Pleural CD14+ monocytes/macrophages of healthy adolescents show a high expression of metallothionein family genes.

Nowadays laparoscopic interventions enable the collection of resident macrophage populations out of the human cavities. We employed this technique to isolate pleural monocytes/macrophages from healthy young adults who underwent a correction of pectus excavatum. High quality CD14+ monocytes/macrophages (plMo/Mφ) were used for RNA-sequencing (RNA-seq) in comparison with human monocyte-derived macrophages (MDM) natural (MDM-0) or IL-4-polarized (MDM-IL4). Transcriptome analysis revealed 7166 and 7076 differentially expressed genes (DEGs) in plMo/Mφ relative to natural MDM-0 and polarized MDM-IL4, respectively. The gene set enrichment analysis, which was used to compare RNA-seq data from plMo/Mφ with single-cell (scRNA-seq) data online from human bronchial lavage macrophages, showed that plMo/Mφs are characterized by a high expression of genes belonging to the metallothionein (MT) family, and that the expression of these genes is significantly higher in plMo/Mφ than in MDM-0 or MDM-IL4. Our results provide additional insights on high MTs-expressing macrophage subsets, which seem to be present not only in bronchial lavage of healthy adults or in pleural exudates of lung cancer patients but also in pleural fluid of healthy young adults. Macrophage subsets expressing high MTs may have specific roles in lung defense, repair, and homeostasis, and require further investigations.

Implementation and validation of a novel instrument for the grading of unexpected events in paediatric surgery: Clavien-Madadi classification.

BACKGROUND: Inconsistent definitions of complications and unexpected events have limited accurate analysis of surgical outcomes. Perioperative outcome classifications currently used for adult patients have limitations when used for children. METHODS: A multidisciplinary group of experts modified the Clavien-Dindo classification to increase its utility and accuracy in paediatric surgery cohorts. Organizational and management errors were considered in the novel Clavien-Madadi classification, which focuses on procedural invasiveness rather than anaesthetic management. Unexpected events were prospectively documented in a paediatric surgery cohort. Results of the Clavien-Dindo and Clavien-Madadi classifications were compared and correlated with procedure complexity. RESULTS: Unexpected events were prospectively documented in a cohort of 17 502 children undergoing surgery between 2017 and 2021. The results of both classifications were highly correlated (ρ = 0.95), although the novel Clavien-Madadi classification identified 449 additional events (organizational and management errors) over the Clavien-Dindo classification, increasing the total number of events by 38 per cent (1605 versus 1158 events). The results of the novel system correlated significantly with the complexity of procedures in children (ρ = 0.756). Furthermore, grading of events > grade III according to the Clavien-Madadi classification showed a higher correlation with procedure complexity (ρ = 0.658) than the Clavien-Dindo classification (ρ = 0.198). CONCLUSION: The Clavien-Madadi classification is a tool for the detection of surgical and non-medical errors in paediatric surgery populations. Further validation in paediatric surgery populations is required before widespread use.

Synthetic retinoid AM80 inhibits IL-17 production of gamma delta T cells and ameliorates biliary atresia in mice.

