Factors associated with pediatric drowning admissions and outcomes at a trauma center, 2010-2017.

BACKGROUND: Drowning is a leading cause of preventable mortality and morbidity in children. Its high fatality rate and frequent severe sequelae (e.g. brain damage and permanent loss of functioning) place a premium on preventive efforts. METHODS: A retrospective analysis of patients ≤21 years of age admitted between 2010 and 2017 to a pediatric trauma center was conducted to identify factors associated with drowning admissions, fatal drowning, and severe outcome (ventilator use, ICU admission, or death). Outcomes were modeled and estimated by use of logistic regression and Poisson regression. RESULTS: Drowning accounted for 153/4931 (3.1%) trauma admissions between 2010 and 2017. The risk of death (13.1% vs. 1.5%, p < .01), and severe outcome (24.8% vs. 7.8%, p < .01) was significantly higher for drownings vs. other causes. All 20 drowning deaths occurred among children left unattended. In Poisson regression analysis, weekends, summer breaks, and hotter days were independently associated with a higher probability of drowning admissions. Additionally, in analyses excluding indicators of severity, the odds of severe outcome were higher for children age ≤ 2 years [adjusted odds ratio (AOR) = 3.88 95% CI (1.58, 9.53)], and injury downtime of >5 min or unknown length [AOR = 6.66 95% CI (2.74-16.15)]. Immediate intervention after the discovery was associated with ~70% lower odds of a severe outcome. CONCLUSIONS: Drowning admissions were both more severe and more often fatal compared to other pediatric injury causes of admission. Enhanced and targeted educational messages for parents of young children, focused on prevention behaviors on high-risk days and immediate bystander intervention, may reduce the occurrence and severity of these tragic accidents. TABLE OF CONTENTS SUMMARY: A retrospective multi-year cohort study to identify modifiable factors associated with drowning admissions, severe complications, and death from a large trauma registry database. WHAT'S KNOWN ON THIS SUBJECT: Drowning is a leading cause of unintentional injury that results in severe morbidity and a high rate of mortality. Children are disproportionately affected by drowning and have a higher risk of long term sequelae and death. WHAT THIS STUDY ADDS: This study identified high-risk populations and periods for drowning, the importance of supervision, and the effectiveness of immediate intervention in reducing unfavorable outcomes after drowning. It also highlights a need for heightened local intervention for drowning prevention.

Extracellular DNA promotes colorectal tumor cell survival after cytotoxic chemotherapy.

BACKGROUND: Inflammation promotes the growth and survival of malignant cells. Inflammation within the tumor microenvironment is a result of damage-associated molecular patterns released by dead or dying cells that provide survival signals to the surrounding cells. It has been proposed that extracellular DNA can act as a damage-associated molecular pattern given the association between circulating DNA and autoimmune diseases. Herein, we demonstrate a novel role for genomic extracellular DNA binding to the Toll-like receptor (TLR)-9 on tumor cells in response to cytotoxic insult. MATERIALS AND METHODS: The colorectal tumor cell line HCCT116 was used to study the role of DNA in tumor cell response to chemotherapy. Cell viability was assessed using CCK-8 assay. Cell death mechanisms were assessed by YOYO-1 and lactate dehydrogenase staining for necrosis and TUNEL staining for apoptosis. Autophagy was measured by LC3 punctate formation. TLR9-short hairpin RNA was used to knockdown TLR-9 and determine its role in tumor cell response to DNA. RESULTS: DNA is released from necrotic tumor cells after chemotherapy. Survival after cytotoxic insult is enhanced by the presence of extracellular DNA as a result of inhibition of apoptosis and enhanced autophagy. Knockdown of TLR-9 enhanced apoptosis, diminished autophagy, and decreased survival after cytotoxic insult in the presence or absence of extracellular DNA. CONCLUSIONS: DNA in the tumor microenvironment promotes survival through induction of autophagy via TLR-9 signaling. This work has important implications for targeting extracellular DNA, TLR-9, and autophagy during treatment with chemotherapy and enhances our understanding of the role of extracellular DNA in the tumor microenvironment.

The receptor for advanced glycation end products promotes pancreatic carcinogenesis and accumulation of myeloid-derived suppressor cells.

