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Paediatric acute liver failure (PALF) is defined as a biochemical evidence of acute liver injury in a child with no previous history of chronic liver disease characterised by an international normalised ratio (INR) of 1·5 or more unresponsive to vitamin K with encephalopathy, or INR of 2·0 or more with or without encephalopathy. PALF can rapidly progress to multiorgan dysfunction or failure. Although the transplant era has substantially changed the outlook for these patients, transplantation itself is not without risks, including those associated with life-long immunosuppression. Consequently, there has been an increased focus on improving medical management to prioritise bridging of patients to native liver survival, which is possible due to improved understanding of the underlying pathophysiology of multiorgan involvement in PALF. In this Review, we discuss recent advances in the medical management of PALF with an aim of reducing the need for liver transplantation. The Review will focus on the non-specific immune-mediated inflammatory response, extracorporeal support devices, neuromonitoring and neuroprotection, and emerging cellular and novel future therapeutic options.

Background : Accurate risk stratification of critically ill patients with coronavirus disease 2019 (COVID-19) is essential for optimizing resource allocation, delivering targeted interventions, and maximizing patient survival probability. Machine learning (ML) techniques are attracting increased interest for the development of prediction models as they excel in the analysis of complex signals in data-rich environments such as critical care. Methods : We retrieved data on patients with COVID-19 admitted to an intensive care unit (ICU) between March and October 2020 from the RIsk Stratification in COVID-19 patients in the Intensive Care Unit (RISC-19-ICU) registry. We applied the Extreme Gradient Boosting (XGBoost) algorithm to the data to predict as a binary outcome the increase or decrease in patients’ Sequential Organ Failure Assessment (SOFA) score on day 5 after ICU admission. The model was iteratively cross-validated in different subsets of the study cohort. Results : The final study population consisted of 675 patients. The XGBoost model correctly predicted a decrease in SOFA score in 320/385 (83%) critically ill COVID-19 patients, and an increase in the score in 210/290 (72%) patients. The area under the mean receiver operating characteristic curve for XGBoost was significantly higher than that for the logistic regression model {0.86 vs. 0.69, P

Family presence during invasive procedures or cardiopulmonary resuscitation (CPR) is a part of the family-centered approach in pediatric intensive care units (PICUs). We established a simulation program aiming at providing communication tools to healthcare professionals. The goal of this study was to evaluate the impact of this program on the stress of PICU professionals and its acceptance. An observational study of a simulation program, with questionnaire, was used to measure pre- and post-simulation stress and the degree of satisfaction of the participants. PICU of Geneva Children’s Hospital, Switzerland. Forty simulations with four different simulation scenarios and various types of parental behavior, as imitated by professional actors, were completed during a 1-year period. Primary outcomes were the difference in perceived stress level before and after the simulation and the degree of satisfaction of healthcare professionals (nursing assistants, nurses, physicians). The impact of previous experience with family members during critical situations or CPR was evaluated by variation in perceived stress level. Overall, 201 questionnaires were analyzed. Perceived stress associated with parental presence decreased from a pre-simulation value of 6 (IQR, 4–7) to 4 (IQR, 2–5) post-simulation on a scale of 1–10. However, in 25.7% of cases, the individually perceived post-simulation stress level was higher than the pre-simulation one. Satisfaction of the participants was high with a median of 10 (IQR, 9–10) out of 10.Conclusions: A simulation program helps reduce PICU team emotional stress associated with the presence of family members during critical situations or CPR, and is welcomed by PICU team members. What is Known:• Family presence during cardiopulmonary resuscitation (CPR) or critical situations is a part of the family-centered approach in pediatric intensive care.• The benefits for the family have been already demonstrated. However, this policy is still controversy among healthcare professionals. What is New:• A simulation program seeking to provide skills focused on family presence management in the PICU is useful to reduce stress and was well accepted by participants.• It might become an indispensable training intervention for the implementation of a PICU policy to allow family presence during CPR or other critical situations.

The impact of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic on pediatric intensive care units (PICUs) is difficult to quantify. We conducted a retrospective cohort study in all eight Swiss PICUs between 02-24-2020 and 06-15-2020 to characterize the logistical and medical aspects of the pandemic and their impact on Swiss PICUs. Out of the 1113 patients under the age of 20, who were tested positive for SARS-CoV-2 in Switzerland during the study period, 6% (63/1113) had to be hospitalized. All nine patients requiring intensive care had pediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) and constituted 14% (9/63) of all hospitalized patients. The patients presented with multiple organ dysfunction, needed longer stays in PICUs (p < 0.0001) and longer positive pressure ventilation (p = 0.025) than the regular PICU patients. They caused a higher workload (total Nine Equivalents of nursing Manpower use Score (NEMS) points, p = 0.0008) and were classified to higher workload categories (p < 0.0001) than regular PICU patients (n = 4881) in 2019. PICU burden was also influenced by different logistical factors such as cancellation of planned surgeries and staff recruitment to adult wards.Conclusions The different logistical and medical factors associated with the pandemic influenced the workload of the individual PICUs differently, depending on the presence of the single factors and their temporal relationship. The experiences of the study period help further to organize Swiss PICUs during the current pandemic to reduce the workload and optimize occupancy.