BACKGROUND & AIMS: Recent evidence suggests that Interleukin (IL)-17-producing gamma delta ( γδ ) T cells are the dominant pathogenic cellular component in designated autoimmune or inflammatory diseases, including biliary atresia (BA). We have previously demonstrated that retinoids effectively suppress T-helper cell (Th) 17 differentiation. METHODS: Here, we established an in vitro system, enabling investigations of the effect of AM80 on the IL-17 production of γδ T cells. Additionally, we tested the therapeutic effect of AM80 in the Rotavirus-induced mouse model of BA. Co-incubation of γδ T cells with IL-23 and anti-CD28 mAb proved most effective in inducing an IL-17 response in vitro. The effect of AM80 on human CCR6+CD26+ V δ 2 cells was assessed by flow cytometry. RESULTS: AM80 efficiently reduced IL-17 production by murine γδ T cells and the expression of the master transcription factor Retinoid-Orphan-Receptor- γ t (ROR γτ ) in a dose-dependent manner. The fraction of human CCR6+CD26+ V δ 2 cells was significantly reduced by co-incubation with AM80. Moreover, AM80 also inhibited IL-17 production by liver-infiltrating γδ T cells isolated from animals suffering from BA. Intraperitoneal treatment with AM80 ameliorated BA-associated inflammation. However, AM80 treatment was not sufficient to control disease progression in the murine model, despite reduced inflammatory activity in the animals. CONCLUSIONS: Retinoids are very efficient in down-regulating IL-17 production by γδ T cells in vitro and, to a lesser extent, in the BA mouse model. However, retinoids do not suffice for the control of disease progression. Thus, our data suggest that IL-17 is not the only factor contributing to the pathogenesis of BA. LAY SUMMARY: Biliary atresia (BA) is a rare disease which affects infants, causing progressive liver failure in most children, and is the most common indication for paediatric liver transplantation. We have previously demonstrated that IL-17, produced by γδ T cells, contributes to hepatic inflammation in the murine model of BA and is increased in the livers of infants suffering from the disease. In the study at hand, we demonstrate that treatment with AM80, a synthetic retinoid with superior pharmacological properties, effectively inhibits the IL-17 production of gamma delta T cells without generating systemic immunosuppression. Although all-trans retinoic acid (ATRA) has been demonstrated to suppress differentiation of IL-17-producing conventional T-helper cells (Th17) in vitro, the therapeutic application of ATRA in vivo is limited by the compound's potential side effects caused by its instability and lack of receptor specificity. Our study is the first to show that AM80 suppresses the IL-17 production of γδ T cells in a very efficient manner and that hepatic inflammation is ameliorated in mice suffering from BA. However, AM80 treatment does not suffice to block the disease progression. We conclude that factors other than IL-17 drive the progressive inflammation in BA. The addition of retinoids to the treatment regime of children suffering from BA might decrease the disease burden; however, further research is needed to clarify the pathomechanism and possible therapeutic interventions in humans.

Hepatocyte growth factor levels in livers and serum at Kasai-portoenterostomy are not predictive of clinical outcome in infants with biliary atresia.

Biliary atresia (BA) is characterized by progressive destruction of the biliary system leading to liver fibrosis and deterioration of liver function. Serum hepatocyte growth factor (HGF) has been shown to be increased in cirrhotic diseases including BA. The aim of this study was to investigate the prognostic value of HGF levels in sera and liver tissue for the further disease course. A total of 49 serum and liver samples from infants with BA were acquired during Kasai-portoenterostomy (KPE) and analyzed by multiplex immunoassay including HGF, as marker of liver regeneration, and Interleukin 6 (IL-6) as a marker of inflammation. Both mediators showed no correlation with the outcome defined as favorable (survival with native liver (SNL)) or, in contrast, rapid deterioration of liver function requiring transplantation. Our data suggest that the degree of liver regeneration indicated by high levels of HGF within the liver is a dismissible factor in the post-KPE disease course.

Long-term outcome and necessity of liver transplantation in infants with biliary atresia are independent of cytokine milieu in native liver and serum.

PURPOSE: Biliary atresia (BA) is a rare disease of unknown pathogenesis in infants characterized by an inflammatory, progressive destruction of the biliary system and deterioration of liver function. The standard treatment for BA is a Kasai-hepatoportoenterostomy (KPE). However, liver transplantation (LTX) becomes necessary in about 50-80% of cases. Therefore, some authors advocate for primary LTX in BA, but this would require early markers to predict which children would benefit from KPE or to show rapid progression to liver cirrhosis (RLC) instead. METHODS: Snap-frozen liver biopsies and sera samples of 57 infants with BA were collected during KPE. Clinical and follow-up data were assessed via the biliary atresia and related diseases registry (BARD-online.com). Protein-levels of 25 pro- and anti-inflammatory mediators of 49 infants were assessed via multiplex protein-immunoassay and analyzed by t-test as well as multidimensional principal component analysis. RESULTS: 22 different immunomodulatory mediators were detectable in livers of children with BA, while serum protein levels were very low to undetectable. Following KPE, 33 BA patients showed RLC that required early LTX, while 24 had favorable course of disease with long-term survival with native liver (SNL). There were no significant differences between RLC and SNL in terms of local (from liver samples) nor systemic (from sera) immunomodulatory mediators. Protein levels were much lower in sera than in livers without statistical correlation. CONCLUSION: Our data suggest that local or systemic immunomodulatory mediators are unsuitable for predicting the disease course of BA. Thus, no deduction for optimal treatment strategy can be drawn. Collectively, we conclude that in BA, the degree of inflammation and protein microenvironment in the liver at the time-point of KPE are dismissible factors for the future course of disease.

