Laryngeal mask vs. laryngeal tube trial in paediatric patients (LaMaTuPe): a single-blinded, open-label, randomised-controlled trial.

BACKGROUND: In hypoxemic children with difficult airway, or for minor elective procedures, the use of a supraglottic airway device may be preferred to endotracheal intubation, whether with a laryngeal mask or laryngeal tube. Second-generation laryngeal masks may offer a better safety profile. Whether they should be preferred to laryngeal tubes is unknown. This study aimed to compare the efficacy and safety of second-generation laryngeal masks and laryngeal tubes in children. METHODS: This randomised-controlled trial was conducted in a single university hospital in children <18 years undergoing elective anaesthesia in urology, minor paediatric surgery and gynaecology. Patients were 1 : 1 randomised to the laryngeal mask or laryngeal tube group. Children were allocated a second-generation laryngeal tube or a second-generation laryngeal mask as the primary airway device. The primary endpoint was insertion time. Secondary endpoints included first-attempt success, overall success and complications, which included hypoxia (SpO2 < 90%), laryngospasm, bronchospasm, aspiration and bleeding. RESULTS: In total, 135 patients were randomised, with 61 allocated to the laryngeal tube and 74 to the laryngeal mask group, with a median age of 5.4 and 4.9 years, respectively. Median insertion time was significantly longer in the laryngeal tube group (37 vs. 31 s; difference of medians: 6.0 s; 95% confidence interval: 0.0-13.0). The laryngeal tube had a significantly lower first-attempt (41.0%) and overall success rate (45.9%) than the laryngeal mask (90.5% and 97.3%, respectively). Those allocated to the laryngeal tube group had a higher ratio of complications (27.8%) compared to the laryngeal mask group (2.7%). CONCLUSION: This randomised-controlled trial reported that in children undergoing elective anaesthesia, the use of a laryngeal tube was associated with a longer insertion time.

Decoding pediatric spinal tumors: a single-center retrospective case series on etiology, presentation, therapeutic strategies, and outcomes.

INTRODUCTION: Spinal tumors (ST) often result in dire prognosis, carrying risks such as permanent paralysis, sensory loss, and sphincter dysfunction. Data on their incidence and etiology in pediatric populations are markedly scant. Our study investigates the etiology, clinical manifestation, treatment, and outcomes of pediatric ST. METHODS: We conducted a retrospective review of our institutional pediatric oncology and neurosurgery database, examining 14 patients under 18 years admitted with ST due to oncological diseases since 2005. We analyzed the clinical presentations, evaluations, molecular diagnostics and treatments for these patients. RESULTS: The study spanned 15 years and included 14 pediatric patients, each diagnosed with distinct spinal tumor entity. The mean patient age was approximately 19.6 ± 10.1 months. Severe axial pain along the vertebral column was observed in 13 patients, while acute neurological deterioration manifested in 7 patients. As a first-line intervention, 13 patients underwent decompressive surgery through laminectomy and tumor resection, and only one patient received chemotherapy solely. Before surgery, seven patients were unable to walk; post-surgery, six of them regained their ability to ambulate. The diagnosis encompassed a range of neoplasms: two instances of Ewing sarcoma, 3 instances of teratoma, one case presenting an atypical teratoid Rhabdoid tumor, two instances each of low-grade astrocytoma and neuroblastoma, and single instances of ependymoma, meningioma, rhabdomyosarcoma, and embryonal tumors with multilayered rosettes (ETMRs). Three patients succumbed two years after initiating therapy. CONCLUSION: Despite their rarity, intraspinal tumors in pediatric patients pose substantial therapeutic challenges. The intertwined complexities of the disease entity and the patient's neurological status demand swift initiation of an individualized therapeutic strategy. This crucial step helps optimize outcomes for this patient cohort, who frequently grapple with debilitating health conditions. Inclusion of these patients within a registry is mandatory to optimize treatment outcomes due to their rarity in pediatric population.

Clinical Relevance of Pathological Diagnosis of Hirschsprung's Disease with Acetylcholine-Esterase Histochemistry or Calretinin Immunohistochemistry.