Pancreatic ductal adenocarcinoma (PDA) has an aggressive natural history and is resistant to therapy. The receptor for advanced glycation end products (RAGE) is a pattern recognition receptor for many damage-associated molecular pattern molecules. RAGE is overexpressed in both human and murine models of PDA as well as most advanced epithelial neoplasms. The immunosuppressive nature of the PDA microenvironment is facilitated, in part, by the accumulation of regulatory immune cell infiltrates such as myeloid-derived suppressor cells (MDSCs). To study the role of RAGE expression in the setting of mutant Ras-promoted pancreatic carcinogenesis (KC), a triple-transgenic model of spontaneous murine PDA in a RAGE-null background (KCR) was generated. KCR mice had markedly delayed pancreatic carcinogenesis and a significant diminution of MDSCs compared with KC mice at comparable time points postweaning. Although RAGE was not required for the development or suppressor activity of MDSCs, its absence was associated with temporally limited pancreatic neoplasia and altered phenotype and function of the myeloid cells. In lieu of MDSCs, KCR animals at comparable time points exhibited mature CD11b(+)Gr1(-)F4/80(+) cells that were not immunosuppressive in vitro. KCR mice also maintained a significantly less suppressive milieu evidenced by marked decreases in CCL22 in relation to CXCL10 and diminished serum levels of IL-6.

The expression of the receptor for advanced glycation endproducts (RAGE) is permissive for early pancreatic neoplasia.

Pancreatic cancer is an almost uniformly lethal disease, characterized by late diagnosis, early metastasis, resistance to chemotherapy, and early mutation of the Kras oncogene. Here we show that the receptor for advanced glycation endproducts (RAGE) is required for the activation of interleukin 6 (IL-6)-mediated mitochondrial signal transducers and activators of transcription 3 (STAT3) signaling in pancreatic carcinogenesis. RAGE expression correlates with elevated levels of autophagy in pancreatic cancer in vivo and in vitro, and this heightened state of autophagy is required for IL-6-induced STAT3 activation. To further explore the intersection of RAGE, autophagy, and pancreatic carcinogenesis, we created a transgenic murine model, backcrossing RAGE-null mice to a spontaneous mouse model of pancreatic cancer, Pdx1-Cre:Kras(G12D/+) (KC). Targeted ablation of Rage in KC mice delayed neoplasia development, decreased levels of autophagy, and inhibited mitochondrial STAT3 activity and subsequent ATP production. Our results suggest a critical role for RAGE expression in the earliest stages of pancreatic carcinogenesis, potentially acting as the "autophagic switch," regulating mitochondrial STAT3 signaling.

Temporal trends in patient characteristics, injury mechanisms and outcomes in pediatric trauma admissions between 2010 and 2017.

INTRODUCTION: Injuries are a leading cause of preventable morbidity and mortality in children. Mechanisms of injuries and presentations are diverse in pediatric injuries and require special attention. Dedicated pediatric trauma care centers are ideal for management of children with injuries simultaneously serving as sources of research data. The objective of the current study was to identify changes in injury mechanisms, modifiable risk factors, and outcomes independently associated with admissions at a large pediatric trauma center in Tampa, Florida. METHODS: We conducted retrospective analysis of 8-years (2010-2017) of pediatric trauma admissions to a large trauma center. Demographic factors and injury characteristics were examined for temporal trends over two year increments. Temporal changes in admissions with major trauma, admission to ICU, and length of stay were examined using logistic regression analysis, and factors associated with independent temporal trends were identified using ordinal logistic regression modeling. RESULTS: During the study period, there were 4,934 trauma admissions with a predominance of falls (45.1%) and traffic injuries (20.5%). Trends were observed with less frequent head injuries (2010-2011: 35.7% vs 2016-2017: 28.3%, p < .01) and abdominal injuries (2010-2011:10.3% vs 2016-2017: 8.2%, p = .03), and more frequent chest injuries (2010-2011: 9.0% vs 2016-2017: 11.4%, p < .01). Over the study period, evaluated in 2-year increments, higher use of private insurance (Adjusted Odds Ratio (AOR)=1.44, 95% Confidence Interval (CI) 95% CI: 1.29-1.61) and helicopter transport (AOR=1.91, 95% CI: 1.58 -2.30) was observed. Admissions for drownings (AOR=1.50, 95% CI: 1.10 -2.02) and animal bites (AOR=1.99, 95% CI: 1.46 -2.71) increased during the study period. Improvement in patient outcomes (adjusted for injury severity) were observed with shorter, ≤1 day length of stay (LOS) (AOR=1.19, 95% CI: 1.06 -1.33), reduction in complications (AOR=0.47, 95% CI: 0.33 -0.66), and more admissions without an intensive care unit (ICU) stay (AOR=1.6 95% CI = 1.36 -1.88). CONCLUSIONS: Significant reductions in LOS, ICU stay, and complications were temporally observed despite an increase in admissions with higher use of helicopter transport. These results can most likely be attributed to dedicated pediatric trauma experts and resources available at an integrated pediatric trauma center.

