). Treatment of diabetic wounds with mesenchymal stem cells (MSCs) has been shown to improve wound healing; however, there has not yet been an assessment of their ability to correct dysregulation of MMPs in diabetic wounds. Furthermore, there has been no prior assessment of the role of microRNA29b (miR-29b), an inhibitory regulatory molecule that targets MMP-9 mRNA. Using in vitro models of fibroblast coculture with MSCs and in vivo murine wound healing models, we tested the hypothesis that MSCs correct dysregulation of MMPs in a microRNA-29b-dependent mechanism. In this study, we first demonstrated that collagen I and III protein content is significantly reduced in diabetic wounds, and treatment with MSCs significantly improves collagen I content in both nondiabetic and diabetic wounds. We then found that MMP-9 gene expression and protein content were significantly upregulated in diabetic wounds, indicating elevated proteolysis. Treatment with MSCs resulted in a decrease in MMP-9 gene expression and protein content level in diabetic wounds 3 and 7 days after wounding. Zymographic analysis indicated that MSC treatment also decreased the amount of activated MMP-9 present in diabetic wounds. Furthermore, miR-29b expression was inversely associated with MMP-9 gene expression; miR-29b expression was decreased in diabetic wounds and diabetic fibroblast. Following treatment of diabetic wounds with MSCs, as well as in diabetic fibroblasts cocultured with MSCs, miR-29b was significantly increased. These findings suggest a potential mechanism through which MSCs enhance diabetic wound healing by improving collagen I content in diabetic wounds through decreasing MMP-9 expression and increasing miR-29b expression.

Mechanisms of mesenchymal stem cell correction of the impaired biomechanical properties of diabetic skin: The role of miR-29a.

Diabetic skin has impaired wound healing properties following injury. We have further shown that diabetic skin has weakened biomechanical properties at baseline. We hypothesize that the biomechanical properties of diabetic skin decline during the progression of the diabetic phenotype, and that this decline is due to the dysregulation of miR-29a, resulting in decreased collagen content. We further hypothesize that treatment with mesenchymal stem cells (MSCs) may improve diabetic wound healing by correction of the dysregulated miR-29a expression. We analyzed the biomechanical properties, collagen gene expression, collagen protein production, and miR-29a levels in skin harvested from 6 to 18 week old mice during the development of the diabetic phenotype. We also examined the correction of these impairments by both MSC treatment and the inhibition of miR-29a. Diabetic skin demonstrated a progressive impairment of biomechanical properties, decreased collagen content, and increased miR-29a levels during the development of the diabetic phenotype. MSC treatment decreased miR-29a levels, increased collagen content, and corrected the impaired biomechanical properties of diabetic skin. Additionally, direct inhibition of miR-29a also increased collagen content in diabetic skin. This decline in the biomechanical properties of diabetic skin during the progression of diabetes may increase the susceptibility of diabetic skin to injury and miR-29a appears to play a key role in this process.

Pyloric stenosis--postoperative care on a nonsurgical ward.

BACKGROUND: Recent progress has been made in the care of infants with hypertrophic pyloric stenosis (HPS), including earlier operative intervention and shorter hospital length of stay (LOS), which is attributable to expedited postoperative feeding protocols developed and implemented by surgeons. We hypothesized that patients with HPS admitted to a unit that is co-managed by nonsurgeon providers postoperatively have a longer LOS than those on the surgical ward. MATERIALS AND METHODS: We reviewed the medical records of infants who underwent pyloromyotomy for HPS at a single institution from April, 2009-July, 2013. RESULTS: A total of 259 patients underwent pyloromyotomy (35 female; 13.5%), 205 (79%) were admitted to the surgical ward; 46 had a planned neonatal intensive care unit (NICU) admission (18%) and were co-managed with the neonatology team. Eight (3%) had an unplanned NICU admission and were excluded from the analysis. The groups did not differ in terms of sex, age, serum electrolytes at presentation, or time between surgeon evaluation and operative intervention. Surgical ward patients had longer preoperative symptom duration. Operative time was longer in the NICU patients. Comparing the two groups, there was no difference in postoperative apnea, hypoxic, or bradycardic episodes. NICU patients achieved ad libitum feeds later than floor patients (2.0 versus 1.4 d; P = 0001) and had a longer postoperative LOS (2.2 versus 1.6 d; P = 0.0012). CONCLUSIONS: Patients with HPS admitted to the NICU postoperatively had a longer time to full feeds and hospital LOS. The reduction in LOS between hospital wards may be improved with implementation of a hospital-wide postoperative protocol for patients with HPS.

