MUC-FIRE: Study protocol for a randomized multicenter open-label controlled trial to show that MUCous FIstula REfeeding reduces the time from enterostomy closure to full enteral feeds.

Background: After enterostomy creation, the distal bowel to the ostomy is excluded from the physiologic passage of stool, nutrient uptake, and growth of this intestinal section. Those infants frequently require long-term parenteral nutrition, continued after enterostomy reversal due to the notable diameter discrepancy of the proximal and distal bowel. Previous studies have shown that mucous fistula refeeding (MFR) results in faster weight gain in infants. The aim of the randomized multicenter open-label controlled MUCous FIstula REfeeding ("MUC-FIRE") trial is to demonstrate that MFR between enterostomy creation and reversal reduces the time to full enteral feeds after enterostomy closure compared to controls, resulting in shorter hospital stay and less adverse effects of parenteral nutrition. Methods/Design: A total of 120 infants will be included in the MUC-FIRE trial. Following enterostomy creation, infants will be randomized to either an intervention or a non-intervention group.In the intervention group, perioperative MFR between enterostomy creation and reversal will be performed. The control group receives standard care without MFR.The primary efficacy endpoint of the study is the time to full enteral feeds. Secondary endpoints include first postoperative bowel movement after stoma reversal, postoperative weight gain, and days of postoperative parenteral nutrition. In addition adverse events will be analyzed. Discussion: The MUC-FIRE trial will be the first prospective randomized trial to investigate the benefits and disadvantages of MFR in infants. The results of the trial are expected to provide an evidence-based foundation for guidelines in pediatric surgical centers worldwide. Trial registration: The trial has been registered at clinicaltrials.gov (number: NCT03469609, date of registration: March 19, 2018; last update: January 20, 2023, https://clinicaltrials.gov/ct2/show/NCT03469609?term=NCT03469609&draw=2&rank=1).

Ovarian torsion in the pediatric population: predictive factors for ovarian-sparing surgery-an international retrospective multicenter study and a systematic review.

STUDY OBJECTIVE: Ovarian torsion (OT) in pediatric age is a challenging condition to diagnose and treat. To date, there is still no clear consensus about its management. Our aim was to assess some possible associated factors that can help surgeons in decision-making. DESIGN: We conducted a retrospective multicentric study of pediatric OT surgically treated between 2010 and 2020 in six Italian and German institutions, comparing our findings with a literature review of the last 10 years (2010-2020). PARTICIPANTS: Patients aged 0-18 years with a diagnosis of OT intraoperatively confirmed and surgically treated at the involved institutions. RESULTS: Ninety-seven patients with a mean age at diagnosis of 8.37 years were enrolled in the study. Severe abdominal pain was present in 82 patients (84.5%). Eighty children (82.5%) presented an enlarged ovary with an US diameter > 5 cm and only 32 (40%) of them underwent conservative surgery. A laparoscopic approach was performed in 60 cases (61.9%) although in 15 (15.5%) conversion to open surgery was deemed necessary. A functional cyst was present in 49 patients (50.5%) while 11 children (11.3%) suffered from OT on a normal ovary. CONCLUSIONS: Our results showed that a post-menarchal age (p = .001), a pre-operative US ovarian size < 5 cm, (p = .001), the presence of severe abdominal pain (p = .002), a laparoscopic approach (p < .001), and the presence of a functional cyst (p = .002) were significantly associated with conservative surgery.

Vacuum-assisted staged omphalocele reduction: A preliminary report.

