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A method is presented for generating free energies relating to nonlinear constitutive equations with memory from known free energies associated with hereditary linear theories. Some applications to viscoelastic solids and hereditary electrical conductors are presented. These new free energies are then used to obtain estimates for nonlinear integro-differential evolution problems describing the behavior of nonlinear plasmas with memory.

Purpose: Intraoperative chest tubes (IOCTs) can be placed during esophageal atresia/tracheoesophageal fistula (EA/TEF) repair to control pneumothoraces and detect esophageal leaks, potentially preventing the need for postoperative chest tubes (POCTs). However, data are lacking regarding IOCTs' effect. We hypothesized that IOCT placement would not reduce the risk of POCT placement and would increase hospital length of stay (LOS)., Methods: This was a single-center case-control study of type C EA/TEF patients repaired at a tertiary referral center between 2006 and 2017. Postoperative complications of patients who received IOCTs (n = 83) were compared to that of patients who did not receive IOCTs (n = 26). Patients were compared via propensity score matching. Additionally, sensitivity analyses excluding low birth weight (LBW) patients and patients undergoing delayed esophageal anastomosis were also performed., Results: There was no significant difference in rates of pneumothoraces or esophageal leaks between the IOCT and no-IOCT groups, nor were either of these complications detected earlier in the IOCT group. Rates of POCT placement and mortality also did not differ between groups. IOCT patients were associated with increased hospital LOS (28 vs 15.5 days, p < 0.001) and esophageal strictures (30% vs 8%, p = 0.04) requiring a return to the operating room (RTOR)., Conclusion: IOCTs did not improve outcomes in EA/TEF repair. IOCTs seem associated with increased LOS and ROTR for esophageal stricture, suggesting that IOCTs may not be beneficial after EA/TEF repair.

Introduction: Nonmedical opioid use is a major public health problem. There is little standardization in opioid-prescribing practices for pediatric ambulatory surgery, which can result in patients being prescribed large quantities of opioids. We have evaluated the variability in postoperative pain medication given to pediatric patients following routine ambulatory pediatric surgical procedures., Methods: Following IRB approval, pediatric patients undergoing umbilical hernia repair, inguinal hernia repair, hydrocelectomy, and orchiopexy from 2/1/2017 to 2/1/2018 at our tertiary care children's hospital were retrospectively reviewed. Data collected include operation, surgeon, resident or fellow involvement, utilization of preoperative analgesia, opioid prescription on discharge, and patient follow-up., Results: Of 329 patients identified, opioids were prescribed on discharge to 37.4% of patients (66.3% of umbilical hernia repairs, 20.6% of laparoscopic inguinal hernia repairs, and 33.3% of open inguinal hernia repairs [including hydrocelectomies and orchiopexies]). For each procedure, there was large intrasurgeon and intersurgeon variability in the number of opioid doses prescribed. Opioid prescription ranged from 0 to 33 doses for umbilical hernia repairs, 0 to 24 doses for laparoscopic inguinal repairs, and 0 to 20 doses prescribed for open inguinal repairs, hydrocelectomies, and orchiopexies. Pediatric surgical fellows were less likely to discharge a patient with an opioid prescription than surgical resident prescribers (P < 0.01). In addition, surgical residents were more likely to prescribe more than twelve doses of opioids than pediatric surgical fellows (P < 0.01). Increasing patient age was associated with an increased likelihood of opioid prescription (P < 0.01). There were two phone calls and two clinic visits for pain control issues with equal numbers for those with and without opioid prescriptions., Conclusions: There is significant variation in opioid-prescribing practices after pediatric surgical procedures; increased awareness may help minimize this variability and reduce overprescribing. Training level has an impact on the frequency and quantity of opioids prescribed., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Purpose: The diagnosis of "closing" or "closed gastroschisis" is made when bowel is incarcerated within a closed or nearly closed ring of fascia, usually with associated bowel atresia. It has been described as having a high morbidity and mortality., Methods: A retrospective review of closing gastroschisis cases (n = 53) at six children's hospitals between 2000 and 2016 was completed after IRB approval., Results: A new classification system for this disease was developed to represent the spectrum of the disease: Type A (15%): ischemic bowel that is constricted at the ring but without atresia; Type B (51%): intestinal atresia with a mass of ischemic, but viable, external bowel (owing to constriction at the ring); Type C (26%): closing ring with nonviable external bowel +/- atresia; and Type D (8%): completely closed defect with either a nubbin of exposed tissue or no external bowel. Overall, 87% of infants survived, and long-term data are provided for each type., Conclusions: This new classification system better captures the spectrum of disease and describes the expected long-term results for counseling. Unless the external bowel in a closing gastroschisis is clearly necrotic, it should be reduced and evaluated later. Survival was found to be much better than previously reported., Type of Study: Retrospective case series with no comparison group., Level of Evidence: Level IV., (Published by Elsevier Inc.)