Evaluating outcomes after correction of the breast conservation therapy deformity.

BACKGROUND: In an effort to preserve the native breast shape, most women with breast cancer are treated with breast conservation therapy (BCT). However, a breast deformity can develop after BCT and can be challenging to repair. The goal of this review was to evaluate outcomes based on the extent of the deformity and reconstructive technique. METHODS: Sixty-three patients treated for a BCT deformity between 2003 and 2012 were included. Data queried included demographics, extent of the deformity, type of reconstruction, and outcomes. A panel judged aesthetic outcomes, and patient satisfaction was determined using the validated Breast Q reconstruction questionnaire. Comparisons were made across reconstructive techniques. RESULTS: There were 22 grade I/II deformities, and 29 grade III/IV deformities. Local scar revision procedures and fat grafting were more common for grade I, and myocutaneous flaps were more common for grade IV. Bilateral reduction techniques (n = 20) and contralateral reduction only (n = 6) were most common for grade II/III defects. Augmentation was used in 9 grade III patients. Combined reconstructive techniques were required in 23% of the patients. Eighty-nine percent had a contralateral symmetry procedure. Complications occurred in 34.9%, with no significant variation across the different modes of reconstruction. There was a trend toward higher complication rates with increasing defect severity (0% for grade 1, 32% for grade 2, 39% for grade 3, and 50% for grade 4). Patients required an average of 1.3 procedures (range, 1-3), at an average follow-up of 2.5 years. Eighty percent of patients had only 1 reconstructive operation, 14% required a second operation, and 6% a third. Patient satisfaction was generally high and the mean aesthetic rating was 5 out of 7, and trended down with the extent of the deformity. Patients who underwent contralateral reduction only had the highest aesthetic scores (5.8/7). CONCLUSIONS: Reconstructive options for the correction of BCT deformities are numerous and need to be appropriately tailored for each patient in part based on the extent of the deformity. Although revisions are not uncommon, good patient satisfaction and esthetic outcomes can be achieved.

A Large Mammalian Model of Myocardial Regeneration After Myocardial Infarction in Fetal Sheep.

Objective: Ischemic heart disease accounts for over 20% of all deaths worldwide. As the global population faces a rising burden of chronic diseases, such as hypertension, hyperlipidemia, and diabetes, the prevalence of heart failure due to ischemic heart disease is estimated to increase. We sought to develop a model that may more accurately identify therapeutic targets to mitigate the development of heart failure following myocardial infarction (MI). Approach: Having utilized fetal large mammalian models of scarless wound healing, we proposed a fetal ovine model of myocardial regeneration after MI. Results: Use of this model has identified critical pathways in the mammalian response to MI, which are differentially activated in the regenerative, fetal mammalian response to MI when compared to the reparative, scar-forming, adult mammalian response to MI. Innovation: While the foundation of myocardial regeneration research has been built on zebrafish and rodent models, effective therapies derived from these disease models have been lacking; therefore, we sought to develop a more representative ovine model of myocardial regeneration after MI to improve the identification of therapeutic targets designed to mitigate the development of heart failure following MI. Conclusions: To develop therapies aimed at mitigating this rising burden of disease, it is critical that the animal models we utilize closely reflect the physiology and pathology we observe in human disease. We encourage use of this ovine large mammalian model to facilitate identification of therapies designed to mitigate the growing burden of heart failure.

Long Noncoding RNA GAS5 Regulates Macrophage Polarization and Diabetic Wound Healing.