Introduction: Omphalocele represents a rare congenital abdominal wall defect. In giant omphalocele, due to the viscero-abdominal disproportion, gradual reintegration of eviscerated organs is often associated with medical challenges. We report our preliminary experience combining staged gravitational reduction with vacuum (VAC) therapy as a novel approach for treatment of giant omphalocele. Patients and methods: Retrospective chart review of six patients (five females) born between September 2018 and May 2022 who underwent staged reduction of giant omphalocele in conjunction with VAC therapy was conducted. Treatment was performed at two German third-level Pediatric Surgery Departments. Biometric and periprocedural data were assessed. Main outcome measure was the feasibility of VAC therapy for giant omphalocele. Data are reported as median and interquartile range (Q1-Q3). Results: Gestational age was 37 (37-38) weeks, and birth weight was 2700 (2500-3000) g. VAC dressing was changed every 3 (3-4) days until abdominal fascia closure at the age of 9 (3-13) days. Time to first/full oral feeds was 3 (1-5)/20 (12-24) days with a hospital stay of 22 (17-30) days. Follow-up was 8 (5-22) months and complications were of minor extent (none: n = 2; Clavien-Dindo I: n = 3; Clavien-Dindo II: n = 1), comprising a delayed neo-umbilical cord rest separation (n = 2) and/or concomitant neo-umbilical site infection (n = 2) with no repeat surgery. Conclusion: In neonates with giant omphalocele, VAC constitutes a promising and technically feasible enhancement of the staged gravitational reduction method. This study shows evidence that VAC may accelerate restoration of the abdominal wall integrity in giant omphalocele, thus minimizing associated comorbidities inherent to a prolonged hospitalization.

Meckel's Diverticulum in Children: A Monocentric Experience and Mini-Review of Literature.

Vitelline duct anomalies (VDA, including Meckel's diverticulum (MD)) result from failed embryologic obliteration. This study aimed for characteristics in symptomatic versus asymptomatic VDA, analyzing clinico-laboratory data from 73 children, aged 1 day to 17 years, treated at a tertiary Pediatric Surgery Institution from 2002-2017. A male preponderance was obtained (ratio 3.6:1). MD accounted for 85% of VDA. Incidence of symptomatic VDA decreased with older age. Leading symptoms were intestinal obstruction and hemorrhage. Mucosal heterotopia (present in 39% of symptomatic MD) was associated with anemia and lowered CRP-levels. On ROC-analysis, hemoglobin < 8.6 g/dL, CRP < 0.6 mg/dL and MD distance to ileocecal valve >40 cm were predictors of ectopic tissue in symptomatic MD. Our data confirmed known characteristics as male preponderance, declined incidence of symptomatic cases with age and predominance of gastric ectopia in symptomatic MD. Moreover, anemia and prolonged distance of MD to ileocecal valve were predictors of ectopic mucosa in symptomatic MD.

Pediatric Urachal Anomalies: Monocentric Experience and Mini-Review of Literature.

BACKGROUND: Surgery is the current mainstay for the treatment of urachal anomalies (UA). Recent literature data support the theory of a spontaneous resolution within the first year of life. The aim of this study, comprising solely surgically treated children, was to identify age specific patterns regarding symptoms and outcomes that may support the non-surgical treatment of UA. METHODS: Retrospective review on the clinico-laboratory characteristics of 52 children aged < 17 years undergoing resection of symptomatic UA at our pediatric surgical unit during 2006-2017. Data was dichotomized into age > 1 (n = 17) versus < 1 year (n = 35), and complicated (pre-/post-surgical abscess formation or peritonitis, n = 10) versus non-complicated course (n = 42). RESULTS: Children aged < 1 year comprised majority (67%) of cohort and had lower complication rates (p = 0.062). Complicated course at surgery exclusively occurred in patients aged > 1 year (p = 0.003). Additionally, complicated group was older (p = 0.018), displayed leukocytosis (p < 0.001) and higher frequencies regarding presence of abdominal pain (p = 0.008) and abdominal mass (p = 0.034) on admission. Regression analysis identified present abdominal pain (OR (95% CI), 11.121 (1.152-107.337); p = 0.037) and leukocytosis (1.435 (1.070-1.925); p = 0.016) being associated with complicated course. CONCLUSIONS: This study provides evidence that symptomatic disease course follows an age-dependent complication pattern with lower complication rates at age < 1 year. Larger, studies have to clarify, if waiting for spontaneous urachal obliteration during the first year of life comprises a reasonable alternative to surgery.