INTRODUCTION: Hirschsprung disease (HD) manifests as a developmental anomaly affecting the enteric nervous system, where there is an absence of ganglion cells in the lower part of the intestine. This deficiency leads to functional blockages within the intestines. HD is usually confirmed or ruled out through rectal biopsy. The identification of any ganglion cells through hematoxylin and eosin (H&E) staining rules out HD. If ganglion cells are absent, further staining with acetylcholine-esterase (AChE) histochemistry or calretinin immunohistochemistry (IHC) forms part of the standard procedure for determining a diagnosis of HD. In 2017, our Institute of Pathology at University Hospital of Heidelberg changed our HD diagnostic procedure from AChE histochemistry to calretinin IHC. In this paper, we report the impact of the diagnostic procedure change on surgical HD therapy procedures and on the clinical outcome of HD patients. METHODS: We conducted a retrospective review of the diagnostic procedures, clinical data, and postoperative progress of 29 patients who underwent surgical treatment for HD in the Department of Pediatric Surgery, University of Heidelberg, between 2012 and 2021. The patient sample was divided into two groups, each covering a treatment period of 5 years. In 2012-2016, HD diagnosis was performed exclusively using AChE histochemistry (AChE group, n = 17). In 2017-2021, HD diagnosis was performed exclusively using calretinin IHC (CR group, n = 12). RESULTS: There were no significant differences between the groups in sex distribution, weeks of gestation, birth weight, length of the aganglionic segment, or associated congenital anomalies. Almost half of the children in the AChE group, twice as many as in the CR group, required an enterostomy before transanal endorectal pull-through procedure (TERPT). In the AChE group, 4 patients (23.5%) required repeat bowel sampling to confirm the diagnosis. Compared to the AChE group, more children in the CR group suffered from constipation post TERPT. DISCUSSION: Elevated AChE expression is linked to hypertrophied extrinsic cholinergic nerve fibers in the aganglionic segment in the majority of patients with HD. The manifestation of increased AChE expression develops over time. Therefore, in neonatal patients with HD, especially those in the first 3 weeks of life, an increase in AChE reaction is not detected. Calretinin IHC reliably identifies the presence or absence of ganglion cells and offers multiple benefits over AChE histochemistry. These include the ability to perform the test on paraffin-embedded tissue sections, a straightforward staining pattern, a clear binary interpretation (negative or positive), cost-effectiveness, and utility regardless of patient age. CONCLUSIONS: The ability of calretinin IHC to diagnose HD early and time-independently prevented repeated intestinal biopsies in our patient population and allowed us to perform a one-stage TERPT in the first months of life, reducing the number of enterostomies and restoring colonic continuity early. Patients undergoing transanal pull-through under the age of 3 months require a close follow-up to detect cases with bowel movement problems.

Pancreatic Surgery in Children: Complex, Safe, and Effective.

OBJECTIVE: The aim of this study was to assess indications for and report outcomes of pancreatic surgery in pediatric patients. BACKGROUND: Indications for pancreatic surgery in children are rare and data on surgical outcomes after pediatric pancreatic surgery are scarce. METHODS: All children who underwent pancreatic surgery at a tertiary hospital specializing in pancreatic surgery between 2003 and 2022 were identified from a prospectively maintained database. Indications, surgical procedures, and perioperative as well as long-term outcomes were analyzed. RESULTS: In total, 73 children with a mean age of 12.8 years (range: 4 mo to 18 y) underwent pancreatic surgery during the observation period. Indications included chronic pancreatitis (n=35), pancreatic tumors (n=27), and pancreatic trauma (n=11). Distal pancreatectomy was the most frequently performed procedure (n=23), followed by pancreatoduodenectomy (n=19), duodenum-preserving pancreatic head resection (n=10), segmental pancreatic resection (n=7), total pancreatectomy (n=3), and others (n=11). Postoperative morbidity occurred in 25 patients (34.2%), including 7 cases (9.6%) with major complications (Clavien-Dindo≥III). There was no postoperative (90-d) mortality. The 5-year overall survival was 90.5%. The 5-year event-free survival of patients with chronic pancreatitis was 85.7%, and 69.0% for patients with pancreatic tumors. CONCLUSION: This is the largest single-center study on pediatric pancreatic surgery in a Western population. Pediatric pancreatic surgery can be performed safely. Centralization in pancreatic centers with high expertise in surgery of adult and pediatric patients is important as it both affords the benefits of pancreatic surgery experience and ensures that surgical management is adapted to the specific needs of children.