Early transition to oral antibiotics for treatment of perforated appendicitis in pediatric patients: Confirmation of the safety and efficacy of a growing national trend.

PURPOSE: We performed a quality improvement initiative to monitor the change in protocol from purely intravenous therapy for perforated appendicitis to oral antibiotics at discharge once patients could tolerate eating. METHODS: Standardized prospective data were gathered on all children with perforated appendicitis treated under the new oral protocol from January 1 to December 31, 2014. Retrospective data through chart review were gathered on all children treated for perforated appendicitis during 2013. We compared demographics, clinical parameters, and hospital charges. RESULTS: Comparing 115 patients in 2013 and 144 in 2014, demographics and clinical characteristics were similar. In 2014, 95% of patients were discharged on oral therapy. Compared to the intravenous group, the enteric group had statistically lower rates of repeat ultrasound imaging (49.6% vs 35.1%) and PICC placement (98.3% vs 9.1%) and similar rates of intraabdominal abscess (20.9% vs 16.0%) and antibiotic change (26.1% vs 22.2%). In 2014, 55% of patients were discharged by postoperative day 5, compared to 33% in 2013. Total antibiotic days and readmission rate were similar, while hospital charges decreased by half. CONCLUSION: Our results reaffirm that transition to oral antibiotics is safe, effective, and cost-efficient in treatment of perforated appendicitis in the child.

Single-Incision Single-Instrument Adnexal Surgery in Pediatric Patients.

Introduction. Pediatric surgeons often practice pediatric gynecology. The single-incision single-instrument (SISI) technique used for appendectomy is applicable in gynecologic surgery. Methods. We retrospectively analyzed the records of patients undergoing pelvic surgery from 2008 to 2013. SISI utilized a 12 mm transumbilical trocar and an operating endoscope. The adnexa can be detorsed intracorporeally or extracorporealized via the umbilicus for lesion removal. Results. We performed 271 ovarian or paraovarian surgeries in 258 patients. In 147 (54%), the initial approach was SISI; 75 cases (51%) were completed in patients aged from 1 day to 19.9 years and weighing 4.7 to 117 kg. Conversion to standard laparoscopy was due to contralateral oophoropexy, solid mass, inability to mobilize the adnexa, large mass, bleeding, adhesions, or better visualization. When SISI surgery was converted to Pfannenstiel, the principal reason was a solid mass. SISI surgery was significantly shorter than standard laparoscopy. There were no major complications and the overall cohort had an 11% minor complication rate. Conclusion. SISI adnexal surgery is safe, quick, inexpensive, and effective in pediatric patients. SISI was successful in over half the patients in whom it was attempted and offers a scarless result. If unsuccessful, the majority of cases can be completed with standard multiport laparoscopy.

Weight-specific health-related quality of life in adolescents with extreme obesity.