Background: Following the spread of the coronavirus disease 2019 (COVID-19) pandemic a new disease entity emerged, defined as Pediatric Inflammatory Multisystem Syndrome temporally associated with COVID-19 (PIMS-TS), or Multisystem Inflammatory Syndrome in Children (MIS-C). In the absence of trials, evidence for treatment remains scarce.Purpose: To develop best practice recommendations for the diagnosis and treatment of children with PIMS-TS in Switzerland. It is acknowledged that the field is changing rapidly, and regular revisions in the coming months are pre-planned as evidence is increasing.Methods: Consensus guidelines for best practice were established by a multidisciplinary group of Swiss pediatric clinicians with expertise in intensive care, immunology/rheumatology, infectious diseases, hematology, and cardiology. Subsequent to literature review, four working groups established draft recommendations which were subsequently adapted in a modified Delphi process. Recommendations had to reach >80% agreement for acceptance.Results: The group achieved agreement on 26 recommendations, which specify diagnostic approaches and interventions across anti-inflammatory, anti-infectious, and support therapies, and follow-up for children with suspected PIMS-TS. A management algorithm was derived to guide treatment depending on the phenotype of presentation, categorized into PIMS-TS with (a) shock, (b) Kawasaki-disease like, and (c) undifferentiated inflammatory presentation.Conclusion: Available literature on PIMS-TS is limited to retrospective or prospective observational studies. Informed by these cohort studies and indirect evidence from other inflammatory conditions in children and adults, as well as guidelines from international health authorities, the Swiss PIMS-TS recommendations represent best practice guidelines based on currently available knowledge to standardize treatment of children with suspected PIMS-TS. Given the absence of high-grade evidence, regular updates of the recommendations will be warranted, and participation of patients in trials should be encouraged.

Background Recently, cases of multisystem inflammatory syndrome in children (MIS-C) associated with coronavirus disease 2019 (COVID-19) have been reported worldwide. Negative polymerase chain reaction (RT-PCR) testing associated with positive serology in most of the cases suggests a postinfectious syndrome. Because the pathophysiology of this syndrome is still poorly understood, extensive virological and immunological investigations are needed. Methods We report a series of 4 pediatric patients admitted to Geneva University Hospitals with persistent fever and laboratory evidence of inflammation meeting the published definition of MIS-C related to COVID-19, to whom an extensive virological and immunological workup was performed. Results RT-PCRs on multiple anatomical compartments were negative, whereas anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin A (IgA) and immunoglobulin G (IgG) were strongly positive by enzyme-linked immunosorbent assay and immunofluorescence. Both pseudoneutralization and full virus neutralization assays showed the presence of neutralizing antibodies in all children, confirming a recent infection with SARS-CoV-2. The analyses of cytokine profiles revealed an elevation in all cytokines, as reported in adults with severe COVID-19. Although differing in clinical presentation, some features of MIS-C show phenotypic overlap with hemophagocytic lymphohistiocytosis (HLH). In contrast to patients with primary HLH, our patients showed normal perforin expression and natural killer (NK) cell degranulation. The levels of soluble interleukin (IL)-2 receptor (sIL-2R) correlated with the severity of disease, reflecting recent T-cell activation. Conclusion Our findings suggest that MIS-C related to COVID-19 is caused by a postinfectious inflammatory syndrome associated with an elevation in all cytokines, and markers of recent T-cell activation (sIL-2R) occurring despite a strong and specific humoral response to SARS-CoV-2. Further functional and genetic analyses are essential to better understand the mechanisms of host–pathogen interactions.