Sclerotherapy of Venous Malformations Using Polidocanol: Effectiveness, Safety, and Predictors of Outcomes and Adverse Events.

PURPOSE: To assess the effectiveness, safety, and predictors of outcomes and adverse events for percutaneous sclerotherapy using polidocanol for the treatment of venous malformations (VMs). METHODS: A retrospective single-center analysis was performed, including patients with VMs who were treated with sclerotherapy using polidocanol between January 2011 and November 2021 at a tertiary center. Demographic characteristics, clinical data, and radiologic features were analyzed, and the influence of patient- and VM-related factors on the subjective clinical outcome and adverse events were investigated using a multivariate logistic regression analysis. RESULTS: In total, 167 patients who received 325 treatment sessions were included in this study. Overall symptom improvement was observed in 67.5%, stable symptoms were observed in 25.0%, and worsening was reported in 7.5% (clinical follow-up, 1.04 ± 1.67 years). The total adverse event rate was 10.2%, with an overall rate of 4.2% for permanent adverse events within the cohort. In multivariate analysis, the clinical outcome was worse in children (P = .01; 57.1% symptom improvement in children [age, <18 years] and 79.7% in adults), and adverse events were more frequently observed after the treatment of VMs located at the extremities (P < .01; 8.4% for VMs of the extremities and 1.2% for VMs in other locations). CONCLUSIONS: Sclerotherapy using polidocanol can be an effective treatment option for VMs with an acceptable safety profile. However, it can be less effective in children, and adverse events can be more frequently expected for VMs of the extremities.

Comparison of transection techniques in pediatric major hepatectomy: a matched pair analysis.

BACKGROUND: Evidence on safety and efficacy of different liver transection techniques in pediatric major hepatectomy is completely lacking, as no study has been conducted so far. The use of stapler hepatectomy has never before been reported in children. METHODS: Three liver transection techniques were compared: (1) ultrasonic dissector (CUSA), (2) tissue sealing device (LigaSure™), and (3) stapler hepatectomy. All pediatric hepatectomies performed at a referral center in a 12-year study period were analyzed, patients were pair-matched in a 1:1:1-fashion. Intraoperative weight-adjusted blood loss, operation time, use of inflow occlusion, liver injury (peak-transaminase levels), postoperative complications (CCI), and long-term outcome were compared. RESULTS: Of 57 pediatric liver resections, 15 patients were matched as triples based on age, weight, tumor stage, and extent of resection. Intraoperative blood loss was not significantly different between the groups (p = 0.765). Stapler hepatectomy was associated with significantly shorter operation time (p = 0.028). Neither postoperative death nor bile leakage occurred, and no reoperation due to hemorrhage was needed in any patient. CONCLUSION: This is the first comparison of transection techniques in pediatric liver resection and the first report on stapler hepatectomy in children. All three techniques can be safely applied and may harbor individual advantages in pediatric hepatectomy each.

Learning of Intracorporal Knot Tying in Minimally Invasive Surgery by Video or Expert Instruction.

INTRODUCTION: Minimally invasive surgery skill laboratories are indispensable in training, especially for complex procedural skills such as intracorporal suturing and knot tying (ICKT). However, maintaining a laboratory is expensive, and specially trained teachers are in short supply. During the COVID-19 pandemic, in-person instruction has reduced to almost zero, while model learning via video instruction (VID) has become an integral part of medical education. The aim of this study was to compare the learning effectiveness and efficiency of ICKT by laparoscopically inexperienced medical students through video versus direct expert instruction. MATERIALS AND METHODS: A secondary analysis of two randomized controlled trials was performed. We drew data from students who were trained in ICKT with expert instruction (EXP, n = 30) and from students who were trained via VID, n = 30). A laparoscopic box trainer including laparoscope was used for ICKT. Objective Structured Assessment of Technical Skills (OSATS), knot quality, and total ICKT time were the parameters for the assessment in this study. Proficiency criteria were also defined for these parameters. RESULTS: Students in the EXP group performed significantly better in OSATS-procedure-specific checklist (PSC) and knot quality compared with students in the VID group, with no difference in task time. Of the students who reached the proficiency criteria for OSATS-PSC and knot quality, those in the EXP group required fewer attempts to do so than those in the VID group. Students in both groups improved significantly in all parameters over the first hour of evaluation. CONCLUSION: For the laparoscopically inexperienced, training in ICKT through expert instruction presents an advantage compared with video-based self-study in the form of faster understanding of the procedure and the associated consistent implementation of good knot quality. Both teaching methods significantly improved participants' ICKT skills.