The objectives of this multisite study were to: (i) examine differences by gender and race on generic and weight- specific health-related quality of life (HRQOL) in adolescents with extreme obesity (BMI > or = 40 kg/m(2)) and (ii) explore HRQOL differences based on treatment pursued (behavioral vs. bariatric surgery). Study participants included 145 obese adolescents (mean age = 15.3 years; 68% female; 46% black; mean BMI = 50.6) referred to pediatric weight management programs. Participants completed generic (PedsQL) and weight-specific (Impact of Weight on Quality of Life-Kids (IWQOL-Kids)) HRQOL measures. Generic and weight-specific measures indicated global (e.g., all domains) HRQOL impairment and significant differences by race. Physical, emotional, and social scores of the PedsQL (Ps < 0.01) and the physical comfort and body esteem scores of the IWQOL-Kids (Ps < 0.001) were significantly higher for black compared to white adolescents with extreme obesity. Extremely obese adolescents pursuing bariatric surgery reported similar HRQOL to adolescents pursuing behavioral treatment (n = 30 matched pairs). HRQOL did not differ for extremely obese adolescents based on type of treatment sought, but race/ethnicity should be considered when characterizing these youth. Although racial differences in adolescent body image/esteem have been reported, it is unknown why black adolescents with extreme obesity would report less impact of weight on their physical functioning. Overall, these data suggest that HRQOL is not homogenous in adolescents with extreme obesity.

Health-related quality of life before and after bariatric surgery in adolescents.

BACKGROUND: Recent data reaffirm decreased health-related quality of life (HRQL) in obese adults and children. Health-related quality of life is markedly improved after bariatric surgery in adults. Little HRQL data are available in adolescents undergoing bariatric surgery. METHODS: Sixteen patients (14-20 years old) underwent gastric bypass. Thirteen patients completed a general HRQL measure (Short Form 36 [SF-36]) before surgery. Of these, 9 completed the SF-36 again at various follow-up times, as well as a measure of weight-related quality of life (Impact of Weight on Quality of Life-Lite). Three patients completed postsurgical forms only. Data were analyzed using t test and analysis of variance. Results are reported as mean +/- SD. RESULTS: Mean age and body mass index at operation were 18.5 +/- 1.7 years and 54 +/- 7.6 kg/m(2). Postoperatively, patients lost an average of 66% +/- 29% excess weight over a mean follow-up of 17 +/- 12 (range, 1-39) months. Mean preoperative SF-36 physical component score was 34.7 +/- 10 and mental component score was 40.6 +/- 13.5 (adult population mean = 50.0 +/- 10 for each). At last follow-up, mean physical component score had increased to 55.5 +/- 5, and mental component score, to 55.2 +/- 8.6 (P < .0001). Adolescent Impact of Weight on Quality of Life-Lite scores after surgery did not differ from means for normal weight adults (93% +/- 7% vs 96% +/- 7%, P = .15). CONCLUSIONS: Health-related quality of life in adolescents and young adults undergoing bariatric surgery improves dramatically in early follow-up. Long-term data are needed to definitively study this surgical therapy for obesity in adolescents.

Regulation of FAT/CD36 mRNA gene expression by long chain fatty acids in the differentiated 3T3-L1 cells.

Defects in fatty acid translocase (FAT/CD36) have been identified as a major factor in insulin resistance and defective fatty acid and glucose metabolism. Therefore, understanding of the regulation of FAT/CD36 expression and function is important for a potential therapeutic target for type II diabetes. We differentiated 3T3-L1 preadipocytes into matured adipocytes and examined the roles of insulin and long chain fatty acids on FAT/CD36 expression and function. Our results indicate that FAT/CD36 mRNA expression was not detected at preadipocyte but was significantly increased at matured adipocyte. In fully differentiated 3T3-L1 adipocytes, insulin significantly increased FAT/CD36 mRNA and protein expression in a dose dependent manner. The free fatty acid stearic acid reduced FAT/CD36 mRNA expression while the non-metabolizable free fatty acid alpha-bromopalmitate (2-BP) significantly increased FAT/CD36 mRNA and protein expression. Isoproterenol, in contrast, dose-dependently reduced FAT/CD36 mRNA expression and increased free fatty acid release. Mechanism analysis indicated that the effect of insulin and 2-BP on the FAT/CD36 mRNA gene expression may be mediated through activation of PPAR-gamma, suggesting that FAT/CD36 may have important implications in the pathophysiology of defective fatty acid metabolism.

A rat model of childhood diet-induced obesity: Roux-en-Y gastric bypass induced changes in metabolic parameters and gastric peptide ghrelin.

