Indeterminate pediatric acute liver failure: Clinical characteristics of a temporal cluster of five children in the Netherlands in the spring of 2022.

There is increasing global concern of severe acute hepatitis of unknown etiology in young children. In early 2022, our center for liver transplantation in the Netherlands treated five children who presented in short succession with indeterminate acute liver failure. Four children underwent liver transplantation, one spontaneously recovered. Here we delineate the clinical course and comprehensive diagnostic workup of these patients. Three of five patients showed a gradual decline of liver synthetic function and had mild neurological symptoms. Their clinical and histological findings were consistent with hepatitis. These three patients all had a past SARS-CoV-2 infection and two of them were positive for adenovirus DNA. The other two patients presented with advanced liver failure and encephalopathy and underwent dialysis as a bridge to transplantation. One of these children spontaneously recovered. We discuss this cluster of patients in the context of the currently elevated incidence of severe acute hepatitis in children.

In Vitro Evaluation of Pro- and Anticoagulant Drugs in Children with End-Stage Liver Disease Undergoing Liver Transplantation.

BACKGROUND: Pro- and anticoagulant drugs are commonly used in pediatric liver transplantation to prevent and treat thrombotic and bleeding complications. However, the combination of baseline hemostatic changes in children with liver disease and additional changes induced by transplantation makes this very challenging. This study aimed to analyze the efficacy of clinically available pro- and anticoagulant drugs in plasma from children undergoing liver transplantation. METHODS: In vitro effects of pro- and anticoagulant drugs on thrombin generation capacity were tested in plasma samples of 20 children (≤ 16 years) with end-stage liver disease undergoing liver transplantation, and compared with 30 age-matched healthy controls. RESULTS: Addition of pooled normal plasma had no effect in patients or controls, while 4-factor prothrombin complex concentrate increased thrombin generation in both patients and controls, with enhanced activity in patients. At start of transplantation, dabigatran and unfractionated heparin had a higher anticoagulant potency in patients, whereas 30 days after transplantation low molecular weight heparin was slightly less effective in patients. Effects of rivaroxaban were comparable between patients and controls. CONCLUSION: This study revealed important differences in efficacy of commonly used pro- and anticoagulant drugs in children with end-stage liver disease undergoing liver transplantation. Therefore, dose adjustments of these drugs may be required. The results of this study may be helpful in the development of urgently needed protocols for strategies to prevent and treat bleeding and thrombotic complications in pediatric liver transplantation.

Routine Postoperative Antithrombotic Therapy in Pediatric Liver Transplantation: Impact on Bleeding and Thrombotic Complications.

BACKGROUND: Hepatic artery thrombosis (HAT) and portal vein thrombosis (PVT) are serious causes of morbidity and mortality after pediatric liver transplantation. To reduce thrombotic complications, routine antithrombotic therapy consisting of 1 week heparin followed by 3 months acetylsalicylic acid, was implemented in our pediatric liver transplant program in 2003. This study aimed to evaluate incidences of bleeding and thrombotic complications since the implementation of routine antithrombotic therapy and to identify risk factors for these complications. METHODS: This retrospective cohort study includes 200 consecutive pediatric primary liver transplantations performed between 2003 and 2016. Uni- and multivariate logistic regression analysis, Kaplan-Meier method, and Cox regression analysis were used to evaluate recipient outcome. RESULTS: HAT occurred in 15 (7.5%), PVT in 4 (2.0%), and venous outflow tract thrombosis in 2 (1.0%) recipients. Intraoperative vascular interventions (odds ratio [OR] 14.45 [95% confidence interval [CI] 3.75-55.67]), low recipient age (OR 0.81 [0.69-0.95]), and donor age (OR 0.96 [0.93-0.99]) were associated with posttransplant thrombosis. Clinically relevant bleeding occurred in 37%. Risk factors were high recipient age (OR 1.08 [1.02-1.15]), high Child-Pugh scores (OR 1.14 [1.02-1.28]), and intraoperative blood loss in mL/kg (OR 1.003 [1.001-1.006]). Both posttransplant thrombotic (hazard ratio [HR] 3.38 [1.36-8.45]; p = 0.009) and bleeding complications (HR 2.50 [1.19-5.24]; p = 0.015) significantly increased mortality. CONCLUSION: In 200 consecutive pediatric liver transplant recipients receiving routine postoperative antithrombotic therapy, we report low incidences of posttransplant vascular complications. Posttransplant antithrombotic therapy seems to be a valuable strategy in pediatric liver transplantation. Identified risk factors for bleeding and thrombotic complications might facilitate a more personalized approach in antithrombotic therapy.