Impact of supplemental anesthesia in preterm infants undergoing inguinal hernia repair under spinal anesthesia : A retrospective analysis.

BACKGROUND: In preterm infants, spinal anesthesia (SpA) is recognized as an alternative to general anesthesia for inguinal hernia repair (IHR); however, some patients require supplemental anesthesia during surgery. The purpose of this study was to investigate the frequency and impact of supplemental anesthesia on perioperative care and adverse respiratory and hemodynamic events. METHODS: A retrospective study of preterm infants undergoing IHR at Heidelberg University Hospital within the first year of life between 2009 and 2018 was carried out. RESULTS: In total, 230 patients (255 surgeries) were investigated. Among 189 procedures completed using SpA 24 patients received supplemental anesthesia. Reasons for supplemental anesthesia included loss of anesthetic effect, returning motor response, and respiratory complications. Compared to SpA alone, no differences were found concerning hemodynamic parameters; however, patients requiring supplemental anesthesia displayed higher rates of postoperative oxygen supplementation and unexpected admission to the intensive care unit. The rate of perioperative apnea was 2.7%. Apneic events exclusively occurred after supplemental anesthesia. Bilateral IHR and duration of surgery were associated with the need for supplemental anesthesia. CONCLUSION: Whereas SpA might be favorable when compared to general anesthesia for IHR, the data indicate that particular caution is required in patients receiving supplemental anesthesia due to the possible risk for adverse respiratory events.

Generating evidence for diagnosis and therapy of RarE LIVEr disease: the RELIVE Initiative for systematic reviews and meta-analyses.

BACKGROUND: Rare liver lesions and diseases have seldomly aroused major interest of researchers. For most guidelines, presumably similar clinical conditions are pooled without detailed investigations of singularities that they present. MAIN TEXT: A multidisciplinary project aiming to establish evidence-based therapies for rare liver diseases has been founded. A series of systematic reviews and meta-analyses will be the starting point for a structured development of guidelines for rare conditions of the liver affecting pediatric and adult populations. The novel approach will be focusing on case reports and small patient series with distinct rare liver diseases without pooling several presumably acceptably similar conditions. Thus, a vital resource of information will be utilized, which has been largely neglected hitherto. CONCLUSION: Highly specific recommendations based on highest available evidence will therefore be developed for specific conditions, advancing the individualized medicine approach for the afflicted patients.

Alveolar macrophages in early stage COPD show functional deviations with properties of impaired immune activation.

Despite its high prevalence, the cellular and molecular mechanisms of chronic obstructive pulmonary disease (COPD) are far from being understood. Here, we determine disease-related changes in cellular and molecular compositions within the alveolar space and peripheral blood of a cohort of COPD patients and controls. Myeloid cells were the largest cellular compartment in the alveolar space with invading monocytes and proliferating macrophages elevated in COPD. Modeling cell-to-cell communication, signaling pathway usage, and transcription factor binding predicts TGF-ß1 to be a major upstream regulator of transcriptional changes in alveolar macrophages of COPD patients. Functionally, macrophages in COPD showed reduced antigen presentation capacity, accumulation of cholesteryl ester, reduced cellular chemotaxis, and mitochondrial dysfunction, reminiscent of impaired immune activation.

Evidence on Indications and Techniques to Increase the Future Liver Remnant in Children Undergoing Extended Hepatectomy: A Systematic Review and Meta-Analysis of Individual Patient Data.