Quality of Life in Patients With Progressive Familial Intrahepatic Cholestasis: No Difference Between Post-liver Transplantation and Post-partial External Biliary Diversion.

OBJECTIVES: In patients with progressive familial intrahepatic cholestasis (PFIC), partial external biliary diversion (PEBD), which is associated with a permanent stoma, is recommended as first-line therapy, whereas primary liver transplantation (LTx) is restricted to those with cirrhosis. Our aim was to quantify the health-related quality of life (HRQOL) in patients with PFIC and to evaluate whether there is a difference in their HRQOL depending on the surgical approach. METHODS: A prospective HRQOL study on a consecutive series of PFIC was conducted using Pediatric Quality of Life Inventory 4.0 child-self and parent-proxy reports. Patients with PFIC after PEBD who still lived with their native livers were compared to those after LTx. Both groups were compared to healthy children. RESULTS: A total of 32 patients (53% girls) patients with a mean age of 17.7 ±â€Š7.3 years were studied. Twenty-two had undergone LTx at a mean age of 7.8 ±â€Š3.8 years and 10 had undergone PEBD at a mean age of 4.1 ±â€Š3.9 years. At the time of HRQOL assessment, the mean age was 18.9 ±â€Š7.5 years in the LTx group and 15.3 ±â€Š6.5 years in the PEBD group. Child-self and parent-proxy reports showed no significant difference in HRQOL between patients with PFIC after LTx and those after PEBD except for marginal difference in physical functioning/health (P = 0.07). Except for a lower score in patient school functioning of patients after LTx (P = 0.01), HRQOL-results showed no difference from healthy children in any group. CONCLUSIONS: The HRQOL of patients with PFIC after PEBD was similar to those after LTx. The HRQOL in both groups was also similar to that of healthy children. Thus, our data support the current policy of PEBD as primary surgical treatment for patients with PFIC without cirrhosis.

Interleukin 17, Produced by γδ T Cells, Contributes to Hepatic Inflammation in a Mouse Model of Biliary Atresia and Is Increased in Livers of Patients.

BACKGROUND & AIMS: Biliary atresia (BA) is a rare disease in infants, with unknown mechanisms of pathogenesis. It is characterized by hepatobiliary inflammatory, progressive destruction of the biliary system leading to liver fibrosis, and deterioration of liver function. Interleukin (IL) 17A promotes inflammatory and autoimmune processes. We studied the role of IL17A and cells that produce this cytokine in a mouse model of BA and in hepatic biopsy samples from infants with BA. METHODS: We obtained peripheral blood and liver tissue specimens from 20 patients with BA, collected at the time of Kasai portoenterostomy, along with liver biopsies from infants without BA (controls). The tissue samples were analyzed by reverse transcription quantitative polymerase chain reaction (PCR), in situ PCR, and flow cytometry analyses. BA was induced in balb/cAnNCrl mice by rhesus rotavirus infection; uninfected mice were used as controls. Liver tissues were collected from mice and analyzed histologically and by reverse transcriptase PCR; leukocytes were isolated, stimulated, and analyzed by flow cytometry and PCR analyses. Some mice were given 3 intraperitoneal injections of a monoclonal antibody against IL17 or an isotype antibody (control). RESULTS: Livers from rhesus rota virus-infected mice with BA had 7-fold more Il17a messenger RNA than control mice (P = .02). γδ T cells were the exclusive source of IL17; no T-helper 17 cells were detected in livers of mice with BA. The increased number of IL17a-positive γδ T cells liver tissues of mice with BA was associated with increased levels of IL17A, IL17F, retinoid-orphan-receptor C, C-C chemokine receptor 6, and the IL23 receptor. Mice that were developing BA and given antibodies against IL17 had lower levels of liver inflammation and mean serum levels of bilirubin than mice receiving control antibodies (191 µmol/L vs 78 µmol/L, P = .002). Liver tissues from patients with BA had 4.6-fold higher levels of IL17 messenger RNA than control liver tissues (P = .02). CONCLUSIONS: In livers of mice with BA, γδ T cells produce IL17, which is required for inflammation and destruction of the biliary system. IL17 is up-regulated in liver tissues from patients with BA, compared with controls, and might serve as a therapeutic target.