Evidence for a rebalanced hemostatic system in pediatric liver transplantation: A prospective cohort study.

In adults with end-stage liver disease concurrent changes in pro- and antihemostatic pathways result in a rebalanced hemostasis. Children though, have a developing hemostatic system, different disease etiologies, and increased risk of thrombosis. This study aimed to assess the hemostatic state of children during and after liver transplantation. Serial blood samples were obtained from 20 children (≤16 years) undergoing primary liver transplantation (September 2017-October 2018). Routine hemostasis tests, thrombomodulin-modified thrombin generation, clot lysis times, and hemostatic proteins were measured. Reference values were established using an age-matched control group of 30 children. Thrombocytopenia was present in study patients. Von Willebrand factors were doubled and ADAMTS13 levels decreased during and after transplantation up until day 30, when platelet count had normalized. Whereas prothrombin time and activated partial thromboplastin time were prolonged during transplantation, thrombin generation was within normal ranges, except during perioperative heparin administration. Fibrinogen, factor VIII levels, and clot lysis time were elevated up until day 30. In conclusion, children with end-stage liver disease are in tight hemostatic balance. During transplantation a temporary heparin-dependent hypocoagulable state is present, which rapidly converts to a hemostatic balance with distinct hypercoagulable features that persist until at least day 30. This hypercoagulable state may contribute to the risk of posttransplant thrombosis.

Identification enhancement of auditory evoked potentials in EEG by epoch concatenation and temporal decorrelation.

Event-related potentials (ERP) recorded by electroencephalography (EEG) are brain responses following an external stimulus, e.g., a sound or an image. They are used in fundamental cognitive research and neurological and psychiatric clinical research. ERPs are weaker than spontaneous brain activity and therefore it is difficult or even impossible to identify an ERP in the brain activity following an individual stimulus. For this reason, a blind source separation method relying on statistical information is proposed for the isolation of ERP after auditory stimulation. In this paper it is suggested to integrate epoch concatenation into the popular temporal decorrelation algorithm SOBI/TDSEP relying on time shifted correlations. With the proposed epoch concatenation temporal decorrelation (ecTD) algorithm a component representing the auditory evoked potential (AEP) is found in electroencephalographic data from an auditory stimulation experiment lasting 3min. The ecTD result is compared with the averaged AEP and it is superior to the result from the SOBI/TDSEP algorithm. Furthermore the ecTD processing leads to significant increases in the signal-to-noise ratio (shape SNR) of the AEP and reduces the computation time by 50% if compared to the SOBI/TDSEP calculation. It can be concluded that data concatenation in combination with temporal decorrelation is useful for isolating and improving the properties of an AEP especially in a short duration stimulation experiment.

Magnetoencephalography with a chip-scale atomic magnetometer.

We report on the measurement of somatosensory-evoked and spontaneous magnetoencephalography (MEG) signals with a chip-scale atomic magnetometer (CSAM) based on optical spectroscopy of alkali atoms. The uncooled, fiber-coupled CSAM has a sensitive volume of 0.77 mm(3) inside a sensor head of volume 1 cm(3) and enabled convenient handling, similar to an electroencephalography (EEG) electrode. When positioned over O1 of a healthy human subject, α-oscillations were observed in the component of the magnetic field perpendicular to the scalp surface. Furthermore, by stimulation at the right wrist of the subject, somatosensory-evoked fields were measured with the sensors placed over C3. Higher noise levels of the CSAM were partly compensated by higher signal amplitudes due to the shorter distance between CSAM and scalp.

Characterization of motor and somatosensory function for stroke patients.

In a pilot study, stroke patients with a lesion related to the motor system were studied using magnetoencephalography (MEG) and electromyography (EMG). The patients performed sustained finger movements for 30 s followed by 30 s of rest and 20 repetitions of this sequence in total. Task-related cortical signals derived from MEG were observed here at very different frequency scales. Slow signals below 0.1 Hz were extracted by independent component analysis and are associated with the sustained activation of the motor cortex, the dcMEG motor activation. MEG-EMG coupling phenomena in the 10-30 Hz range were analyzed using the imaginary part of coherency and are attributed to cortico-muscular coupling driving the muscles. Additionally a signal from the somatosensory cortex due to an electrical stimulation at the wrist, the N20m, was recorded as a physiological marker. Field maps and time series associated with the three types of signals are presented for one patient and one control subject as the signal quality of the patient data was not sufficient to achieve a group result. The feasibility of a comprehensive electrophysiological measuring and analysis procedure of the motor function for stroke research is demonstrated by the results.