Background: Techniques to increase the future liver remnant (FLR) have fundamentally changed the indications and criteria of resectability in adult liver surgery. In pediatric patients however, these procedures have rarely been applied and the potential benefit or harm as well as suited indications are unclear. Methods: A systematic literature search of MEDLINE, Web of Science, and CENTRAL was conducted. Based on a PRISMA-compliant, predefined methodology, all studies reporting pediatric patients (< 18y) undergoing liver resection with either associating liver partition and portal vein ligation for stages hepatectomy (ALPPS) or preoperative portal vein embolization or ligation (PVE/PVL) were included. Baseline data, periinterventional morbidity, increase of FLR and outcomes were analyzed. Results: 15 studies reporting on 21 pediatric patients with a mean age of 4 years and 7 months (range 1.8 months - 17 years) were included. 12 ALPPS procedures, 8 PVE and 1 PVL were performed. The applied criteria for performing ALPPS or PVE were heterogenous and thresholds for minimally acceptable FLR varied. Mean FLR [% of total liver volume] before the intervention was 23.6% (range 15.0 - 39.3%) in the ALPPS group and 31.4% (range 21.5 - 56.0%) in the PVE group. Mean increase of FLR before stage 2 resection was 69.4% (range 19.0 - 103.8%) for ALPPS and 62.8% (range 25.0 - 108.0%) after PVE. No postoperative death occurred, one early intrahepatic recurrence after an ALPPS procedure was reported. Overall postoperative morbidity was 23.8%. Conclusion: Validated criteria for minimal FLR in pediatric liver resection are lacking and so are clear indications for ALPPS or PVE. In special cases, ALPPS and PVE can be valuable techniques to achieve complete resection of pediatric liver tumors. However, more data are needed, and future studies should focus on a definition and validation of posthepatectomy liver failure as well as the minimally needed FLR in pediatric patients undergoing extended hepatectomy. Systematic Review Registration: [www.clinicaltrials.gov], identifier [PROSPERO 2021 CRD42021274848].

Neutralizing antibody responses 300 days after SARS-CoV-2 infection and induction of high antibody titers after vaccination.

Neutralizing antibodies against SARS-CoV-2 are important to protect against infection and/or disease. Using an assay to detect antibodies directed against the receptor binding domain (RBD) of SARS-CoV-2 Spike, we identified individuals with SARS-CoV-2 infection after an outbreak at a local health institution. All but one COVID-19 patient developed detectable anti-RBD antibodies and 77% had virus neutralizing antibody titers of >1:25. Antibody levels declined slightly over time. However, we still detected virus neutralizing antibody titers in 64% of the COVID-19 patients at >300 days after infection, demonstrating durability of neutralizing antibody levels after infection. Importantly, full COVID-19 vaccination of these individuals resulted in higher antibody titers compared to fully vaccinated individuals in the absence of prior infection. These data demonstrate long-lived antibody-mediated immunity after SARS-CoV-2 infection, and a clear benefit of two vaccine doses for recovered individuals.

The role of liver resection in metastatic nephroblastoma: a systematic review and Meta-regression analysis.

BACKGROUND: The impact of hepatic resection for liver metastases (LM) on the survival of pediatric patients with Wilms' tumor (WT) is unclear. So far, there is a lack of studies investigating the best suited treatment for patients with WTLM, and the role of liver resection has rarely been investigated. Thus, the development of evidence-based guidelines concerning indications of liver resection for WTLM remains difficult. AIM: To investigate the role of surgery in the therapy of WTLM. All available data on liver resections and subgroup outcomes of patients with WTLM are analyzed. Main research question is whether liver resection improves survival rates of patients with WTLM compared to non-surgical treatment. METHODS: A systematic literature search of MEDLINE, Web of Science, and Central provided the basis for this PRISMA-compliant systematic review. For the main analysis (I), all studies reporting on surgical treatment of pediatric WTLM were included. To provide a representative overview of the general outcome of WTLM patients, in analysis II all studies with cohorts of at least five WTLM patients, regardless of the kind of treatment, were reviewed and analyzed. A Multiple meta-regression model was applied to investigate the impact liver resection on overall survival. RESULTS: 14 studies with reports of liver resection for WTLM were found (Analysis I). They included a total of 212 patients with WTLM, of which 93 underwent a liver resection. Most studies had a high risk of bias, and the quality was heterogenous. For the analysis II, eight studies with subgroups of at least five WTLM patients were found. The weighted mean overall survival (OS) of WTLM patients across the studies was 55% (SD 29). A higher rate of liver resection was a significant predictor of better OS in a multiple meta-regression model with 4 covariates (I2 29.43, coefficient 0.819, p = 0.038). CONCLUSIONS: This is the first systematic review on WTLM. Given a lack of suited studies that specifically investigated WTLM, ecological bias was high in our analyses. Generating evidence is complicated in rare pediatric conditions and this study must be viewed in this context. Meta-regression analyses suggest that liver resection may improve survival of patients with WTLM compared to non-surgical treatment. Especially patients with persisting disease after neoadjuvant chemotherapy but also patients with metachronous LM seem to benefit from resection. Complete resection of LM is vital to achieve higher OS. Studies that prospectively investigate the impact of surgery on survival compared to non-surgical treatment for WTLM are highly needed to further close the current evidence gap. STUDY REGISTRATION: PROSPERO 2021 CRD42021249763  https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=249763 .