A central feature of diabetic (Db) wounds is the persistence of chronic inflammation, which is partly due to the prolonged presence of proinflammatory (M1) macrophages. Using in vivo and in vitro analyses, we have tested the hypothesis that long noncoding RNA GAS5 is dysregulated in Db wounds. We have assessed the contribution of GAS5 to the M1 macrophage phenotype, as well as the functional consequences of knocking down its expression. We found that expression of GAS5 is increased significantly in Db wounds and in cells isolated from Db wounds. Hyperglycemia induced GAS5 expression in macrophages in vitro. Overexpression of GAS5 in vitro promoted macrophage polarization toward an M1 phenotype by upregulating signal transducer and activator of transcription 1. Of most significance in our judgment, GAS5 loss-of-function enhanced Db wound healing. These data indicate that the relative level of long noncoding RNA GAS5 in wounds plays a key role in the wound healing response. Reductions in the levels of GAS5 in wounds appeared to enhance healing by promoting transition of M1 macrophages to M2 macrophages. Thus, our results suggest that targeting long noncoding RNA GAS5 may provide a therapeutic intervention for correcting impaired Db wound healing.

Mesenchymal stromal cells contract collagen more efficiently than dermal fibroblasts: Implications for cytotherapy.

BACKGROUND: Stem cell therapy is the next generation a well-established technique. Cell therapy with mesenchymal stem cells (MSC) has been demonstrated to enhance wound healing in diabetic mice, at least partly due to improved growth factor production. However, it is unclear whether MSC can biomechanically affect wound closure. Utilizing the well-established cell-populated collagen gel contraction model we investigated the interactions between MSC and the extracellular matrix. METHODS: Murine fetal liver-derived Mesenchymal Stem Cells (MSCs) or fetal Dermal Fibroblasts (DFs) were cultured in cell-populated collagen gels (CPCGs). The effect of cell density, conditioned media, growth factors (TGF-B1, FGF, PDGF-BB), cytoskeletal disruptors (colchicine, cytochalasin-D), and relative hypoxia on gel contraction were evaluated. Finally, we also measured the expression of integrin receptors and some growth factors by MSCs within the contracting gels. RESULTS: Our results show that at different densities, MSCs induced a higher gel contraction compared to DFs. Higher cell density resulted in faster and more complete contraction of CPCGs. Cytoskeletal inhibitors either inhibited or prevented MSC-mediated contraction in a dose dependent fashion. Growth factors, conditioned media from both MSC and DF, and hypoxia all influenced CPCG contraction. DISCUSSION: The results suggest that MSCs are capable of directly contributing to wound closure through matrix contraction, and they are more effective than DF. In addition, this study demonstrates the importance of how other factors such as cell concentration, cytokines, and oxygen tension can provide potential modulation of therapies to correct wound healing impairments.

Differential Expression of Transforming Growth Factor-ß1 Is Associated With Fetal Regeneration After Myocardial Infarction.

BACKGROUND: Global extracellular matrix (ECM)-related gene expression is decreased after myocardial infarction (MI) in fetal sheep when compared with adult sheep. Transforming growth factor (TGF)-ß1 is a key regulator of ECM; therefore we hypothesize that TGF-ß1 is differentially expressed in adult and fetal infarcts after MI. METHODS: Adult and fetal sheep underwent MI via ligation of the left anterior descending coronary artery. Expression of TGF-ß1 and ECM-related genes was evaluated by ovine-specific microarray and quantitative polymerase chain reaction. Fibroblasts from the left ventricle of adult and fetal hearts were treated with TGF-ß1 or a TGF-ß1 receptor inhibitor (LY36497) to evaluate the effect of TGF-ß1 on ECM-related genes. RESULTS: Col1a1, col3a1, and MMP9 expression were increased in adult infarcts 3 and 30 days after MI but were upregulated in fetal infarcts only 3 days after MI. Three days after MI elastin expression was increased in adult infarcts. Despite upregulation in adult infarcts both 3 and 30 days after MI, TGF-ß1 was not upregulated in fetal infarcts at any time point. Inhibition of the TGF-ß1 receptor in adult cardiac fibroblasts decreased expression of col1a1, col3a1, MMP9, elastin, and TIMP1, whereas treatment of fetal cardiac fibroblasts with TGF-ß1 increased expression of these genes. CONCLUSIONS: TGF-ß1 is increased in adult infarcts compared with regenerative, fetal infarcts after MI. Although treatment of fetal cardiac fibroblasts with TGF-ß1 conveys an adult phenotype, inhibition of TGF-ß1 conveys a fetal phenotype to adult cardiac fibroblasts. Decreasing TGF-ß1 after MI may facilitate myocardial regeneration by "fetalizing" the otherwise fibrotic, adult response to MI.