Childhood morbid obesity is reaching epidemic proportions. Roux-en-Y gastric bypass (RYGB) results in many metabolic alterations, including changes in glucose and lipid metabolism, and changes in levels of the gastric hormone, ghrelin. As more children are undergoing RYGB, an animal model would be beneficial to further study RYGB and its subsequent metabolic effects. DIO Sprague Dawley rats underwent RYGB, sham jejunojejunostomy (SH), or no operation (HFC) after 6 weeks of high-fat diet. Non-obese rats fed standard chow (SC) were a final control group. Animals were post-operatively fed standard chow for 7 days before sacrifice. At sacrifice, venous blood and gastric mucosa was collected for metabolic parameters and ghrelin determination. RYGB rats weighed less than SH and HFC (361 +/- 8.8 vs. 437 +/- 9.3 and 443 +/- 6.2 g, P < 0.05). Compared to HFC, RYGB animals had decreased plasma glucose (292 +/- 23 vs. 141 +/- 10 mg/dL), cholesterol (80 +/- 12 vs. 45 +/- 5 mg/dL), triglycerides (138 +/- 37 vs. 52 +/- 7 mg/dL), HDL (43 +/- 5 vs. 20 +/- 3 mg/dL), and free fatty acids (0.72 +/- 0.14 vs. 0.23 +/- 0.02 mEq/L), all P < 0.05. Plasma ghrelin increased in RYGB rats compared to SC and HFC (116.22 +/- 32.27 vs. 31.60 +/- 2.66 and 31.75 +/- 0.75 pg/mL, P < 0.05). In a rat model of RYGB, we demonstrated improved metabolic parameters and increased plasma and gastric mRNA ghrelin levels. The rat model for RYBG appears to be a reasonable model for future study of the cellular and molecular regulatory pathways of obesity and its surgical treatment.

The role of hyperglycemia in FAT/CD36 expression and function.

FAT/CD36 is a long-chain fatty acid transporter and scavenger receptor for oxidized LDL. Defects in FAT/CD36 have been linked to the hypertriglyceridemia and insulin resistance. Expression of FAT/CD36 was reported increase in type 1 diabetes; however, it remains unclear whether serum glucose or insulin plays an important role in this regulation. To elucidate the individual contribution of plasma glucose and insulin in the regulation of FAT/CD36 mRNA expression, we induced type 1 diabetes in male Sprague-Dawley rats using streptozotocin (STZ) and compared traditional insulin treatment with administration of the orally absorbed chemical agent vanadate, which reduces blood glucose levels via mechanisms that bypass insulin receptor action. STZ-exposed animals showed significant decreases in body weight (285.5 +/- 2.8 vs. 233.1 +/- 3.5 g, P < 0.001) and serum insulin levels (9.7 +/- 0.7 vs. 2.8 +/- 0.6 microU/ml, P < 0.05), accompanied by significant increases in blood glucose (71 +/- 3 vs. 433 +/- 11 mg/dl, P < 0.001), water intake (38.9 +/- 0.9 vs. 205.9 +/- 3.3 ml/day, P < 0.001) and food intake (22.0 +/- 0.4 vs. 36.9 +/- 1.0 g/day, P < 0.001). Diabetic animals demonstrated significant increases in FAT/CD36 mRNA levels in duodenum (2.2-fold), jejunum (1.8-fold), ileum (1.5-fold), adipose tissue (1.7-fold), and heart (2.5-fold) (P < 0.05). Insulin treatment reversed body weight loss and corrected hyperglycemia at diabetic rats as expected. Insulin treatment also corrected increased FAT/CD36 mRNA expression at diabetic rats. Vanadate significantly reduced serum glucose levels without increasing serum insulin or affecting body weight but reversed increased FAT/CD36 mRNA expression in diabetic rats. These data suggest that plasma glucose levels play more important role in the regulation of FAT/CD36 expression than concurrent changes in plasma insulin.

Revision Nissen fundoplication can be completed laparoscopically with a low rate of complications: a single-institution experience with 72 children.