A Systematic Review and Meta-Analysis of Malignant Rhabdoid and Small Cell Undifferentiated Liver Tumors: A Rational for a Uniform Classification.

Background: Rhabdoid liver tumors in children are rare and have a devastating prognosis. Reliable diagnosis and targeted treatment approaches are urgently needed. Immunohistochemical and genetic studies suggest that tumors formerly classified as small cell undifferentiated hepatoblastoma (SCUD) belong to the entity of malignant rhabdoid tumors of the liver (MRTL), in contrast to hepatoblastomas with focal small cell histology (F-SCHB). This may have relevant implications on therapeutic approaches. However, studies with larger cohorts investigating the clinical relevance of the histological and genetic similarities for patients are lacking. Purpose: To analyze possible similarities and differences in patient characteristics, tumor biology, response to treatment, and clinical course of patients with MRTL, SCUD and F-SCHB. Applied therapeutic regimens and prognostic factors are investigated. Methods: A systematic literature search of MEDLINE, Web of Science, and CENTRAL was performed for this PRISMA-compliant systematic review. All studies of patients with MRTL, SCUD and F-SCHB that provided individual patient data were included. Demographic, histological, and clinical characteristics of the three subgroups were compared. Overall survival (OS) was estimated with the Kaplan-Meier method and prognostic factors investigated in a multivariable Cox regression model. Protocol registered: PROSPERO 2021 CRD42021258760. Results: Fifty-six studies with a total of 118 patients were included. The two subgroups MRTL and SCUD did not differ significantly in baseline patient characteristics. However, heterogenous diagnostic and therapeutic algorithms were applied. Large histological and clinical overlap between SCUD and MRTL could be shown. Two-year OS was 22% for MRTL and 13% for SCUD, while it was significantly better in F-SCHD (86%). Chemotherapeutic regimens for hepatoblastoma proved to be ineffective for both SCUD and MRTL, but successful in F-SCHB. Soft tissue sarcoma chemotherapy was associated with significantly better survival for MRTL and SCUD, but was rarely applied in SCUD. Patients who did not undergo surgical tumor resection had a significantly higher risk of death. Conclusions: While F-SCHB is a subtype of HB, SCUD should be classified and treated as a type of MRTL. Surgical tumor resection in combination with intensive, multi-agent chemotherapy is the only chance for cure of these tumors. Targeted therapies are highly needed to improve prognosis. Currently, aggressive regimens including soft tissue sarcoma chemotherapy, extensive resection, radiotherapy or even liver transplantation are the only option for affected children.

Structure of a bacterial Rhs effector exported by the type VI secretion system.