Distinct phenotypic features of neonatal murine macrophages.

Neonates rely on their innate immune system. Resident tissue macrophages are considered to be initiators and regulators of the innate immune response and thus, appear to be especially important to neonates. We hypothesized that the phenotype and function of neonatal tissue macrophages differ from their adult counterparts. Peritoneal macrophages from neonatal (<24 h) and adult (6 weeks old) C57BL/6J mice were isolated and analyzed by high-content chipcytometry. After stimulation for 6 h with LPS (0, 1, 10, 100 ng/mL), macrophage transcriptome was analyzed by microarray and cytokine release was measured using multiparametric bead assays. Antigen presenting capacity was compared by T-cell stimulation assays. We observed that neonatal murine peritoneal macrophages are characterized by selective lack of expression of F4/80, MHC class II, and costimulatory molecules (CD80, CD86). Furthermore, we found differences in the transcriptome between neonatal and adult macrophages, unstimulated and after LPS stimulation. Although neonatal macrophages showed a significantly increased secretion of proinflammatory cytokines upon LPS stimulation, their potential to induce T-cell proliferation was significantly reduced. In conclusion, we observed a distinct phenotype of the neonatal macrophage population. The specific functions of this macrophage population could help to understand the excessive inflammatory reactions observed in the very young.

The viral dsRNA analogue poly (I:C) induces necrotizing enterocolitis in neonatal mice.

BACKGROUND: Necrotizing enterocolitis (NEC) is a life-threatening gastrointestinal disease in premature infants with high mortality and morbidity with uncertain pathogenesis. Recent research focused on the role of intraluminal bacteria and lipopolysaccharide (LPS). However, an additional role of viral agents in the pathogenesis of NEC has recently been postulated. We assessed the role of polyinosinic:polycytidylic acid (pIC) mimicking viral dsRNA in contributing to the development of NEC in neonatal mice. METHODS: Four-d-old C57BL/6J pups were stressed by asphyxia and hypothermia twice daily. Animals were either fed by formula only (FO), formula containing LPS or pIC. After 72 h, mice were euthanized, intestines harvested, and the severity of NEC was assessed. RESULTS: Breastfed mice showed no evidence of NEC. Very mild NEC-like lesions were observed in mice fed by FO. Supplementation of LPS or pIC to the formula led to increased intestinal tissue damage and inflammation compared with FO in a similar manner. CONCLUSION: Our study demonstrates the ability of viral factors to induce NEC in neonatal mice even in the absence of LPS. Furthermore, we present a new mouse model of pIC-induced NEC which may be used to obtain further mechanistic insights in the pathogenesis of this disease.

3-Dimensional (3D) laparoscopy improves operating time in small spaces without impact on hemodynamics and psychomental stress parameters of the surgeon.