Background Coronavirus disease 2019 (COVID-19) is associated with a high disease burden with 10% of confirmed cases progressing towards critical illness. Nevertheless, the disease course and predictors of mortality in critically ill patients are poorly understood. Methods Following the critical developments in ICUs in regions experiencing early inception of the pandemic, the European-based, international RIsk Stratification in COVID-19 patients in the Intensive Care Unit (RISC-19-ICU) registry was created to provide near real-time assessment of patients developing critical illness due to COVID-19. Findings As of April 22, 2020, 639 critically ill patients with confirmed SARS-CoV-2 infection were included in the RISC-19-ICU registry. Of these, 398 had deceased or been discharged from the ICU. ICU-mortality was 24%, median length of stay 12 (IQR, 5-21) days. ARDS was diagnosed in 74%, with a minimum P/F-ratio of 110 (IQR, 80-148). Prone positioning, ECCO2R, or ECMO were applied in 57%. Off-label therapies were prescribed in 265 (67%) patients, and 89% of all bloodstream infections were observed in this subgroup (n = 66; RR=3·2, 95% CI [1·7-6·0]). While PCT and IL-6 levels remained similar in ICU survivors and non-survivors throughout the ICU stay (p = 0·35, 0·34), CRP, creatinine, troponin, d-dimer, lactate, neutrophil count, P/F-ratio diverged within the first seven days (p

We report the case of a 5-year-old boy who developed chronic plastic bronchitis after Fontan surgery for a complex congenital heart disease. During a new admission for acute exacerbation of plastic bronchitis, he started on a mucolytic treatment with inhaled rhDNAse instead of inhaled fibrinolytics because of the potential bleeding risk in a patient on combined coumarin and aspirin treatment. Respiratory symptoms resolved promptly, and the patient was discharged home on rhDNAse treatment. He remained clinically stable on rhDNAse treatment without further hospitalization until definitive treatment with dynamic lymphangiography and percutaneous embolization.

RationaleEndogenous tissue mediators inducing lung inflammation in the context of ventilator-induced lung injury (VILI) and acute respiratory distress syndrome (ARDS) are ill-defined.ObjectivesTo test whether mitochondrial alarmins are released during VILI, and are associated with lung inflammation.MethodsRelease of mitochondrial DNA, adenosine triphosphate (ATP), and formyl-Met-Leu-Phe (fMLP) peptide-dependent neutrophil chemotaxis were measured in conditioned supernatants from human alveolar type II-like (A549) epithelial cells submitted to cyclic stretch in vitro. Similar measurements were performed in bronchoalveolar lavage fluids from rabbits submitted to an injurious ventilatory regimen, and from patients with ARDS.Measurements and main resultsMitochondrial DNA was released by A549 cells during cell stretching, and was found elevated in BAL fluids from rabbits during VILI, and from ARDS patients. Cyclic stretch-induced interleukin-8 (IL-8) of A549 cells could be inhibited by Toll-like receptor 9 (TLR9) blockade. ATP concentrations were increased in conditioned supernatants from A549 cells, and in rabbit BAL fluids during VILI. Neutrophil chemotaxis induced by A549 cells conditioned supernatants was essentially dependent on fMLP rather than IL-8. A synergy between cyclic stretch-induced alarmins and lipopolysaccharide (LPS) was found in monocyte-derived macrophages in the production of IL-1ß.ConclusionsMitochondrial alarmins are released during cyclic stretch of human epithelial cells, as well as in BAL fluids from rabbits ventilated with an injurious ventilatory regimen, and found in BAL fluids from ARDS patients, particularly in those with high alveolar inflammation. These alarmins are likely to represent the proximal endogenous mediators of VILI and ARDS, released by injured pulmonary cells.

Mutations in the T-box transcription factor TBX4 gene have been reported in patients with Ischiocoxopodopatellar syndrome (MIM# 147891) and childhood-onset pulmonary arterial hypertension. Whole exome sequencing of DNA from a 1 day old deceased newborn, with severe diffuse developmental lung disorder exhibiting features of acinar dysplasia, and her unaffected parents identified a de novo TBX4 missense mutation p.E86Q (c.256G>C) in the DNA-binding T-box domain. We propose phenotypic expansion of the TBX4-related clinical disease spectrum to include acinar dysplasia of the lungs. The reported mutation is the first identified genetic variant causative for acinar dysplasia. © 2016 Wiley Periodicals, Inc.

In this Letter to the Editor we report the case of two siblings with fatal pneumococcal meningitis as the initial manifestation of IRAK-4 deficiency caused by previously undescribed mutations in IRAK4. The letter also highlights the importance of invasive pneumococcal infection as a critical 'red flag' warning of the potential for an underlying primary immunodeficiency and identifies some of the challenges in making the clinical diagnosis of IRAK-4 deficiency.