The intestinal barrier is often disrupted in disease states, and intestinal barrier failure leads to sepsis. Ursodeoxycholic acid (UDCA) is a bile acid that may protect the intestinal barrier. We hypothesized that UDCA would protect the intestinal epithelium in injury models. To test this hypothesis, we utilized an in vitro wound-healing assay and a mouse model of intestinal barrier injury. We found that UDCA stimulates intestinal epithelial cell migration in vitro, and this migration was blocked by inhibition of cyclooxygenase 2 (COX-2), epidermal growth factor receptor (EGFR), or ERK. Furthermore, UDCA stimulated both COX-2 induction and EGFR phosphorylation. In vivo UDCA protected the intestinal barrier from LPS-induced injury as measured by FITC dextran leakage into the serum. Using 5-bromo-2'-deoxyuridine and 5-ethynyl-2'-deoxyuridine injections, we found that UDCA stimulated intestinal epithelial cell migration in these animals. These effects were blocked with either administration of Rofecoxib, a COX-2 inhibitor, or in EGFR-dominant negative Velvet mice, wherein UDCA had no effect on LPS-induced injury. Finally, we found increased COX-2 and phosphorylated ERK levels in LPS animals also treated with UDCA. Taken together, these data suggest that UDCA can stimulate intestinal epithelial cell migration and protect against acute intestinal injury via an EGFR- and COX-2-dependent mechanism. UDCA may be an effective treatment to prevent the early onset of gut-origin sepsis. NEW & NOTEWORTHY In this study, we show that the secondary bile acid ursodeoxycholic acid stimulates intestinal epithelial cell migration after cellular injury and also protects the intestinal barrier in an acute rodent injury model, neither of which has been previously reported. These effects are dependent on epidermal growth factor receptor activation and downstream cyclooxygenase 2 upregulation in the small intestine. This provides a potential treatment for acute, gut-origin sepsis as seen in diseases such as necrotizing enterocolitis.

The use of lactobacilli in prevention of necrotizing enterocolitis (NEC) is hampered by insufficient knowledge about optimal species/strains and effects on intestinal bacterial populations. We therefore sought to identify lactobacilli naturally occurring in postnatal rats and examine their ability to colonize the neonatal intestine and protect from NEC. L. murinus, L. acidophilus, and L. johnsonii were found in 42, 20, and 1 out of 51 4-day old rats, respectively. Higher proportion of L. murinus in microbiota correlated with lower NEC scores. Inoculation with each of the three species during first feeding significantly augmented intestinal populations of lactobacilli four days later, indicating successful colonization. L. murinus, but not L. acidophilus or L. johnsonii, significantly protected against NEC. Thus, lactobacilli protect rats from NEC in a species- or strain-specific manner. Our results may help rationalizing probiotic therapy in NEC., Competing Interests: The authors have declared that no competing interests exist.