PURPOSE: Recurrent gastroesophageal reflux is a common complication after fundoplication and is often treated with revision fundoplication. We report our experience with laparoscopic redo fundoplication. METHODS: The medical records of all patients in whom laparoscopic revision fundoplication was attempted over a 7 1/2-year period were reviewed. RESULTS: Redo laparoscopic fundoplication was attempted in 72 pediatric patients. Ten patients had undergone initial open fundoplication, and 9 additional patients had prior abdominal surgery. Fifty-one percent of patients were neurologically impaired. Laparoscopic fundoplication was completed in 89% of first-time redo operations and 68% of second revisions with average operative times of 2.2 +/- 1.0 and 2.6 +/- 0.9 hours, respectively. Herniation of the fundoplication through the hiatus was common (75%) and the fundoplication was intact in 49%. Conversions to laparotomy were because of difficulties with dissection or visualization. No patients required intraoperative transfusion. No patients required reoperation in the perioperative period. There were no perioperative deaths. Twenty-six percent of the 72 patients went on to a third operation for gastroesophageal reflux, and 4 of these had a fourth. CONCLUSION: Revision laparoscopic fundoplication is a technically challenging operation but can usually be completed and is characterized by a low rate of complications.

One-year outcomes of Roux-en-Y gastric bypass for morbidly obese adolescents: a multicenter study from the Pediatric Bariatric Study Group.

BACKGROUND/PURPOSE: Little is known about the metabolic outcomes of adolescent bariatric surgery. We report changes in weight, metabolic profile, and types of complications seen in a multicenter cohort. METHODS: One-year outcomes were included. For weight loss comparisons, a nonsurgical cohort (n = 12) was used. The primary outcome was weight change (n = 30) and secondary outcomes were metabolic variables (n = 24) and complications (n = 36). Data were analyzed using signed rank or paired t tests. RESULTS: Mean body mass index fell 37% (from 56.5 preoperatively to 35.8 kg/m2; P < .001) in surgical patients and 3% (from 47.2 to 46 kg/m2; P = NS) in nonsurgical patients. Surgical patients showed significant improvements in triglycerides (-65 mg/dL), total cholesterol (-28 mg/dL), fasting blood glucose (-12 mg/dL), and fasting insulin (-21 microM/mL]). Improvement in high-density lipoprotein cholesterol (-3.9 mg/dL) and low-density lipoprotein cholesterol (-8.8 mg/dL) was not statistically significant. Sixty-one percent of surgical patients had no complications. Of 15 patients with complications, 9 had minor complications with no long-term sequelae, 4 had at least 1 moderate complication with sequelae for at least 1 month and 2 had at least 1 severe medical complication with long-term consequences (including beriberi and death). There were no perioperative deaths or other severe surgical complications in this series. CONCLUSIONS: Postoperatively, adolescents lose significant weight and realize major metabolic improvements. The complication profile compares favorably to severely obese (body mass index >40 kg/m2) adults; however, small sample size precludes calculation of complication rates. Although there are considerable risks of bariatric surgery, early experience suggests that risks are offset by health benefits.

Molecular mechanism of the intracellular segments of the melanocortin-4 receptor for NDP-MSH signaling.

Mutations of the human melanocortin-4 receptor (hMC4R) have been previously identified to be the most common cause of monogenic human obesity. Specifically, mutations of the intracellular C terminus and the third intracellular loop of hMC4R have been reported to play an important role in human obesity. However, the molecular basis of these hMC4R intracellular segments in receptor function remains unclear. In this study, we utilized deletions and mutations of specific portions of the hMC4R to determine the molecular mechanism of both the C terminus and the third intracellular loop in receptor signaling. Our results indicate that deletions of the distal 25 (the entire C terminus), 22, 18, 17, 16, and 15 amino acids of the C terminus result in the complete loss of both [Nle(4)-d-Phe(7)]-alpha-melanocyte stimulating hormone (NDP-MSH) binding and NDP-MSH-mediated cAMP production. Deletion of the distal 14 amino acids of the C terminus significantly decreases both NDP-MSH binding affinity and potency, but deletion of the distal 13 amino acids of the C terminus does not affect NDP-MSH activity. Further analysis revealed that the proximal 12 amino acids of the C terminus are not only important for receptor signaling but also important for ligand binding. Our results also indicate that the third intracellular loop of the hMC4R is important for receptor signaling but not ligand binding. In summary, our findings suggest that the proximal region of the melanocortin-4 receptor (MC4R) C terminus is crucial not only for receptor signaling but also for ligand binding, while the third intracellular loop is important mainly for receptor signaling.