Use of Cerium Oxide Nanoparticles Conjugated with MicroRNA-146a to Correct the Diabetic Wound Healing Impairment.

BACKGROUND: Diabetic wounds have become one of the most challenging public health issues of the 21st century, yet there is no effective treatment available. We have previously shown that the diabetic wound healing impairment is associated with increased inflammation and decreased expression of the regulatory microRNA miR-146a. We have conjugated miR-146a to cerium oxide nanoparticles (CNP-miR146a) to target reactive oxygen species (ROS) and inflammation. This study aimed to evaluate the consequences of CNP-miR146a treatment of diabetic wounds. STUDY DESIGN: Eight-millimeter wounds were created on the dorsal skin of Db/Db mice and treated with PBS or differing concentrations of CNP-mir146a (1; 10; 100; or 1,000 ng) at the time of wounding. Rate of wound closure was measured until the wounds were fully healed. At 4 weeks post-healing, a dumbbell-shaped skin sample was collected, with the healed wound in the center, and an Instron 5942 testing unit was used to measure the maximum load and modulus. RESULTS: Our data showed that diabetic wounds treated with PBS or 1 ng CNP-miR146a took 18 days to heal. Treatment with 10, 100, or 1,000 ng of CNP+miR-146a effectively enhanced healing, and wounds were fully closed at day 14 post-wounding. The healed skin from the CNP-miR146a-treated group showed a trend of improved biomechanical properties (increased maximum load and modulus), however it did not reach significance. CONCLUSIONS: We found that a 100-ng dose of CNP-miR146a improved diabetic wound healing and did not impair the biomechanical properties of the skin post-healing. This nanotechnology-based therapy is promising, and future studies are warranted to transfer this therapy to clinical application.

Improved Mortality Associated With the Use of Extracorporeal Membrane Oxygenation.

BACKGROUND: Our objective was to evaluate the association of bridge to transplant (BTT) extracorporeal membrane oxygenation (ECMO) on survival after lung transplantation (LTx) and determine the degree to which transplant center volume affects this relationship. METHODS: Using the United Network for Organ Sharing database, we performed a retrospective cohort study evaluating the survival of patients undergoing LTx between 2005 and 2017. On the basis of previous literature, LTx centers were classified into 3 groups using their average annual LTx volume over the preceding 5 years: less than 25, 25 to 49, and more than 50. Survival of BTT ECMO and non-ECMO patients was analyzed using a log-rank test. Propensity scores for BTT ECMO were calculated, and a weighted proportional hazards model was used to compare BTT ECMO and non-ECMO patients by center volume. RESULTS: There were 20,976 patients who met inclusion criteria, with 611 (2.9%) undergoing BTT ECMO. Overall, BTT ECMO was associated with increased posttransplantation hazard of mortality (hazard ratio, 1.37; 95% confidence interval, 1.14 to 1.64). Kaplan-Meier plots by center volume suggest that BTT ECMO-associated mortality may be mitigated at high-volume LTx centers. In the propensity score-weighted proportional hazards model, we determined that when centers perform more than 35 LTxs per year, the increased hazard of BTT ECMO on mortality is no longer observed. CONCLUSIONS: BTT ECMO can be performed as a bridge to LTx without significantly increasing patient mortality in high-volume centers. Patients undergoing BTT ECMO at LTx centers that perform more than 35 LTxs annually have equivalent mortality to those who do not require ECMO before transplantation.

Pediatric appendicitis: Is referral to a regional pediatric center necessary?