BACKGROUND AND PURPOSE: Three-dimensional (3D) imaging, a recent technical innovation in laparoscopic surgery, has been postulated to enhance depth perception and facilitate operations. However, it has never been evaluated in conditions where the focus is close to the optical system. Thus, it is unclear whether 3D cameras can improve laparoscopic surgical performance in neonates and infants. We tested 3D versus two-dimensional (2D) vision during laparoscopic surgery in rabbits, mimicking the size of a neonatal patient. MATERIALS AND METHODS: Cadaver New Zealand white rabbits (mean weight 2,755 g) were operated by two surgeons experienced in 2D laparoscopic surgery and two surgical residents (with basic skills in 2D laparoscopy). All surgeons had never performed 3D laparoscopic surgery. Animals underwent six operations: Nissen fundoplication, small bowel anastomosis, and closure of a diaphragmatic defect using either 2D or 3D. Primary endpoint was cumulative operating time and operating time of each operation. Secondary endpoints included the hemodynamic response and psychomental stress level of the surgeons. Finally, subjective data on depth perception were assessed by questionnaires. RESULTS: Cumulative operating time of all three types of operations was significantly shorter with 3D laparoscopy in experts (3D: 23.01 ± 5.65 min vs 2D: 29.51 ± 7.51 min, p < 0.01) and residents (3D: 27.95 ± 3.69 min vs 2D: 33.95 ± 6.21 min, p < 0.05). This effect could be shown for each operation in the expert group and the Nissen fundoplication in the resident group. There were no differences in the hemodynamic response as well as the psychomental stress level between 2D and 3D imaging. 3D provided better depth perception. CONCLUSION: 3D laparoscopy in small spaces is associated with a significant shorter operating time. It induces no additional physical or psychomental stress in surgeons naive to 3D imaging. 3D may therefore facilitate minimal invasive surgery in neonates and infants.

Google Glass for documentation of medical findings: evaluation in forensic medicine.

BACKGROUND: Google Glass is a promising premarket device that includes an optical head-mounted display. Several proof of concept reports exist, but there is little scientific evidence regarding its use in a medical setting. OBJECTIVE: The objective of this study was to empirically determine the feasibility of deploying Glass in a forensics setting. METHODS: Glass was used in combination with a self-developed app that allowed for hands-free operation during autopsy and postmortem examinations of 4 decedents performed by 2 physicians. A digital single-lens reflex (DSLR) camera was used for image comparison. In addition, 6 forensic examiners (3 male, 3 female; age range 23-48 years, age mean 32.8 years, SD 9.6; mean work experience 6.2 years, SD 8.5) were asked to evaluate 159 images for image quality on a 5-point Likert scale, specifically color discrimination, brightness, sharpness, and their satisfaction with the acquired region of interest. Statistical evaluations were performed to determine how Glass compares with conventionally acquired digital images. RESULTS: All images received good (median 4) and very good ratings (median 5) for all 4 categories. Autopsy images taken by Glass (n=32) received significantly lower ratings than those acquired by DSLR camera (n=17) (region of interest: z=-5.154, P<.001; sharpness: z=-7.898, P<.001; color: z=-4.407, P<.001, brightness: z=-3.187, P=.001). For 110 images of postmortem examinations (Glass: n=54, DSLR camera: n=56), ratings for region of interest (z=-8.390, P<.001) and brightness (z=-540, P=.007) were significantly lower. For interrater reliability, intraclass correlation (ICC) values were good for autopsy (ICC=.723, 95% CI .667-.771, P<.001) and postmortem examination (ICC=.758, 95% CI .727-.787, P<.001). Postmortem examinations performed using Glass took 42.6 seconds longer than those done with the DSLR camera (z=-2.100, P=.04 using Wilcoxon signed rank test). The battery charge of Glass quickly decreased; an average 5.5% (SD 1.85) of its battery capacity was spent per postmortem examination (0.81% per minute or 0.79% per picture). CONCLUSIONS: Glass was efficient for acquiring images for documentation in forensic medicine, but the image quality was inferior compared to a DSLR camera. Images taken with Glass received significantly lower ratings for all 4 categories in an autopsy setting and for region of interest and brightness in postmortem examination. The effort necessary for achieving the objectives was higher when using the device compared to the DSLR camera thus extending the postmortem examination duration. Its relative high power consumption and low battery capacity is also a disadvantage. At the current stage of development, Glass may be an adequate tool for education. For deployment in clinical care, issues such as hygiene, data protection, and privacy need to be addressed and are currently limiting chances for professional use.

Validation of the Clavien-Madadi Classification for Unexpected Events in Pediatric Surgery: A Collaborative ERNICA Project.