The lymphocyte-to-monocyte ratio may distinguish complicated from non-complicated pediatric appendicitis: A retrospective study and literature review.

BACKGROUND: To date, no parameter with satisfactory accuracy exists for the diagnosis of appendicitis. This retrospective study describes the discriminatory value of preoperative hematologic factors associated with complicated and non-complicated pediatric appendicitis. METHODS: Clinical and laboratory data were obtained from 294 children diagnosed with appendicitis on admission and treated at our tertiary-level pediatric hospital from 2015 to 2017; they were divided into three groups: control group (n = 118), histologically proven complicated (n = 120), and non-complicated (n = 56) appendicitis. RESULTS: Complicated appendicitis was associated with male preponderance and elevated neutrophil and monocyte levels (all p < 0.001). Non-complicated appendicitis was associated with elevated eosinophil levels (p = 0.023), and unaltered lymphocyte levels (p = 0.30). Compared to non-complicated disease, the lymphocyte-to-monocyte ratio (LMR) was decreased in complicated appendicitis (p = 0.003) but unaltered in the control group (p = 0.38). In the discrimination analysis, LMR had high accuracy (AUC 0.73 ± 0.05; p < 0.001; odds ratio (OR) (95% confidence interval (CI)) 6.0 (2.4-15.3)) and was the only parameter independently associated with complicated appendicitis on regression analysis (OR (95% CI), 0.544 (0.359-0.825); p = 0.004). CONCLUSION: We identified LMR as a novel potential marker for the differentiation of complicated from non-complicated pediatric appendicitis. This has implications on the treatment approach, either surgical in complicated disease or conservative in non-complicated disease.

Neutrophil to Lymphocyte Ratio and Platelet to Lymphocyte Ratio Might Predict Pediatric Ovarian Torsion: A Single-Institution Experience and Review of the Literature.

STUDY OBJECTIVE: To determine clinical and laboratory characteristics of ovarian torsion (OT; n = 28) compared with a non-OT control (OC; n = 64) group. DESIGN: Retrospective single-center review performed between January 2006 and December 2016. SETTING: Academic department of pediatric surgery. PARTICIPANTS AND INTERVENTIONS: Postoperative diagnosis of pediatric ovarian pathology (International Classification of Diseases, 10th Revision code N83) in 88 patients who underwent 92 surgeries for suspected OT, aged from 3 days to 17.8 years. MAIN OUTCOME MEASURES: Predictive value for OT according to biometric, procedural, and laboratory parameters at the time of admission. RESULTS: Compared with OC, OT in patients aged older than 1 year was associated with elevated values regarding white blood cell count, neutrophils, neutrophil to lymphocyte ratio (NLR; all P < .001), platelet to lymphocyte ratio (PLR; P = .003), platelets (P = .011), and a trend toward raised C-reactive protein (P = .054), whereas lymphocytes and lymphocyte to C-reactive protein ratio (both P < .001) were decreased. Using receiver operating characteristic analysis for differentiating OC from OT, besides lymphocytes and NLR (both area under the curve > 0.9), PLR elicited strongest discriminatory accuracy (area under the curve = 0.946 ± 0.037; P < .001; sensitivity 82%; specificity 90%). At binary logistic regression analysis PLR (P = .018) was independently predictive of OT. OT was suspected on ultrasound imaging in 15/18 (83%), showed a right-sided dominance in 13/18 (72%), and was associated with younger age (P = .003). No differences regarding laboratory or procedural parameters in patients aged younger than 1 year were discerned. CONCLUSION: Blood count indices such as PLR, NLR, and lymphocyte to C-reactive protein ratio might be helpful in identification of inflammatory processes as induced by ischemia in OT. Together with ultrasound and clinical features, these parameters constitute potential predictors of OT in girls aged older than 1 year.

Does metabolic alkalosis influence cerebral oxygenation in infantile hypertrophic pyloric stenosis?