BACKGROUND: Acute appendicitis is the most common emergent surgical procedure performed among children in the United States, with an incidence exceeding 80,000 cases per year. Appendectomies are often performed by both pediatric surgeons and adult general/trauma and acute care (TACS) surgeons. We hypothesized that children undergoing appendectomy for acute appendicitis have equivalent outcomes whether a pediatric surgeon or a TACS surgeon performs the operation. METHODS: A retrospective chart review was performed for patients 6 to 18 years of age, who underwent appendectomy at either a regional children's hospital (Children's Hospital of Colorado [CHCO], n = 241) or an urban safety-net hospital (n = 347) between July 2010 and June 2015. The population of patients operated on at the urban safety-net hospital was further subdivided into those operated on by pediatric surgeons (Denver Health Medical Center [DHMC] pediatric surgeons, n = 68) and those operated on by adult TACS surgeons (DHMC TACS, n = 279). Baseline characteristics and operative outcomes were compared between these patient populations utilizing one-way analysis of variance and χ test for independence. RESULTS: When comparing the CHCO and DHMC TACS groups, there were no differences in the proportion of patients with perforated appendicitis, operative time, rate of operative complications, rate of postoperative infectious complications, or rate of 30-day readmission. Length of stay was significantly shorter for the DHMC TACS group than that for the CHCO group. CONCLUSIONS: Our data demonstrate that among children older than 5 years undergoing appendectomy, length of stay, risk of infectious complications, and risk of readmission do not differ regardless of whether they are operated on by pediatric surgeons or adult TACS surgeons, suggesting resources currently consumed by transferring children to hospitals with access to pediatric surgeons could be allocated elsewhere. LEVEL OF EVIDENCE: Therapeutic/Care management, level III.

Long non-coding RNA Lethe regulates hyperglycemia-induced reactive oxygen species production in macrophages.

Type 2 diabetes mellitus is a complex, systemic metabolic disease characterized by insulin resistance and resulting hyperglycemia, which is associated with impaired wound healing. The clinical complications associated with hyperglycemia are attributed, in part, to the increased production of reactive oxygen species (ROS). Recent studies revealed that long non-coding RNAs (lncRNAs) play important regulatory roles in many biological processes. Specifically, lncRNA Lethe has been described as exhibiting an anti-inflammatory effect by binding to the p65 subunit of NFκB and blocking its binding to DNA and the subsequent activation of downstream genes. We therefore hypothesize that dysregulation of Lethe's expression plays a role in hyperglycemia-induced ROS production. To test our hypothesis, we treated RAW264.7 macrophages with low glucose (5 mM) or high glucose (25 mM) for 24h. High glucose conditions significantly induced ROS production and NOX2 gene expression in RAW cells, while significantly decreasing Lethe gene expression. Overexpression of Lethe in RAW cells eliminated the increased ROS production induced by high glucose conditions, while also attenuating the upregulation of NOX2 expression. Similar results was found also in non-diabetic and diabetic primary macrophage, bone marrow derived macrophage (BMM). Furthermore, overexpression of Lethe in RAW cells treated with high glucose significantly reduced the translocation of p65-NFkB to the nucleus, which resulted in decreased NOX2 expression and ROS production. Interestingly, these findings are consistent with the decreased Lethe gene expression and increased NOX2 gene expression observed in a mouse model of diabetic wound healing. These findings provide the first evidence that lncRNA Lethe is involved in the regulation of ROS production in macrophages through modulation of NOX2 gene expression via NFκB signaling. Moreover, this is the first report to describe a role of lncRNAs, in particular Lethe, in impaired diabetic wound healing. Further studies are warranted to determine if correction of Lethe expression in diabetic wounds could improve healing.

Cardiac Progenitor Cell Recruitment Drives Fetal Cardiac Regeneration by Enhanced Angiogenesis.