Background: Intestinal failure-associated liver disease causes significant mortality in patients with short bowel syndrome. Steatosis, a major component of intestinal failure-associated liver disease has been shown to persist even after weaning from parenteral nutrition. We sought to determine whether steatosis occurs in our murine model of short bowel syndrome and whether steatosis was affected by manipulation of the intestinal microbiome., Methods: Male C57BL6 mice underwent 50% small bowel resection and orogastric gavage with vancomycin or vehicle for 10 weeks. DNA was extracted from stool samples then sequenced using 16s rRNA. Liver lipid content was analyzed. Bile acids were measured in liver and stool., Results: Compared with unoperated mice, small bowel resection resulted in significant changes in the fecal microbiome and was associated with a >25-fold increase in steatosis. Oral vancomycin profoundly altered the gut microbiome and was associated with a 15-fold reduction in hepatic lipid content after resection. There was a 17-fold reduction in fecal secondary bile acids after vancomycin treatment., Conclusion: Massive small bowel resection in mice is associated with development of steatosis and prevented by oral vancomycin. These findings implicate a critical role for gut bacteria in intestinal failure-associated liver disease pathogenesis and illuminate a novel, operative model for future investigation into this important morbidity., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: The incidence of intestinal stricture is low for most conditions requiring a primary small bowel stoma in infants. Routine performance of contrast enemas (CE) prior to stoma closure adds cost and radiation exposure. We hypothesized that routine CE prior to ostomy reversal is not necessary in all infants, and sought to identify a subset of patients who may benefit from preoperative CE., Methods: Medical records of infants under age 1 (N=161) undergoing small bowel stoma reversal at a single institution between 2003 and 2013 were retrospectively reviewed. Student's T-test was used to compare groups., Results: Contrast enemas were performed on 80% of all infants undergoing small bowel ostomy reversal during the study period. Infants with necrotizing enterocolitis (NEC) were more likely to have a CE than those with intestinal atresia (p=0.03) or those with all other diagnoses combined (p=0.03). Nine strictures were identified on CE. Of those, 8 (89%) were in patients with NEC, and only 4 were clinically significant and required operative resection. The overall relevant stricture rate was 2.5%. No patient that underwent ostomy takedown without CE had a stricture diagnosed intraoperatively or an unrecognized stricture that presented clinically after stoma takedown., Conclusions: Routine CE is not required prior to small bowel ostomy reversal in infants. We recommend judicious use of enema studies in patients with NEC and high likelihood of stricture., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: Achalasia is an uncommon disorder in children. Currently, there is no consensus regarding the optimal treatment for achalasia. We investigate the effectiveness of symptom relief in patients who underwent endoscopic treatments versus Heller myotomy (HM)., Methods: We conducted a retrospective review of all children (age 0-18 years) treated for achalasia at two pediatric hospitals from 2004 to 2014. Demographics, presenting symptoms, outcomes, and complications were analyzed., Results: Twenty-three patients (61% male) were identified with a mean age at diagnosis of 11.6 ± 5.0 years. About 47.8% of the cohort had no comorbidities. Common presenting symptoms included weight loss/failure to thrive (87.0%), emesis (69.6%), and dysphagia (69.6%). Mean time from symptom onset to diagnosis was 18 ± 18.9 months. Nine patients underwent laparoscopic HM as their primary treatment, whereas 14 received esophageal dilatation (ED) as their first-line therapy. Patients who underwent ED as their initial treatment were younger (9.92 versus 15.6 years, P = .047). Patients who underwent HM were more likely to attain symptom resolution compared to those managed with ED alone (P = .004). Of the 14 patients who underwent ED initially, 10 subsequently required HM due to persistent symptoms. None of the 4 patients who underwent ED alone achieved long-term symptom relief and, on the average, required an increased number of procedures compared to their HM counterparts (5.25 versus 2.47, P = .010). There was a trend toward increased intraoperative mucosal perforation in patients who underwent preoperative ED and botulinum injections., Conclusion: Our data suggest that HM is superior to balloon dilatation or botulinum injection in children with achalasia. We conclude that HM should be recommended for newly diagnosed children with achalasia as a first-line therapy.

We present and calibrate a dynamic model that characterizes the labor market for computer scientists. In our model, firms can recruit computer scientists from recently graduated college students, from STEM workers working in other occupations or from a pool of foreign talent. Counterfactual simulations suggest that wages for computer scientists would have been 2.8-3.8% higher, and the number of Americans employed as computers scientists would have been 7.0-13.6% higher in 2004 if firms could not hire more foreigners than they could in 1994. In contrast, total CS employment would have been 3.8-9.0% lower, and consequently output smaller.

Although necrotizing enterocolitis (NEC) is the most lethal gastrointestinal disease in the neonatal population, its pathogenesis is poorly understood. Risk factors include prematurity, bacterial colonization, and formula feeding. This review examines how mucosal injury permits opportunistic pathogens to breach the gut barrier and incite an inflammatory response that leads to sustained overproduction of mediators such as nitric oxide and its potent adduct, peroxynitrite. These mediators not only exacerbate the initial mucosal injury, but they also suppress the intestinal repair mechanisms, which further compromises the gut barrier and culminates in bacterial translocation, sepsis, and full-blown NEC.

While society debates whether and how to use public funds to support work on human embryonic stem cells (hESCs), many scientific groups and businesses debate a different question - the extent to which patents that cover such stem cells should be permitted to limit or to tax their research. The Wisconsin Alumni Research Foundation (WARF), a non-profit foundation that manages intellectual property generated by researchers at the University of Wisconsin at Madison, owns three patents that have been at the heart of the latter controversy The story of WARF's patents and the controversy they have fostered highlights not only continuing tensions between proprietary and nonproprietary approaches to developing science and technology, but also an at least partly reassuring capacity of public and private sectors to deal with those tensions in a way that can render them substantially manageable, and frequently more manageable as a technology matures. More particularly, the cumulative story of WARF's patents features three leitmotifs that suggest how an attentive and engaged public sector might commonly succeed in working with public and private sector actors to achieve workable balances between proprietary rights and more general social interests: (1) right holders' decisions to pursue less than full rights assertion or enforcement; (2) the ability of government and other public sector actors to help bring about such decisions through co-option or pressure; and (3) the frequent availability or development of technological alternatives that limit research bottlenecks.