BACKGROUND: This pilot study focuses on regional tissue oxygenation (rSO2) in patients with infantile hypertrophic pyloric stenosis in a perioperative setting. To investigate the influence of enhanced metabolic alkalosis (MA) on cerebral (c-rSO2) and renal (r-rSO2) tissue oxygenation, two-site near-infrared spectroscopy (NIRS) technology was applied. MATERIALS AND METHODS: Perioperative c-rSO2, r-rSO2, capillary blood gases, and electrolytes from 12 infants were retrospectively compared before and after correction of MA at admission (T1), before surgery (T2), and after surgery (T3). RESULTS: Correction of MA was associated with an alteration of cerebral oxygenation without affecting renal oxygenation. When compared to T1, 5-min mean (± standard deviation) c-rSO2 increased after correction of MA at T2 (72.74 ± 4.60% versus 77.89 ± 5.84%; P = 0.058), reaching significance at T3 (80.79 ± 5.29%; P = 0.003). Furthermore, relative 30-min c-rSO2 values at first 3 h of metabolic compensation were significantly lowered compared with postsurgical states at 16 and 24 h. Cerebral oxygenation was positively correlated with levels of sodium (r = 0.37; P = 0.03) and inversely correlated with levels of bicarbonate (r = -0.34; P = 0.05) and base excess (r = -0.36; P = 0.04). Analysis of preoperative and postoperative cerebral and renal hypoxic burden yielded no differences. However, a negative correlation (r = -0.40; P = 0.03) regarding hematocrite and mean r-rSO2, indirectly indicative of an increased renal blood flow under hemodilution, was obtained. CONCLUSIONS: NIRS seems suitable for the detection of a transiently impaired cerebral oxygenation under state of pronounced MA in infants with infantile hypertrophic pyloric stenosis. Correction of MA led to normalization of c-rSO2. NIRS technology constitutes a promising tool for optimizing perioperative management, especially in the context of a possible diminished neurodevelopmental outcome after pyloromyotomy.

Neuronal in vitro activity is more sensitive to valproate than intracellular ATP: Considerations on conversion problems of IC50 in vitro data for animal replacement.

We investigated the effects of acute valproate (VPA) on mouse embryonic primary cortex cells (MEPCs). Intracellular ATP concentrations were compared with changes in the mean action potential (AP) frequencies of MEPC networks growing on microelectrode arrays. Our data implies biphasic reactions towards increasing VPA concentrations for both parameters. Intracellular ATP and mean AP frequencies increased around characteristic concentrations of 0.15 and 0.07mM to hormetic plateaus of approx. 120% and 160% of their controls, before fading around 17 and 1.7 mM, respectively. The biphasic in vitro behavior of the two parameters hinders a simple extraction of IC50 and Hillslope values. Different ways of data-fitting with single and double logistic functions are discussed. For a typical hormetic increase of 60% above control, IC50 and Hillslope were decreased by 37% and 15%, respectively. Despite these marginal effects at a logarithmic concentration scale, the hormetic and double logistic behavior of parameters may provide information on the mode of action of toxic compounds. Comparison of our values with the LD50 of mice, recalculated by normalization to body mass, suggests that a neurotoxic rather than a cytotoxic mechanism is killing the animals. The future use of cellular microsystems to replace animal experiments will motivate the development of new microsensors, as well as the consideration of newly accessible parameters in systems biology models.

Experiences with LESS-appendectomy in Children.