BACKGROUND: In contrast to adults, the fetal response to myocardial infarction (MI) is regenerative, requiring the recruitment of cardiac progenitor cells to replace infarcted myocardium. Macrophage contribution to tissue repair depends on their phenotype: M1 are proinflammatory and initiate angiogenesis; M2a are profibrotic and contribute to blood vessels maturation; and M2c are proremodeling and proangiogenesis. The goal of the present study was to expand on this work by examining cardiac progenitor cells recruitment, and the role of macrophages in promoting angiogenesis and cardiac regeneration in the fetal heart after MI. METHODS: Fetal and adult sheep underwent MI and were sacrificed 3 or 30 days after MI. Some fetal hearts received stromal cell-derived factor-1α-inhibitor treatment. The microvasculature was evaluated by micro-computed tomography, gene expression was evaluated by real-time polymerase chain reaction, and vessels counts were evaluated by immunohistochemistry. RESULTS: Micro-computed tomography analysis showed restoration of microvasculature in fetal hearts after MI. Vascular endothelial growth factor-α increased, and the expression of tissue markers associated with the M1, M2a, and M2c macrophage phenotypes were elevated at day 3 after MI, but returned to baseline by 30 days after MI. In contrast, adult hearts after MI exhibited low vascular endothelial growth factor-α and persistent upregulation of all macrophage markers, consistent with prolonged inflammation, fibrosis, and remodeling. Inhibition of stromal cell-derived factor-1α in fetal infarcts prevented angiogenesis, decreased vascular endothelial growth factor-α, and was associated with a sustained increase in M1, M2a, and M2c markers after MI. CONCLUSIONS: Changes in angiogenesis and macrophage phenotype-related gene expression after MI are important for the fetal regenerative response to MI and are mediated at least in part by cardiac progenitor cells recruitment.

Association of sentinel lymph node diameter with melanoma metastasis.

BACKGROUND: Lymph nodes are an important part of the immune system and the size of the lymph node reflects local immunologic activity. The purpose of this study was to examine the association between sentinel lymph node (SLN) size and the presence of nodal metastasis in patients with melanoma. METHODS: Retrospective review of a prospectively maintained database of patients undergoing SLN biopsy for cutaneous melanoma between February 1995 and January 2013. The maximum pathologic diameter and the volume of the largest node was used. A nodal diameter of 1.5 cm, included in 2 interquartile ranges of both positive and negative SLNs, was used as the cutoff for multivariate regression. RESULTS: Of 1,017 SLN biopsies, 826 (81%) had complete size measurements and were included in the analysis. Patients with a positive SLN were younger (median 50 vs 53 years, P = .032), had deeper primary lesions (2 vs 1.4 mm, P < .001), and had larger SLN volume (.8 vs .6 cc, P = .009) or maximum diameter (1.9 vs. 1.6 cm, P = .03). Sex, pathologic ulceration, mitosis, and the type or location of the primary was not statistically different. On multivariate analysis; age, depth of primary, and both SLN volume and maximum diameter remained significant. An SLN greater than 1.5 cm in maximum diameter has a 60% increased odds ratio of being positive after adjusting for age, sex, and depth of primary lesion (P = .046). CONCLUSIONS: Larger SLN maximum diameter is associated with nodal positivity independent of age, sex, depth of primary lesion, and location of SLN biopsy. The etiology and significance of larger SLNs warrant further analysis.

Analysis of melanoma recurrence following a negative sentinel lymph node biopsy.

Little attention has been paid to the characteristics and outcomes of patients who experience distant, local or regional recurrence of melanoma following a negative sentinel lymph node biopsy. This article aims to review the published literature on the topic and presents some general summaries regarding this patient population. Patients who experience a disease recurrence following a negative sentinel lymph node biopsy have a worse overall survival compared with patients with a positive sentinel lymph node biopsy. The implications and possible explanations for these findings are discussed in order to both underscore the need for in-depth investigation of local, regional or distant melanoma recurrence among patients following a true negative sentinel lymph node biopsy, as well as increased efforts to minimize the rate of false negative sentinel lymph node biopsies.

Delays reducing waterborne and water-related infectious diseases in China under climate change.

Despite China's rapid progress improving water, sanitation and hygiene (WSH) access, in 2011, 471 million people lacked access to improved sanitation and 401 million to household piped water. Because certain infectious diseases are sensitive to changes in both climate and WSH conditions, we projected impacts of climate change on WSH-attributable diseases in China in 2020 and 2030 by coupling estimates of the temperature sensitivity of diarrheal diseases and three vector-borne diseases, temperature projections from global climate models, WSH-infrastructure development scenarios, and projected demographic changes. By 2030, climate change is projected to delay China's rapid progress toward reducing WSH-attributable infectious disease burden by 8-85 months. This development delay summarizes the adverse impact of climate change on WSH-attributable infectious diseases in China, and can be used in other settings where a significant health burden may accompany future changes in climate even as the total burden of disease falls due to non-climate reasons.