Toll-like receptors (TLR) are pattern recognition receptors that play a pivotal role in the initiation of immune responses. Here we report that the murine mammary carcinoma 4T1 constitutively expressed genes encoding TLR2, 3, 4 and 5. Moreover, treatment of the 4T1 cell line with peptidoglycan (PGN), polyinosinic-polycytidylic acid (Poly(I:C)) or lipopolysaccharide (LPS), agonists for TLR2, 3 or 4 respectively, induced nuclear translocation of NFkappaB and secretion of CCL2, CCL5 and CXCL1 in a dose dependent manner. Although treating the tumor cells with the TLR agonists did not modulate growth or viability of the tumor cells in vitro, 4T1 exhibited a decreased growth rate in vivo following treatment with LPS that was dependent upon the presence of CD8(+) T cells. Analysis of 3 additional murine mammary carcinomas revealed that they also secreted CCL2, CCL5 and CXCL1 in response to TLR agonist treatment, and LPS treated 168 and SM1 tumors exhibited decreased growth rates in vivo, but not in vitro. These data indicated that 4 out of 4 murine mammary carcinomas secreted proinflammatory chemokines following treatment with TLR agonists, and 3 out of 4 of the mammary carcinomas responded to LPS treatment in a manner that decreased tumor growth in vivo.

Besides functioning as a chemotactic factor, CCL5 has been associated with progression of disease in women with breast cancer, immune modulation and metastasis. Here we asked whether CCL5 produced by tumor cells contributed to growth or metastasis of breast cancer. For this purpose, we used two murine mammary carcinomas, the 4T1 tumor which is metastatic and constitutively expresses CCL5, and the 168 tumor which is not metastatic and does not constitutively express CCL5. RNA interference was used to inhibit CCL5 expression from the 4T1 tumor, and a CCL5 transgene was used to express CCL5 by the 168 tumor. Six different clones of 4T1 that exhibited stable reduction in CCL5 expression, and three different clones of 168 that exhibited stable CCL5 expression were compared to the parental tumors and vector transfected controls. Significantly, in both models, tumor-derived CCL5 expression did not correlate with MHC expression, growth rate, or metastatic ability of the tumors. These results show that tumor-derived CCL5 expression alone does not make a significant contribution to breast cancer progression.

Dendritic cells are key components of successful immunological responses bridging innate and adaptive defenses. In this study we wanted to know whether ligation of toll-like receptors (TLR) expressed by dendritic cells would induce differential proinflammatory mediator expression and whether these dendritic cells would differentially impact T cell function. For this purpose bone marrow-derived dendritic cells from OTII mice were used. The dendritic cells showed detectable levels of TLR1, 2, 4, 6, 7, 8 and 9, with TLR2 and TLR4 expressed at the highest levels. To determine whether TLR ligation differentially influenced proinflammatory mediator expression the dendritic cells were stimulated with peptidoglycan (PGN) or lipopolysaccharide (LPS) for TLR2 or TLR4, respectively. Comparisons were made to dendritic cells exposed to TNF-alpha or saline as controls. Whereas, both LPS and PGN were equally effective at inducing CXCL1 and TNF-alpha expression from the dendritic cells, LPS was unique at inducing CCL2 expression, and PGN was unique at inducing IL-1beta expression. Despite these differences, LPS and PGN treated dendritic cells were equally effective at eliciting IFN-gamma expression from T cells in an antigen-specific manner. These data indicate that ligation of TLR by components of Gram+ and Gram- bacteria differentially influence dendritic cell proinflammatory mediator expression, and that differential mediator production by dendritic cells upon TLR stimulation does not impact T cell cytokine production.

The role of Abs in protection against respiratory infection with the intracellular bacterium Francisella tularensis is not clear. To investigate the ability of Abs to clear bacteria from the lungs and prevent systemic spread, immune serum was passively administered i.p. to naive mice before intranasal F. tularensis live vaccine strain infection. It was found that immune serum treatment provided 100% protection against lethal challenge while normal serum or Ig-depleted immune serum provided no protection. Protective efficacy was correlated with increased clearance of bacteria from the lung and required expression of FcgammaR on phagocytes, including macrophages and neutrophils. However, complement was not required for protection. In vitro experiments demonstrated that macrophages were more readily infected by Ab-opsonized bacteria but became highly efficient in killing upon activation by IFN-gamma. Consistent with this finding, in vivo Ab-mediated protection was found to be dependent upon IFN-gamma. SCID mice were not protected by passive Ab transfer, suggesting that T cells but not NK cells serve as the primary source for IFN-gamma. These data suggest that a critical interaction of humoral and cellular immune responses is necessary to provide sterilizing immunity against F. tularensis. Of considerable interest was the finding that serum Abs were capable of conferring protection against lethal respiratory tularemia when given 24-48 h postexposure. Thus, this study provides the first evidence for the therapeutic use of Abs in Francisella-infected individuals.