BACKGROUND: The Clavien-Madadi classification is a novel instrument for the assessment and grading of unexpected events in pediatric surgery, based on the Clavien-Dindo classification. The system has been adjusted to better fit the pediatric population in a prospective single-center study. There is a need now to validate the Clavien-Madadi classification within an international expert network. METHODS: A pediatric surgical working group created 19 case scenarios with unexpected events in a multi-staged process. Those were circulated within the European Reference Network of Inherited and Congenital Anomalies (ERNICA) and surgeons were instructed to rate the scenarios according to the Clavien-Madadi vs. Clavien-Dindo classification. RESULTS: 59 surgeons from 12 European countries completed the questionnaire. Based on ratings of the case scenarios, the Clavien-Madadi classification showed significantly superior agreement rates of the respondents (85.9% vs 76.2%; p < 0.05) and was less frequently considered inaccurate for rating the pediatric population compared to Clavien-Dindo (2.1% vs 11.1%; p = 0.05). Fleiss' kappa analysis showed slightly higher strength of agreement using the Clavien-Madadi classification (0.74 vs 0.69). Additionally, intraclass correlation coefficient was slightly higher for the Clavien-Madadi compared to the Clavien-Dindo classification (ICCjust 0.93 vs 0.89; ICCunjust 0.93 vs 0.89). More pediatric surgeons preferred the Clavien-Madadi classification for the case scenarios (43.0% vs 11.8%; p = 0.002) and advantages of the Clavien-Madadi were confirmed by 81.4% of the surgeons. CONCLUSION: The Clavien-Madadi classification is an accurate and reliable instrument for the grading of unexpected events in pediatric surgery. We therefore recommend its application in clinical and academic pediatric surgical practice. LEVEL OF EVIDENCE: III.

Definition, Documentation, and Classification of Complications in Pediatric Surgical Literature-A Plea for Standardization.

Severity grading systems for complications in surgical patients have been used since 1992. An increasing assessment of these instruments in pediatric surgery is also noticed, without their validation in children. To analyze the current practice, we performed a literature review with focus on the assessment and grading of complications. The review was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. Studies reporting on postoperative complications as a primary or secondary endpoint using a severity grading system were included. Definition for simple adverse events, classification systems used, and the time horizon of postoperative documentation were analyzed. A total of 566 articles were screened, of which 36 met the inclusion criteria. About 86.1% of the papers were retrospective and 13.9% prospective analyses. None of the studies were prospective-randomized trials. Twenty (55.6%) studies did not include a definition of adverse events, whereas the remaining 16 (44.4%) showed variations in their definitions. All studies applied the Clavien-Dindo classification, whereas five (13.9%) additionally used the Comprehensive Complication Index. One study compared alternative grading instruments with the Clavien-Dindo classification, without demonstrating the superiority of any classification in pediatric surgery. Twenty-two studies (61.1%) did not report the time horizon of perioperative complication documentation, while 8 studies (22.2%) used 30 days and 6 studies (16.7%) used 3 months of postoperative documentation. Definition and classification of postoperative complications are inconsistent in the pediatric surgical literature. Establishment of a standardized protocol is mandatory to accurately compare outcome data.

Laparoscopic versus Open Inguinal Hernia Repair Is Feasible in Infants with Caudal Anesthesia and Spontaneous Respiration.

INTRODUCTION: Minimally invasive surgery (i.e., laparoscopy) and minimally invasive anesthesia (i.e., caudal anesthesia with spontaneous respiration) have separately shown benefits for inguinal hernia repair in infants, yet to what degree these techniques can be combined remains unknown. This study investigated whether laparoscopy impacts the feasibility of performing caudal anesthesia with spontaneous respiration in infants. METHODS: Prospectively collected data of all infants less than 12 months old and over 3 kg weight who underwent laparoscopic indirect hernia repair (LAP) at our department from 2019 to 2021 were compared with a historical control-matched group of infants who underwent open repair (OPEN) from 2017 to 2021. We assessed the patients' characteristics, anesthesia, and surgical data as well as intra- and postoperative complications. RESULTS: A total of 87 infants were included (LAP n = 29, OPEN n = 58). Caudal anesthesia with spontaneous respiration was feasible in 62.1% of cases (LAP n = 55.2%, OPEN n = 65.5%; nonsignificant). Neither group registered anesthetic intra- or postoperative complications. Sedatives were utilized in 97% of LAP patients versus 56.9% of OPEN patients (p < 0.00001). The airway was secured with a laryngeal mask in 89.7% of patients during LAP versus 41.4% during OPEN (p < 0.00001). No significant differences were found regarding the use frequency of opioids (48.3% LAP vs. 34.5% OPEN; nonsignificant) or neuromuscular blockers (6.9% LAP vs. 5.2% OPEN; nonsignificant). CONCLUSION: This is the first comparative study on caudal anesthesia and spontaneous respiration in infants undergoing laparoscopic versus open inguinal hernia surgery. Laparoscopy increased the need for ventilatory support and sedatives but did not significantly impair the feasibility of caudal anesthesia and spontaneous respiration.

