Recommendations for endotracheal tube insertion depths in children.

BACKGROUND: Endotracheal tube (ETT) malposition is frequent in paediatric intubation. The current recommendations for ETT insertion depths are based on formulae that hold various limitations. This study aimed to develop age-based, weight-based and height-based curve charts and tables for ETT insertion depth recommendations in children. METHODS: In this retrospective single-centre study, we determined the individual optimal ETT insertion depths in paediatric patients by evaluating postintubation radiographic images. Age-based, weight-based and height-based ETT insertion depth recommendations were developed using regression analysis. We compared the insertion depths predicted by the models with previously published formulae. RESULTS: Intubations of 167 children (0-17.9 years) were analysed. Best-fit curves generated with logistic regression analysis revealed R2 values between 0.784 and 0.880. The insertion depths predicted by the models corresponded well with published age-based and height-based formulae. However, they demonstrated the unsuitability of weight-related linear formulae to predict ETT depth in children. CONCLUSION: The recommendations developed in this study facilitate a fast and accurate determination of recommended ETT insertion depths in children. Our recommendations provide greater accuracy than previously published formulae and demonstrate that weight-related linear formulae are unsuitable for predicting ETT depth in children.

Intestinal B cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling.

BACKGROUND & AIMS: The progression of non-alcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC. METHODS: C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH-inducing diets or standard chow for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and µMT mice (containing B cells only in the gastrointestinal tract) were fed a choline-deficient high-fat diet, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with simple steatosis, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and single-cell RNA-sequencing analysis were performed in liver and gastrointestinal tissue to characterise immune cells in mice and humans. RESULTS: Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B cells; additionally, we observed a positive correlation between IgA levels and activated FcRg+ hepatic myeloid cells, as well the extent of liver fibrosis. CONCLUSIONS: Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for the treatment of NASH. IMPACT AND IMPLICATIONS: There is currently no effective treatment for non-alcoholic steatohepatitis (NASH), which is associated with a substantial healthcare burden and is a growing risk factor for hepatocellular carcinoma (HCC). We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we show that the absence of B cells prevented HCC development. B cell-intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets for combinatorial NASH therapies against inflammation and fibrosis.

Teaching fiberoptic-assisted tracheoscopy in very low birth weight infants: A randomized controlled simulator study.

Objective: We developed a fiberoptic-assisted tracheoscopy (FAST) method to avoid direct laryngoscopy during surfactant replacement therapy and compared two training approaches on a very low birth weight (VLBW) infant simulator. Design: This prospective randomized controlled study was conducted at the Department of Neonatology and Pediatric Intensive Care Medicine of the University Medical Center Hamburg-Eppendorf, Germany. Participants: We recruited physicians, trainees, students, and nurses without prior experience in endoscopic techniques. Interventions: Participants were assigned randomly to a group that received instructions according to Peyton's Four-Step Approach and a control group that received standard bedside teaching only. Main outcome measures: Primary endpoints were the total and the component times required to place the bronchoscope and the method success. Results: We recruited 186 participants. Compared with the control group, the Peyton group had a lower mean (±standard deviation) FAST completion time (33.2 ± 27.5 s vs. 79.5 ± 47.9 s, p < 0.001; d = 1.12) and a higher FAST success rate (95% vs. 84%, p = 0.036, V = 0.18). Conclusion: After standardized training, the vast majority of novices completed FAST successfully. Peyton's four-step approach resulted in faster and more successful performance than standardized training.

Recommendations for nasotracheal tube insertion depths in neonates.

Background: Endotracheal tube (ETT) malposition is common in neonatal intubation. Recommendations for ETT insertion depths predominantly address orotracheal intubation. The aim of this study was to develop gestational age-, weight-, and length-based curve charts and tables for nasotracheal ETT insertion depth recommendations in neonates. Method: In this retrospective single-center study, the individual optimal ETT insertion depths in neonates were determined by evaluating postintubation radiographic images. Gestational age-, weight-, and length-based best-fit curves and tables were generated using regression analysis to calculate related ETT insertion depths. The insertion depths predicted by the models were compared with previously published recommendations. Results: We analyzed intubations of 178 neonates (gestational age range at intubation: 23.7-43.0 weeks). Applying sigmoidal logistic regression models, curves, and tables revealed R 2 values between 0.766 and 0.837. The insertion depths predicted by the models revealed certain deviations when compared with four previously published recommendations for nasotracheal ETT depth estimation in neonates. Conclusion: The charts and tables developed in this study enable a fast and accurate determination of recommended nasotracheal ETT insertion depths in neonates.