PURPOSE: To evaluate the outcome of laparoendoscopic single-site (LESS-A) through one transumbilical port vs. 3-port laparoscopic (3TA) appendectomy in children. METHODS: We reviewed the records of 309 children (65 LESS-A, 244 3TA) operated on between 2008 and 2012. One hundered forty-nine patients had acute catarrhalis (CA), 133 phlegmonous (PLA), and 27 perforated appendicitis (PA). We compared the duration of operation (DO) the incidence of abdominal abscesses (AA) and wound infections (WI), as well as the degree of appendiceal inflammation (DI) among surgeons with and without board certification. RESULTS: For all DI, LESS-A resulted in a shorter DO than 3TA (CA 57.9 ± 22.8 vs. 68.5 ± 23.2, P = 0.014; PLA 51.5±16.5 vs. 68.4±33.0, P = 0.006; PA 66.0 ± 29.0 vs. 97.3 ± 41.8, P = 0.039). LESS-A was not used for less complicated cases when compared to 3TA (CA 50.8% vs. 47.5%; PLA 33.8% vs. 45.5%; PA 15.4% vs. 7.0%; CA vs. PLA, P = 0.292; CA vs. PA, P = 0.142; PLA vs. PA, P = 0.031). Surgeons without board certification were assigned to a similar percentage to perform both techniques for any DI (CA 30.3% vs. 37.1%, P = 0.541; PLA 31.8% vs. 40.5%, P= 0.484; PA 40% vs. 35.3%, P = 1.0). We found no significant differences concerning AA (1.5% vs. 1.2%, P = 1.0) and WI (3.1% vs. 1.6%, P = 0.61). CONCLUSIONS: LESS-A can be done by surgeons with and without board certification for all DI, with shorter DO and similar complication rates as compared to 3TA.

Cell Monitoring and Manipulation Systems (CMMSs) based on Glass Cell-Culture Chips (GC³s).

We developed different types of glass cell-culture chips (GC³s) for culturing cells for microscopic observation in open media-containing troughs or in microfluidic structures. Platinum sensor and manipulation structures were used to monitor physiological parameters and to allocate and permeabilize cells. Electro-thermal micro pumps distributed chemical compounds in the microfluidic systems. The integrated temperature sensors showed a linear, Pt1000-like behavior. Cell adhesion and proliferation were monitored using interdigitated electrode structures (IDESs). The cell-doubling times of primary murine embryonic neuronal cells (PNCs) were determined based on the IDES capacitance-peak shifts. The electrical activity of PNC networks was detected using multi-electrode arrays (MEAs). During seeding, the cells were dielectrophoretically allocated to individual MEAs to improve network structures. MEA pads with diameters of 15, 20, 25, and 35 µm were tested. After 3 weeks, the magnitudes of the determined action potentials were highest for pads of 25 µm in diameter and did not differ when the inter-pad distances were 100 or 170 µm. Using 25-µm diameter circular oxygen electrodes, the signal currents in the cell-culture media were found to range from approximately -0.08 nA (0% O2) to -2.35 nA (21% O2). It was observed that 60-nm thick silicon nitride-sensor layers were stable potentiometric pH sensors under cell-culture conditions for periods of days. Their sensitivity between pH 5 and 9 was as high as 45 mV per pH step. We concluded that sensorized GC³s are potential animal replacement systems for purposes such as toxicity pre-screening. For example, the effect of mefloquine, a medication used to treat malaria, on the electrical activity of neuronal cells was determined in this study using a GC³ system.

The effect of hyperbaric air on the electric activity of neuronal in vitro networks.

Breathing hyperbaric air or gas mixtures, for example during diving or when working underwater is known to alter the electrophysiological behavior of neuronal cells, which may lead to restricted cognition. During the last few decades, only very few studies into hyperbaric effects have been published, especially for the most relevant pressure range of up to 10 bar. We designed a pressurized measuring chamber to record pressure effects on the electrical activity of neuronal networks formed by primary cells of the frontal cortex of NMRI mice. Electrical activity was recorded with multi-electrode arrays (MEAs) of glass neuro chips while subjected to a step-by-step pressure increase from atmospheric pressure (1 bar) to 2 and 4 bar, followed by a decompression to 1 bar, in order to record recovery effects. The effects of pressure on the total spike rates (TSRs), which were averaged from at least 45 chips, were detected in two cell culture media with different compositions. In a DMEM medium with 6% horse serum, the TSR was increased by 19% after a pressure increase to 2 bar and remained stable at 4 bar. In NMEM medium with 2% B27, the TSR was not altered by a pressure increase to 2 bar but increased by 9% at 4 bar. After decompression to 1 bar, the activities decreased to 76% and 101% of their respective control levels in the two media. MEA recordings from neuronal networks in miniaturized hyperbaric measuring chambers provide new access for exploring the neuronal effects of hyperbaric breathing gases.