The type VI secretion system (T6SS) is a widespread protein export apparatus found in Gram-negative bacteria. The majority of T6SSs deliver toxic effector proteins into competitor bacteria. Yet, the structure, function, and activation of many of these effectors remains poorly understood. Here, we present the structures of the T6SS effector RhsA from Pseudomonas protegens and its cognate T6SS spike protein, VgrG1, at 3.3 Å resolution. The structures reveal that the rearrangement hotspot (Rhs) repeats of RhsA assemble into a closed anticlockwise ß-barrel spiral similar to that found in bacterial insecticidal Tc toxins and in metazoan teneurin proteins. We find that the C-terminal toxin domain of RhsA is autoproteolytically cleaved but remains inside the Rhs 'cocoon' where, with the exception of three ordered structural elements, most of the toxin is disordered. The N-terminal 'plug' domain is unique to T6SS Rhs proteins and resembles a champagne cork that seals the Rhs cocoon at one end while also mediating interactions with VgrG1. Interestingly, this domain is also autoproteolytically cleaved inside the cocoon but remains associated with it. We propose that mechanical force is required to remove the cleaved part of the plug, resulting in the release of the toxin domain as it is delivered into a susceptible bacterial cell by the T6SS.

Quality of Life Improves Following Laparoscopic Hemifundoplication in Neurologically Non-Impaired Children with Gastroesophageal Reflux Disease: A Propensity Score-Matched Analysis.

BACKGROUND: Quality of life (QOL) data following pediatric fundoplication for gastroesophageal reflux disease (GERD) are rare. Present study assessed the QOL in neurologically non-impaired children before and after laparoscopic hemifundoplication (LHF) in comparison to healthy controls. METHODS: PedsQL™ questionnaires assessed data on gastrointestinal symptoms (GIS) and general well-being (GWB) were compared in a propensity score-matched analysis (60 patients' pairs for time-point of surgery and 51 for follow-up). RESULTS: Preoperatively, the LHF group had more GIS (72.2 ± 53.9 vs. 38.8 ± 31.6; p < 0.001) and a lower GWB (16.7 ± 5.5 vs. 23.8 ± 3.5, p < 0.001) compared with controls. Postoperatively, GIS decreased significantly (74.3 ± 52.9 vs. 36.3 ± 33.5; p < 0.001) and the GWB was significantly higher (16.2 ± 6.0 vs. 20.8 ± 5.8; p < 0.001). GIS were similar in the LHF and control groups (39.1 ± 36.4 vs. 40.1 ± 31.0; p = 0.885) but GWB was lower in the LHF group than the control group (20.5 ± 6.3 vs. 23.4 ± 3.9; p = 0.009). CONCLUSIONS: QOL significantly improves after LHF in neurologically non-impaired children.

Biliary Rhabdomyosarcoma in Pediatric Patients: A Systematic Review and Meta-Analysis of Individual Patient Data.

BACKGROUND: The biliary tree is a rare location of pediatric rhabdomyosarcoma. Due to the low incidence, there is a lack of evidence concerning therapeutic guidelines for this tumor location. In particular, the impact of surgery is discussed controversially. PURPOSE: Objective is to generate evidence-based treatment guidelines for pediatric biliary rhabdomyosarcoma (BRMS). All available published data on therapeutic regimens and important prognostic factors are investigated with a focus on the role of surgery. METHODS: A systematic literature search of MEDLINE, Web of Science, and CENTRAL was performed. Patient data were entered individually. Data was pooled and qualitative and quantitative analyses of demographic data, therapy, postoperative/interventional outcomes, relapse, and survival were conducted. In an individual patient data analysis, cox regression was applied to identify key factors predicting the outcome of patients with BRMS. RESULTS: 65 studies met the inclusion criteria, providing data on 176 patients with BRMS. Individual patient data analysis showed a 5-year overall survival and progression-free survival of 51% and 50% for the total study population. For patients treated after 2000, 5-year OS and PFS was 65% and 59%, respectively. Absence of surgical tumor resection was an independent risk factor for death (Hazard ratio 8.9, 95%-CI 1.8-43.6, p = 0.007) and significantly associated with recurrent disease and disease-related death. CONCLUSION: This analysis provides comprehensive information on the largest number of patients hitherto reported in the literature. BRMS is still associated with high morbidity and mortality. Surgical tumor resection is essential for appropriate oncological treatment of BRMS. International cooperation studies are needed to enhance evidence and improve the outcome of this orphan disease. PROTOCOL REGISTRATION: PROSPERO (CRD42021228911) https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42021228911.