[Transient Ischemia of One Leg in a Very Low Birthweight Infant]. / Transiente Ischämie eines Beines bei einem Frühgeborenen der 31+0 Schwangerschaftswoche.

Ischemias in the extremities are rather rare in the neonatal period. Both intrauterine and postnatal factors can cause ischemias. We present the diagnostic procedure and the course in a female very low birthweight (VLBW) infant with transient ischemia in the lower extremity.

Estimation of Optimal Nasotracheal Tube Insertion Depth in Neonates Based on Fetal Biometric Measurements.

BACKGROUND: Current recommendations for neonatal endotracheal tube (ETT) insertion depths require the knowledge of anthropometric measurements, which are not immediately available in the delivery room setting. OBJECTIVE: This study aimed to develop recommendations based on prenatally available fetal biometric measurements. METHODS: In this retrospective study, the optimal ETT depths for nasotracheal insertion were correlated with fetal demographic and biometric data. Using linear regression analysis, diagrams with best-fit lines and tables for the recommendation of ETT insertion depth based on the prenatally available data were generated. RESULTS: We analyzed optimal nasotracheal ETT insertion depth in 98 neonates (gestational age range: 23.7-42.0 weeks). Linear regression analysis revealed high correlations between fetal measurements and the optimal ETT insertion depth (R2 = 0.712-0.837). CONCLUSION: We provide recommendations for neonatal nasotracheal ETT insertion depths based on prenatally available data with the potential to facilitate rapid and accurate intubation of neonates.

Anatomic accuracy, physiologic characteristics, and fidelity of very low birth weight infant airway simulators.

BACKGROUND: Medical simulation training requires realistic simulators with high fidelity. This prospective multi-center study investigated anatomic precision, physiologic characteristics, and fidelity of four commercially available very low birth weight infant simulators. METHODS: We measured airway angles and distances in the simulators Premature AirwayPaul (SIMCharacters), Premature Anne (Laerdal Medical), Premie HAL S2209 (Gaumard), and Preterm Baby (Lifecast Body Simulation) using computer tomography and compared these to human cadavers of premature stillbirths. The simulators' physiologic characteristics were tested, and highly experienced experts rated their physical and functional fidelity. RESULTS: The airway angles corresponded to those of the reference cadavers in three simulators. The nasal inlet to glottis distance and the mouth aperture to glottis distance were only accurate in one simulator. All simulators had airway resistances up to 20 times higher and compliances up to 19 times lower than published reference values. Fifty-six highly experienced experts gave three simulators (Premature AirwayPaul: 5.1 ± 1.0, Premature Anne 4.9 ± 1.1, Preterm Baby 5.0 ± 1.0) good overall ratings and one simulator (Premie HAL S2209: 2.8 ± 1.0) an unfavorable rating. CONCLUSION: The simulator physiology deviated significantly from preterm infants' reference values concerning resistance and compliance, potentially promoting a wrong ventilation technique. IMPACT: Very low birth weight infant simulators showed physiological properties far deviating from corresponding patient reference values. Only ventilation with very high peak pressure achieved tidal volumes in the simulators, as aimed at in very low birth weight infants, potentially promoting a wrong ventilation technique. Compared to very low birth weight infant cadavers, most tested simulators accurately reproduced the anatomic angular relationships, but their airway dimensions were relatively too large for the represented body. The more professional experience the experts had, the lower they rated the very low birth weight infant simulators.

Improved Less Invasive Surfactant Administration Success in Preterm Infants after Procedure Standardization.