With as many as 1.8 million workers at risk for hazardous-materials exposure, OSHA and the EPA have recently published rules regulating hazmat safety operations. This article summarizes these rules, commonly referred to as HAZWOPER, and addresses their impact on EMS agencies and employees.

Heterophil function was evaluated in 16 healthy chickens and in 46 chickens with experimentally induced staphylococcal tenosynovitis. In paired blood samples, heterophils from chickens with tenosynovitis had a significant increase in adherence, chemotaxis, phagocytosis, and bacterial killing of Staphylococcus aureus compared to heterophils from healthy chickens. The percent adherence of heterophils to nylon fiber columns increased significantly from a 78.4% mean +/- 6.6% standard deviation to 87.6% +/- 3.2% after induction of staphylococcal tenosynovitis. Heterophil movement following in vitro exposure to saline or endotoxin was increased in chickens with tenosynovitis; 3 +/- 1 heterophils/0.25 mm2 to 10 +/- 6 heterophils/0.25 mm2 and 136 +/- 29 heterophils/0.25 mm2 to 340 +/- 74 heterophils/0.25 mm2, respectively. Endotoxin-activated serum was chemoattractive for heterophils from all chickens. Flow cytometry was used to define the heterophil population on light scatter histograms, evaluate individual cell phagocytosis of latex beads, and quantitate the number of beads phagocytosed per heterophil. When incubated with increased numbers of beads, only heterophils from chickens with tenosynovitis phagocytosed higher numbers of beads. At heterophil to bead ratios of 1:10, the percentage of heterophils that phagocytosed beads increased from baseline values of 37.8% +/- 9.0% to post-infection values of 67.3% +/- 7.5%. Using 1:20 heterophil to bead ratios, heterophil phagocytosis increased from 38.7% +/- 9.9% to post-infection values of 79.8% +/- 7.3%. Heterophils from all chickens were able to phagocytose and kill log phase staphylococcal bacteria. After phagocytosis, the heterophils from chickens with staphylococcal tenosynovitis rapidly decreased the number of viable bacterial colony forming-units per milliliter by approximately one log.(ABSTRACT TRUNCATED AT 250 WORDS)

Mouse macrophages infected with Trypanosoma cruzi in vitro may be activated to reduce parasite infection by interferon gamma (IFN-gamma). The addition of up to 10,000 units of IFN-gamma however, does not result in a 100% reduction of intracellular parasites. We, therefore, investigated the possibility that macrophages require an additional signal or signals to completely clear T. cruzi infection. Because the combination of IFN-gamma with lipopolysaccharide greatly enhanced macrophages ability to decrease the number of intracellular parasites, the interaction of IFN-gamma with tumor necrosis factor (TNF) was examined. TNF alone and the combination of TNF with IFN-gamma did not have a significant effect on reducing parasite numbers below that obtained with IFN-gamma alone. This was also true for lymphotoxin, a lymphokine similar to TNF in structure and function. The effect of IFN-gamma in combination with a cytokine-rich supernatant containing IL-2, IL-3, IL-4, IL-5, and IFN-gamma on macrophage clearance of the parasite was also examined. The cytokine-rich supernatant alone had no effect on reducing parasite infection of the macrophages; indeed, in some experiments the addition of the supernatant resulted in an increase in the level of parasite infection. However, 1000 units of IFN-gamma combined with the complex cytokine mixture caused a decrease in parasite infection of nearly 100% compared to that of control cultures treated with media alone. To determine which cytokine or cytokines in the supernatant were responsible for this synergistic activity, anti-cytokine antibodies were added to the supernatant prior to its addition with IFN-gamma to the cultures. Anti-IL-4 was the only antibody found to inhibit the synergism of IFN-gamma with the cytokine-rich supernatant. IL-4, however, did not significantly enhance the ability of IFN-gamma to induce macrophage clearance of the parasite, and IL-4 alone caused a slight increase in parasite infection in vitro. These results further define the role that cytokines play in T. cruzi infection of macrophages in vitro and suggest that the interaction of cytokine networks within this system is complex.