To document and compare the prevalence of asynchrony events during invasive-assisted mechanical ventilation in pressure support mode and in neurally adjusted ventilatory assist in children.Prospective, randomized, and crossover study.Pediatric and Neonatal Intensive Care Unit, University Hospital of Geneva, Switzerland.Intubated and mechanically ventilated children, between 4 weeks and 5 years old.Two consecutive ventilation periods (pressure support and neurally adjusted ventilatory assist) were applied in random order. During pressure support, three levels of expiratory trigger setting were compared: expiratory trigger setting as set by the clinician in charge (PSinit), followed by a 10% (in absolute values) increase and decrease of the clinician's expiratory trigger setting. The pressure support session with the least number of asynchrony events was defined as PSbest. Therefore, three periods were compared: PSinit, PSbest, and neurally adjusted ventilatory assist. Asynchrony events, trigger delay, and inspiratory time in excess were quantified for each of them.Data from 19 children were analyzed. Main asynchrony events during PSinit were autotriggering (3.6 events/min [0.7-8.2]), ineffective efforts (1.2/min [0.6-5]), and premature cycling (3.5/min [1.3-4.9]). Their number was significantly reduced with PSbest: autotriggering 1.6/min (0.2-4.9), ineffective efforts 0.7/min (0-2.6), and premature cycling 2/min (0.1-3.1), p0.005 for each comparison. The median asynchrony index (total number of asynchronies/triggered and not triggered breaths ×100) was significantly different between PSinit and PSbest: 37.3% [19-47%] and 29% [24-43%], respectively, p0.005). With neurally adjusted ventilatory assist, all types of asynchrony events except double-triggering and inspiratory time in excess were significantly reduced resulting in an asynchrony index of 3.8% (2.4-15%) (p0.005 compared to PSbest).Asynchrony events are frequent during pressure support in children despite adjusting the cycling off criteria. Neurally adjusted ventilatory assist allowed for an almost ten-fold reduction in asynchrony events. Further studies should determine the clinical impact of these findings.

Cysteine-rich protein-61 (CYR61), also known as connective tissue growth factor, CYR61, and nephroblastoma overexpressed gene 1 (CCN1), is a heparin-binding protein member of the CCN family of matricellular proteins. Gene expression profiles showed that Cyr61 is upregulated in human acute lung injury (ALI), but its functional role is unclear. We hypothesized that CYR61 contributes to ALI in mice. First, we demonstrated that CYR61 expression increases after bleomycin-induced lung injury. We then used adenovirus-mediated gene transfer to determine whether CYR61 overexpression in the lungs was sufficient to cause ALI. Mice instilled with CYR61 adenovirus showed greater weight loss, increased bronchoalveolar lavage total neutrophil counts, increased protein concentrations, and increased mortality compared with mice instilled with empty-vector adenovirus. Immunohistochemical studies in lungs from humans with idiopathic pulmonary fibrosis revealed CYR61 expression on the luminal membrane of alveolar epithelial cells in areas of injury. We conclude that CYR61 is upregulated in ALI and that CYR61 overexpression exacerbates ALI in mice.

BACKGROUND: Several new generation neonatal ventilators that incorporate conventional as well as high frequency ventilation (HFOV) have appeared on the market. Most of them offer the possibility to use HFOV in a volume-targeted mode, despite absence of any preclinical data. With a bench test, we evaluated the performances of 4 new neonatal HFOV devices and compared them to the SensorMedics HFOV device. METHODS: Expiratory tidal volumes (VT) were measured for various ventilator settings and lung characteristics (ie, modifications of compliance and resistance of the system), to mimic several clinical conditions of pre-term and term infants. RESULTS: Increasing the frequency proportionally decreased the VT for all the ventilators, although the magnitude of the decrease was highly variable between ventilators. At 15 Hz and a pressure amplitude of 60 cm H2O, the delivered VT ranged from 3.5 to 5.9 mL between devices while simulating pre-term infant conditions and from 2.6 to 6.3 mL while simulating term infant conditions. Activating the volume-targeted mode in the 3 machines that offer this mode allowed the VT to remain constant over the range of frequencies and with changes of lung mechanical properties, for pre-term infant settings only while targeting a VT of 1 mL. CONCLUSIONS: These new generation neonatal ventilators were able to deliver adequate VT under pre-term infant, but not term infant respiratory system conditions. The clinical relevance of these findings will need to be determined by further studies.