Surgical management of large tracheoesophageal fistula in infants after button battery ingestion.

OBJECTIVES: In recent years, an increase in severe and even fatal outcomes related to oesophageal or airway button battery (BB) ingestion by infants and small children has been reported. Extensive tissue necrosis caused by lodged BB can lead to major complications, including tracheoesophageal fistula (TEF). In these instances, best treatment remains controversial. While small defects may warrant a conservative approach, surgery often remains inevitable in highly complex cases with large TEF. We present a series of small children that underwent successful surgical management by a multidisciplinary team in our institution. METHODS: This is a retrospective analysis of n = 4 patients <18 months undergoing TEF repair from 2018 to 2021. RESULTS: Surgical repair under extracorporeal membrane oxygenation (ECMO) support was feasible in n = 4 patients by reconstructing the trachea with decellularized aortic homografts that were buttressed with pedicled latissimus dorsi muscle flaps. While direct oesophageal repair was feasible in 1 patient, 3 required esophagogastrostomy and secondary repair. The procedure was completed successfully in all 4 children with no mortality and acceptable morbidity. CONCLUSIONS: Tracheo-oesophageal repair after BB ingestion remains challenging and is associated with major morbidity. Bioprosthetic materials in conjunction with the interposition of vascularized tissue flaps between trachea and oesophagus appear to be a valid approach to manage severe cases.

Titanium nitride coating of pectus bar increases metal contamination after minimally-invasive repair of pectus excavatum.

INTRODUCTION: Previous studies demonstrated a release of toxic metals, e.g. nickel and chromium, from stainless steel bars used for minimally invasive repair of pectus excavatum (MIRPE). In the present study, we investigated the impact of titanium nitride coating on the metal release and exposure of MIRPE patients. MATERIAL AND METHODS: We analyzed the courses of nickel and chromium levels in blood, urine and local tissue in patients undergoing MIRPE with a titanium nitride coated pectus bar between 03/2017 and 10/2018. Sample collection was scheduled prior to MIRPE, at defined postoperative time points and at bar removal. Additionally, we evaluated irritative symptoms. Results were compared to a control group who received uncoated stainless steel bars in a previous time period (03/2015-02/2017). RESULTS: 12 patients received coated pectus bars (mean age 15.7 years). The control group included 28 patients. After implantation of a titanium nitride coated bar, significant increase in systemic nickel and chromium levels after one, two and three years was noted. In an interim analysis one year after MIRPE, we observed patients with coated bars to have significantly elevated trace metal values compared to the control group. This elevation persisted throughout the observation period. Tissue metal values were also significantly increased. Irritative symptoms occurred significantly more often in study patients compared to controls (50.0% vs. 14.3%). CONCLUSIONS: Coating of pectus bars with titanium nitride failed to reduce metal contamination after MIRPE. Instead, it resulted in a significant increase of trace metal levels after MIRPE, compared to patients with stainless steel bars, which may be explained by wear of the coating and inter-component mobilization processes.

The Impact of Thrombophilic Factors on Disease Progression in Children with Biliary Atresia-A Single-Centre Cohort Study.