Less invasive surfactant administration (LISA) has been introduced at our tertiary Level IV perinatal center since 2016 with an unsatisfactory success rate, which we attributed to an inconsistent, non-standardized approach and ambiguous patient inclusion criteria. This study aimed to improve the LISA success rate to at least 75% within 12 months by implementing a highly standardized LISA approach combined with team training. The Plan Do Study Act method of quality improvement was used for this initiative. Baseline assessment included a review of patient medical records 12 months before the intervention regarding patient characteristics, method success rate, respiratory, and adverse outcomes. A multi-professional team developed a standardized LISA approach and a training program including an educational film, checklists, pocket cards, and team briefings. Twenty-one preterm infants received LISA before and 24 after the intervention. The mean LISA success rate improved from 62% before the intervention to 92% (p = 0.029) after the intervention. Implementing a highly standardized LISA approach and multi-professional team training significantly improved the methods' success rate.

A prospective observational trial evaluating factors predictive of accurate endotracheal tube positioning in neonates and small infants.

BACKGROUND: There is a high incidence of endotracheal tube malposition in neonates and small infants. Yet, verification of accurate endotracheal tube location via radiographic imaging involves radiation exposure. AIMS: This study aimed to identify demographic and clinical parameters associated with accurate endotracheal tube positioning. METHODS: We conducted a prospective single-center study with term and preterm neonates and small infants between January 2018 and November 2019. We investigated correlations between ten variables and accurate endotracheal tube position. RESULTS: One hundred and sixty eight nasal intubations in 139 patients (weight 390-5000 g) were analyzed. An accurate tube position was confirmed by radiographic imaging in 71.4% of the intubations. The endotracheal tube was high in 8.3% and low in 20.2% of the cases. Male gender was the only variable that significantly correlated with an accurate endotracheal tube position (OR 2.5; 95% CI: 1.3, 5.0; P = .010). CONCLUSION: So far, no parameter has proven to be able to predict accurate endotracheal tube position in neonates reliably. These findings emphasize the indispensability of postintubation imaging in neonates and small infants.

Indoor Climate and Air Quality in a Neonatal Intensive Care Unit.

INTRODUCTION AND OBJECTIVE: The skin and respiratory system of premature neonates are in permanent contact with indoor room air. We longitudinally analyzed the room air climate and quality in neonatal intensive care inside and outside an incubator. METHODS: Sampling was performed in 2 patient rooms and inside a neonatal incubator (Caleo, Draeger Medical, Lübeck, Germany) over 6 weeks with 5-min resolution resulting in 12,090 samples (U-Monitor, U-Earth Biotech, London, UK). Temperature, humidity, and air pollutants, including particulate matter (<1 µm [PM1] and <2.5 µm [PM2.5]), volatile organic compounds (VOC), and odorous gases (OG), were recorded. Room air parameters were analyzed using time series analysis. A linear regression model was used to check for statistically significant linear trends. Statistical analysis was performed using decompensation of time series analysis and spectral analysis by fast Fourier transformation. RESULTS: The indoor climate target values of the ward's central ventilation system for temperature and humidity were not always met. Room air parameters (PM, VOC, and OG) showed significant daytime-dependent fluctuations with different oscillation frequencies per day. The daily mean (first quartile - third quartile) concentrations of PM2.5 were significantly higher inside the incubator compared to the surrounding ambient air (2,158 [1,948-2,298] pcs/L vs. 2,018 [1,852-2,058] pcs/L; p < 0.001). OG were significantly lower inside the incubator compared to ambient air. VOC levels inside the incubator were substantially higher during the first 5 days of the observation period compared to VOC levels in the surrounding ambient air. CONCLUSIONS: The indoor climate of neonatal intensive care units should be monitored in real time to detect deviations from target parameters quickly. In our neonatal intensive care unit, indoor air quality fluctuated significantly depending on the time of day. We highly suspect that air pollutants are carried into the direct patient environment by visitors and medical staff. The incubator does not protect against PM and VOC exposure but reduces exposure to OG. Cleaning procedures may lead to substantially higher concentrations of VOC inside the incubator and may represent a potentially harmful factor for premature infants.

Platelet GPIbα is a mediator and potential interventional target for NASH and subsequent liver cancer.