Establishing a Standardized Measure of Quality in Pediatric Liver Surgery: Definition and Validation of Textbook Outcome With Associated Predictors.

Purpose: To establish comparable reporting of surgical results in pediatric liver surgery, the recently introduced composite outcome measures Textbook Outcome (TO) and Comprehensive Complication Index (CCI) are applied and validated in a pediatric surgery context for the first time. In a representative cohort of pediatric patients undergoing liver resection, predictive factors for TO and CCI are investigated, and outcomes are compared to available literature on surgical outcomes of pediatric liver resection. Methods: All liver resections for patients under 21 years of age performed at the Department of General, Visceral, Transplantation and Pediatric Surgery of the University of Heidelberg between 2009 and 2020 were included in the analysis. Criteria for TO were defined prior to the analysis. Univariate and Multivariate regression was applied to identify factors associated with TO and CCI. Results: Fifty-three pediatric patients underwent liver resections during the observation period. No 30- or 90-day mortality occurred. Twenty-three patients (43.4%) had a TO. CCI and TO showed highly significant correlation (b = -30.33, 95% CI [-37.44; -23.22], p < 0.001). Multivariate analyses revealed significant association between intraoperative blood loss (adjusted for circulating blood volume) and CCI (b = 0.70, 95%CI [0.22; 1.32], p = 0.008) and failure to achieve TO (OR = 0.85, 95%CI [0.69; 0.97], p = 0.048). Conclusion: TO and CCI are suited outcome measures in pediatric surgical studies and offer objective comparability of results. Their application in clinical studies will be a major step forward to establish evidence-based therapies in pediatric surgery. Systematic utilization of TO and CCI can aid in generating comparable studies on surgical techniques and outcomes in pediatric liver resection.

Cell-Type-Specific High Throughput Toxicity Testing in Human Midbrain Organoids.

Toxicity testing is a crucial step in the development and approval of chemical compounds for human contact and consumption. However, existing model systems often fall short in their prediction of human toxicity in vivo because they may not sufficiently recapitulate human physiology. The complexity of three-dimensional (3D) human organ-like cell culture systems ("organoids") can generate potentially more relevant models of human physiology and disease, including toxicity predictions. However, so far, the inherent biological heterogeneity and cumbersome generation and analysis of organoids has rendered efficient, unbiased, high throughput evaluation of toxic effects in these systems challenging. Recent advances in both standardization and quantitative fluorescent imaging enabled us to dissect the toxicities of compound exposure to separate cellular subpopulations within human organoids at the single-cell level in a framework that is compatible with high throughput approaches. Screening a library of 84 compounds in standardized human automated midbrain organoids (AMOs) generated from two independent cell lines correctly recognized known nigrostriatal toxicants. This approach further identified the flame retardant 3,3',5,5'-tetrabromobisphenol A (TBBPA) as a selective toxicant for dopaminergic neurons in the context of human midbrain-like tissues for the first time. Results were verified with high reproducibility in more detailed dose-response experiments. Further, we demonstrate higher sensitivity in 3D AMOs than in 2D cultures to the known neurotoxic effects of the pesticide lindane. Overall, the automated nature of our workflow is freely scalable and demonstrates the feasibility of quantitatively assessing cell-type-specific toxicity in human organoids in vitro.

Immune cellular networks underlying recovery from influenza virus infection in acute hospitalized patients.

How innate and adaptive immune responses work in concert to resolve influenza disease is yet to be fully investigated in one single study. Here, we utilize longitudinal samples from patients hospitalized with acute influenza to understand these immune responses. We report the dynamics of 18 important immune parameters, related to clinical, genetic and virological factors, in influenza patients across different severity levels. Influenza disease correlates with increases in IL-6/IL-8/MIP-1α/ß cytokines and lower antibody responses. Robust activation of circulating T follicular helper cells correlates with peak antibody-secreting cells and influenza heamaglutinin-specific memory B-cell numbers, which phenotypically differs from vaccination-induced B-cell responses. Numbers of influenza-specific CD8+ or CD4+ T cells increase early in disease and retain an activated phenotype during patient recovery. We report the characterisation of immune cellular networks underlying recovery from influenza infection which are highly relevant to other infectious diseases.