Behaviour of the plathelminth Symsagittifera roscoffensis under different light conditions and the consequences for the symbiotic algae Tetraselmis convolutae.

Symsagittifera roscoffensis is a plathelminth living in symbiosis with the green algae Tetraselmis convolutae. Host and symbiont are a model system for the study of endosymbiosis, which has so far mainly focused on their biochemical interactions. Symsagittifera roscoffensis is well known for its positive phototaxis that is hypothesized to optimize the symbiont's light perception for photosynthesis. In this study, we conducted a detailed analysis of phototaxis using light sources of different wavelength and brightness by videotracking. Furthermore, we compared the behavioural data with the electron transfer rate of the photosystem from cultured symbiotic cells. The symbiotic algae is adapted to low light conditions, showing a positive electron transfer rate at a photosynthetically active radiation of 0.112 µmol photons m(-2) s(-1), and S. roscoffensis showed a positive phototactic behaviour for light intensities up to 459.17 µmol photons m(-2) s(-1), which is not optimal regarding the needs of the symbiotic cells and may even harm host and symbiont. Red light cannot be detected by the animals and therefore their eyes seem not to be suitable for measuring the exact photosynthetically active radiation to the benefit of the photosymbionts.

Can a simplified algorithm prevent incomplete laparoscopic pyloromyotomy?

PURPOSE: The purpose of this study is to analyze an algorithm intended to prevent incomplete pyloromyotomy in 3-port laparoscopic (3TP) and laparoendoscopic single-site (LESS-P) procedures in a teaching hospital. METHODS: We defined the pyloroduodenal and pyloroantral junctions as anatomical margins prior pyloromyotomy by palpating and coagulating the serosa with the hook cautery instrument. Incomplete pyloromyotomies, mucosa perforations, serosa lacerations, and wound infections were recorded for pediatric surgical trainees (PST) and board-certified pediatric surgeons (BC). RESULTS: We reviewed the medical files of 233 infants, who underwent LESS-P (n=21), 3TP (n=71), and open pyloromyotomy (OP, n=141). No incomplete pyloromyotomies occurred. In contrast to OP, mucosa perforations did not occur in the laparoscopic procedures during the study period (6.38% vs. 0%, P=.013). OP had insignificantly more serosal lacerations (3.5% vs. 1.4%, P=.407). There was no difference in the rate of wound infections between OP and laparoscopic procedures (2.8% vs. 4.3%, P=.715). In the latter, all wound infections were associated with the use of skin adhesive. CONCLUSIONS: This algorithm helps avoiding incomplete laparoscopic pyloromyotomy during the learning curve and in a teaching setting. It is not risky to assist 3TP and LESS-P to PST as this led to a decreased rate of mucosa perforations without experiencing incomplete pyloromyotomies.

ß-Secretase BACE1 regulates hippocampal and reconstituted M-currents in a ß-subunit-like fashion.

The ß-secretase BACE1 is widely known for its pivotal role in the amyloidogenic pathway leading to Alzheimer's disease, but how its action on transmembrane proteins other than the amyloid precursor protein affects the nervous system is only beginning to be understood. We report here that BACE1 regulates neuronal excitability through an unorthodox, nonenzymatic interaction with members of the KCNQ (Kv7) family that give rise to the M-current, a noninactivating potassium current with slow kinetics. In hippocampal neurons from BACE1(-/-) mice, loss of M-current enhanced neuronal excitability. We relate the diminished M-current to the previously reported epileptic phenotype of BACE1-deficient mice. In HEK293T cells, BACE1 amplified reconstituted M-currents, altered their voltage dependence, accelerated activation, and slowed deactivation. Biochemical evidence strongly suggested that BACE1 physically associates with channel proteins in a ß-subunit-like fashion. Our results establish BACE1 as a physiologically essential constituent of regular M-current function and elucidate a striking new feature of how BACE1 impacts on neuronal activity in the intact and diseased brain.