Non-alcoholic fatty liver disease ranges from steatosis to non-alcoholic steatohepatitis (NASH), potentially progressing to cirrhosis and hepatocellular carcinoma (HCC). Here, we show that platelet number, platelet activation and platelet aggregation are increased in NASH but not in steatosis or insulin resistance. Antiplatelet therapy (APT; aspirin/clopidogrel, ticagrelor) but not nonsteroidal anti-inflammatory drug (NSAID) treatment with sulindac prevented NASH and subsequent HCC development. Intravital microscopy showed that liver colonization by platelets depended primarily on Kupffer cells at early and late stages of NASH, involving hyaluronan-CD44 binding. APT reduced intrahepatic platelet accumulation and the frequency of platelet-immune cell interaction, thereby limiting hepatic immune cell trafficking. Consequently, intrahepatic cytokine and chemokine release, macrovesicular steatosis and liver damage were attenuated. Platelet cargo, platelet adhesion and platelet activation but not platelet aggregation were identified as pivotal for NASH and subsequent hepatocarcinogenesis. In particular, platelet-derived GPIbα proved critical for development of NASH and subsequent HCC, independent of its reported cognate ligands vWF, P-selectin or Mac-1, offering a potential target against NASH.

Single cell polarity in liquid phase facilitates tumour metastasis.

Dynamic polarisation of tumour cells is essential for metastasis. While the role of polarisation during dedifferentiation and migration is well established, polarisation of metastasising tumour cells during phases of detachment has not been investigated. Here we identify and characterise a type of polarisation maintained by single cells in liquid phase termed single-cell (sc) polarity and investigate its role during metastasis. We demonstrate that sc polarity is an inherent feature of cells from different tumour entities that is observed in circulating tumour cells in patients. Functionally, we propose that the sc pole is directly involved in early attachment, thereby affecting adhesion, transmigration and metastasis. In vivo, the metastatic capacity of cell lines correlates with the extent of sc polarisation. By manipulating sc polarity regulators and by generic depolarisation, we show that sc polarity prior to migration affects transmigration and metastasis in vitro and in vivo.

A Dual Role of Caspase-8 in Triggering and Sensing Proliferation-Associated DNA Damage, a Key Determinant of Liver Cancer Development.

Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur. Accumulated levels of hepatocyte apoptosis determine and predict subsequent hepatocarcinogenesis. Proliferation-associated DNA damage is sensed by a complex comprising caspase-8, FADD, c-FLIP, and a kinase-dependent function of RIPK1. This platform requires a non-apoptotic function of caspase-8, but no caspase-3 or caspase-8 cleavage. It may represent a DNA damage-sensing mechanism in hepatocytes that can act via JNK and subsequent phosphorylation of the histone variant H2AX.

An integrated approach for efficient biomethane production from solid bio-wastes in a compact system.

BACKGROUND: Solid bio-wastes (or organic residues) are worldwide produced in high amount and increasingly considered bioenergy containers rather than waste products. A complete bioprocess from recalcitrant solid wastes to methane (SW2M) via anaerobic digestion (AD) is believed to be a sustainable way to utilize solid bio-wastes. However, the complex and recalcitrance of these organic solids make the hydrolysis process inefficient and thus a rate-limiting step to many AD technologies. Effort has been made to enhance the hydrolysis efficiency, but a comprehensive assessment over a complete flow scheme of SW2M is rare. RESULTS: In this study, it comes to reality of a complete scheme for SW2M. A novel process to efficiently convert organic residues into methane is proposed, which proved to be more favorable compared to conventional methods. Brewers' spent grain (BSG) and pig manure (PM) were used to test the feasibility and efficiency. BSG and PM were enzymatically pre-hydrolyzed and solubilized, after which the hydrolysates were anaerobically digested using different bioreactor designs, including expanded granular sludge bed (EGSB), continuously stirred tank reactor (CSTR), and sequencing batch reactor (SBR). High organic loading rates (OLRs), reaching 19 and 21 kgCOD · m(-3) · day(-1) were achieved for the EGSBs, fed with BSG and PM, respectively, which were five to seven times higher than those obtained with direct digestion of the raw materials via CSTR or SBR. About 56% and 45% organic proportion of the BSG and PM can be eventually converted to methane. CONCLUSIONS: This study proves that complex organic solids, such as cellulose, hemicellulose, proteins, and lipids can be efficiently hydrolyzed, yielding easy biodegradable/bio-convertible influents for the subsequent anaerobic digestion step. Although the economical advantage might not be clear, the current approach represents an efficient way for industrial-scale treatment of organic residues with a small footprint and fast conversion of AD.