Epidemiological evidence suggests that thrombophilic factors, including male sex, non-O blood type, MTHFRnt677TT mutation, factor V Leiden G1691A mutation, and prothrombin G20210A polymorphism, may contribute to the progression of fibrosis and occurrence of portal vein thrombosis in liver disease. We retrospectively investigated the effect of potentially thrombophilic factors on native liver survival as a patient-relevant endpoint of disease progression in a cohort of 142 children being followed up for biliary atresia at Hannover Medical School from April 2017 to October 2019. No significant association could be determined. There was no evidence for relevant differences in native liver survival for the Factor V Leiden G1691A mutation (hazard ratio [HR] = 0.86, 95% confidence interval [CI] 0.38-1.98, p = 0.73), prothrombin G20210A polymorphism (HR = 0.96, 95%CI 0.24-3.65, p = 0.96), non-O blood type (HR = 0.79, 95%CI 0.51-1.21, p = 0.28) or MTHFRnt677TT mutation (HR = 1.24, 95%CI 0.60-2.56, p = 0.56). A certain, albeit not strong, evidence of reduced native liver survival in male patients after Kasai hepatoportoenterostomy, particularly during the first 2000 days (42%; HR = 1.41, 95%CI 0.92-2.18, p = 0.11) was found. All children with pre-transplant portal vein thrombosis (n = 7) had non-O blood types. Larger multi-centre studies are necessary to show if the male sex or other thrombophilic factors could be potentially associated with reduced native liver survival.

Laparoscopic versus Open Pediatric Surgery: Three Decades of Comparative Studies.

INTRODUCTION: Despite its wide acceptance, the superiority of laparoscopic versus open pediatric surgery has remained controversial. There is still a call for well-founded evidence. We reviewed the literature on studies published in the last three decades and dealing with advantages and disadvantages of laparoscopy compared to open surgery. MATERIALS AND METHODS: Studies comparing laparoscopic versus open abdominal procedures in children were searched in PubMed/MEDLINE. Reports on upper and lower gastrointestinal as hepatobiliary surgery and on surgery of pancreas and spleen were included. Advantages and disadvantages of laparoscopic surgery were analyzed for different types of procedures. Complications were categorized using the Clavien-Dindo classification. RESULTS: A total of 239 studies dealing with 19 types of procedures and outcomes in 929,157 patients were analyzed. We identified 26 randomized controlled trials (10.8%) and 213 comparative studies (89.2%). The most frequently reported advantage of laparoscopy was shorter hospital stay in 60.4% of studies. Longer operative time was the most frequently reported disadvantage of laparoscopy in 52.7% of studies. Clavien-Dindo grade I to III complications (mild-moderate) were less frequently identified in laparoscopic compared to open procedures (80.3% of studies). Grade-IV complications (severe) were less frequently reported after laparoscopic versus open appendectomy for perforated appendicitis and more frequently after laparoscopic Kasai's portoenterostomy. We identified a decreased frequency of reporting on advantages after laparoscopy and increased reporting on disadvantages for all surgery types over the decades. CONCLUSION: Laparoscopic compared with open pediatric surgery seems to be beneficial in most types of procedures. The number of randomized controlled trials (RCTs) remains limited. However, the number of reports on disadvantages increased during the past decades.

Nickel contamination after minimally-invasive repair of pectus excavatum persists after bar removal.

BACKGROUND: Minimally-invasive repair of pectus excavatum (MIRPE) has been shown to be associated with high release of trace metals into patient's body. The aim of our study was to analyze the kinetics of metal contamination after MIRPE and after bar removal. METHODS: We prospectively assessed nickel and chromium changes in blood, urine, and local tissue in patients undergoing MIRPE with stainless-steel bar(s). Baseline samples were taken prior to surgery, further samples were taken at six defined time points until 30 months after bar removal. Clinical symptoms were evaluated at the time of every sample collection. RESULTS: 28 patients were included (mean age 16.4 years). At four weeks after MIRPE and persisting up to bar removal, we found significantly elevated trace metal levels in blood and urine. Tissue nickel and chromium levels were significantly elevated at the time of bar removal. After bar removal, the concentration of trace metal in urine and the concentration of chromium in plasma decreased gradually. In contrast, nickel levels in blood further increased. Five patients showed irritative symptoms after MIRPE, all symptomatic patients had elevated metal levels. CONCLUSIONS: Following MIRPE, we found a rapid systemic increase of nickel and chromium. Our data indicate that trace metal release could cause irritative symptoms. The prolonged elevated systemic nickel levels beyond bar removal necessitate further investigations of the long-term side effects of MIRPE.