To document the prevalence of asynchrony events during noninvasive ventilation in pressure support in infants and in children and to compare the results with neurally adjusted ventilatory assist.Prospective randomized cross-over study in children undergoing noninvasive ventilation.The study was performed in a PICU.From 4 weeks to 5 years.Two consecutive ventilation periods (pressure support and neurally adjusted ventilatory assist) were applied in random order. During pressure support (PS), three levels of expiratory trigger (ETS) setting were compared: initial ETS (PSinit), and ETS value decreased and increased by 15%. Of the three sessions, the period allowing for the lowest number of asynchrony events was defined as PSbest. Neurally adjusted ventilator assist level was adjusted to match the maximum airway pressure during PSinit. Positive end-expiratory pressure was the same during pressure support and neurally adjusted ventilator assist. Asynchrony events, trigger delay, and cycling-off delay were quantified for each period.Six infants and children were studied. Trigger delay was lower with neurally adjusted ventilator assist versus PSinit and PSbest (61 ms [56-79] vs 149 ms [134-180] and 146 ms [101-162]; p = 0.001 and 0.02, respectively). Inspiratory time in excess showed a trend to be shorter during pressure support versus neurally adjusted ventilator assist. Main asynchrony events during PSinit were autotriggering (4.8/min [1.7-12]), ineffective efforts (9.9/min [1.7-18]), and premature cycling (6.3/min [3.2-18.7]). Premature cycling (3.4/min [1.1-7.7]) was less frequent during PSbest versus PSinit (p = 0.059). The asynchrony index was significantly lower during PSbest versus PSinit (40% [28-65] vs 65.5% [42-76], p0.001). With neurally adjusted ventilator assist, all types of asynchronies except double triggering were reduced. The asynchrony index was lower with neurally adjusted ventilator assist (2.3% [0.7-5] vs PSinit and PSbest, p0.05 for both comparisons).Asynchrony events are frequent during noninvasive ventilation with pressure support in infants and in children despite adjusting the cycling-off criterion. Compared with pressure support, neurally adjusted ventilator assist allows improving patient-ventilator synchrony by reducing trigger delay and the number of asynchrony events. Further studies should determine the clinical impact of these findings.

to the editor: We would like to thank Dr. Weiskirchen ([5][1]) for his interest in our recent publication ([3][2]). As we mentioned in the discussion and as pointed out by Dr. Weiskirchen, the absence of protein data in our adenovirus model represents a limitation of our study. Regarding the RNA

Antenatal hydronephrosis (ANH) is a frequent anomaly detected on fetal ultrasound scans. There is no consensus recommendation for the postnatal follow-up and/or the necessity to perform a voiding cystourethrography (VCUG) to diagnose vesicoureteral reflux (VUR). We conducted a cohort/non-randomized trial of 121 patients with ANH, defined as an anterior posterior diameter (APD) ≥ 5 mm after the 20th week of gestation, to evaluate the ability of the antenatal and postnatal ultrasonography results to predict VUR. All infants had two successive ultrasounds at 5 days and 1 month, respectively, after birth. A VCUG was performed at 6 weeks in children with a persistent APD ≥ 5 mm and/or an ureteral dilatation observed on at least one of two postnatal ultrasounds. In total, 88 patients had VCUG and nine had VUR, with five having high-grade reflux (>grade II). The risk of VUR increased significantly with the degree of APD detected on the postnatal ultrasound scan (p = 0.03). The odds ratios were 5.0 [95% confidence interval (CI) 0.5-51.2] for APD = 7-9 mm and 9.1 (95% CI 1.0-80.9) for APD ≥ 10 mm. The results of this study show that among our patient cohort antenatal ultrasound was not predictive of reflux. There was, however, a relation between the importance of the postnatal renal pelvis diameter and the risk of VUR. A cut-off of 7 mm showed a fair ability of ultrasonography to predict VUR and a cut-off of 10 mm enabled all severe refluxes in the 88 patients who had a VCUG to be diagnosed.

We present a mechanically active cell culture substrate that produces complex strain patterns and generates extremely high strain rates. The transparent miniaturized cell stretcher is compatible with live cell microscopy and provides a very compact and portable alternative to other systems. A cell monolayer is cultured on a dielectric elastomer actuator (DEA) made of a 30 μm thick silicone membrane sandwiched between stretchable electrodes. A potential difference of several kV’s is applied across the electrodes to generate electrostatic forces and induce mechanical deformation of the silicone membrane. The DEA cell stretcher we present here applies up to 38% tensile and 12% compressive strain, while allowing real-time live cell imaging. It reaches the set strain in well under 1 ms and generates strain rates as high as 870 s−1, or 87%/ms. With the unique capability to stretch and compress cells, our ultra-fast device can reproduce the rich mechanical environment experienced by cells in normal physiological conditions, as well as in extreme conditions such as blunt force trauma. This new tool will help solving lingering questions in the field of mechanobiology, including the strain-rate dependence of axonal injury and the role of mechanics in actin stress fiber kinetics.