Metabolic activation of intrahepatic CD8+ T cells and NKT cells causes nonalcoholic steatohepatitis and liver cancer via cross-talk with hepatocytes.

Hepatocellular carcinoma (HCC), the fastest rising cancer in the United States and increasing in Europe, often occurs with nonalcoholic steatohepatitis (NASH). Mechanisms underlying NASH and NASH-induced HCC are largely unknown. We developed a mouse model recapitulating key features of human metabolic syndrome, NASH, and HCC by long-term feeding of a choline-deficient high-fat diet. This induced activated intrahepatic CD8(+) T cells, NKT cells, and inflammatory cytokines, similar to NASH patients. CD8(+) T cells and NKT cells but not myeloid cells promote NASH and HCC through interactions with hepatocytes. NKT cells primarily cause steatosis via secreted LIGHT, while CD8(+) and NKT cells cooperatively induce liver damage. Hepatocellular LTßR and canonical NF-κB signaling facilitate NASH-to-HCC transition, demonstrating that distinct molecular mechanisms determine NASH and HCC development.

RIP3, a kinase promoting necroptotic cell death, mediates adverse remodelling after myocardial infarction.

AIMS: Programmed necrosis (necroptosis) represents a newly identified mechanism of cell death combining features of both apoptosis and necrosis. Like apoptosis, necroptosis is tightly regulated by distinct signalling pathways. A key regulatory role in programmed necrosis has been attributed to interactions of the receptor-interacting protein kinases, RIP1 and RIP3. However, the specific functional role of RIP3-dependent signalling and necroptosis in the heart is unknown. The aims of this study were thus to assess the significance of necroptosis and RIP3 in the context of myocardial ischaemia. METHODS AND RESULTS: Immunoblots revealed strong expression of RIP3 in murine hearts, indicating potential functional significance of this protein in the myocardium. Consistent with a role in promoting necroptosis, adenoviral overexpression of RIP3 in neonatal rat cardiomyocytes and stimulation with TNF-α induced the formation of a complex of RIP1 and RIP3. Moreover, RIP3 overexpression was sufficient to induce necroptosis of cardiomyocytes. In vivo, cardiac expression of RIP3 was up-regulated upon myocardial infarction (MI). Conversely, mice deficient for RIP3 (RIP3(-/-)) showed a significantly better ejection fraction (45 ± 3.6 vs. 32 ± 4.4%, P < 0.05) and less hypertrophy in magnetic resonance imaging studies 30 days after experimental infarction due to left anterior descending coronary artery ligation. This was accompanied by a diminished inflammatory response of infarcted hearts and decreased generation of reactive oxygen species. CONCLUSION: Here, we show that RIP3-dependent necroptosis modulates post-ischaemic adverse remodelling in a mouse model of MI. This novel signalling pathway may thus be an attractive target for future therapies that aim to limit the adverse consequences of myocardial ischaemia.

Endothelial chemokine receptors as facilitators of tumor cell extravasation?

Metastasis is a multistep process characterized by the ability of tumor cells to "communicate" and to interact with their microenvironment to establish tumors in distant organs. A significant proportion of the metastatic microenvironment consists of leukocytes, mostly of the innate immune system, contributing to tumor invasion and outgrowth.

Endothelial CCR2 signaling induced by colon carcinoma cells enables extravasation via the JAK2-Stat5 and p38MAPK pathway.

Increased expression of the chemokine CCL2 in tumor cells correlates with enhanced metastasis, poor prognosis, and recruitment of CCR2(+)Ly6C(hi) monocytes. However, the mechanisms driving tumor cell extravasation through the endothelium remain elusive. Here, we describe CCL2 upregulation in metastatic UICC stage IV colon carcinomas and demonstrate that tumor cell-derived CCL2 activates the CCR2(+) endothelium to increase vascular permeability in vivo. CCR2 deficiency prevents colon carcinoma extravasation and metastasis. Of note, CCR2 expression on radio-resistant cells or endothelial CCR2 expression restores extravasation and metastasis in Ccr2(-/-) mice. Reduction of CCR2 expression on myeloid cells decreases but does not prevent metastasis. CCL2-induced vascular permeability and metastasis is dependent on JAK2-Stat5 and p38MAPK signaling. Our study identifies potential targets for treating CCL2-dependent metastasis.