Coherence and imaginary part of coherency identifies cortico-muscular and cortico-thalamic coupling.

The understanding of the interaction between muscle control and cortical areas and between subcortical and cortical areas is important for the effective treatment of patients with movement disorders. The combination of coherence (COH) and the imaginary part of coherency (iCOH) is applied here to electrophysiological data from patients with a movement disorder and to data from healthy subjects performing finger movements. The COH and iCOH between magnetoencephalographic (MEG) and electromyographic (EMG) signals of the healthy subjects yields the expected result for cortico-muscular coupling. Based on this the COH and iCOH between sub-thalamic nucleus local field potentials (STN-LFP) and MEG signals are assessed for deep brain stimulation patients with externalized LFP electrodes. The results suggest interactions in the 10 to 20 Hz range. Artificially mimicking volume conduction by re-referencing the STN electrodes to a surface EEG electrode leads to large changes in the COH and iCOH. This suggests that volume conduction is not important for the analysis of interactions between MEG and bipolar STN electrodes.

A nationwide study on hospital admissions due to dehydration in exclusively breastfed infants in the Netherlands: its incidence, clinical characteristics, treatment and outcome.

AIMS: To estimate the incidence and clinical characteristics in hospital admissions due to dehydration or undernutrition and their laboratory evaluation and treatment outcome in exclusively breastfed infants. METHODS: All hospital admissions during the first 3 months of life assessed by the Dutch Paediatric Surveillance Unit (DPSU) between mid 2003 and mid 2005. RESULTS: Nationwide 158 cases reported, correspond to an incidence of 58/y/100,000 breastfed infants; it is lower for severe dehydration at risk for hypernatraemia; 20/y/100,000. Sixty-five per cent of cases were <2 weeks old, their median weight loss was 9.3% and median age at admission 5 days; Serum sodium value was measured in only 12% of all cases. Insufficient volume intake and inadequate growth were most frequently reported (61% and 41%). Lethargy, jaundice or clinical dehydration was scored in 11-25%, seizures or shock in 3%. A breast pump at home was used in only 31%. In the hospital breast pumps were available (82%) as lactation consultants (73%). For treatment 65% was offered formula, in 30% by nasogastric drip. Most admissions lasted up to 3 days, all recovered fully and 33% were breastfed exclusively at discharge. CONCLUSION: The incidence of severe dehydration in the Netherlands is relatively low. With extended use of breast pumps at home it could be lower. To prevent complications, we recommend applying a reference weight chart, a full clinical examination and more extensive screening of serum sodium and glucose.

DC-magnetoencephalography and time-resolved near-infrared spectroscopy combined to study neuronal and vascular brain responses.

The temporal relation between vascular and neuronal responses of the brain to external stimuli is not precisely known. For a better understanding of the neuro-vascular coupling changes in cerebral blood volume and oxygenation have to be measured simultaneously with neuronal currents. With this motivation modulation dc-magnetoencephalography was combined with multi-channel time-resolved near-infrared spectroscopy to simultaneously monitor neuronal and vascular parameters on a scale of seconds. Here, the technique is described, how magnetic and optical signals can be measured simultaneously. In a simple motor activation paradigm (alternating 30 s of finger movement with 30 s of rest for 40 min) both signals were recorded non-invasively over the motor cortex of eight subjects. The off-line averaged signals from both modalities showed distinct stimulation related changes. By plotting changes in oxy- or deoxyhaemoglobin as a function of magnetic field a characteristic trajectory was created, which was similar to a hysteresis loop. A parametric analysis allowed quantitative results regarding the timing of coupling: the vascular signal increased significantly slower than the neuronal signal.

Cross-correlation analysis of the correspondence between magnetoencephalographic and near-infrared cortical signals.

OBJECTIVES: The study of neurovascular coupling greatly benefits from combined measurements of neuronal and vascular signals. Two-step signal processing is developed to extract parameters describing the coupling. METHODS: Using a magnetometer in an extremely well shielded room a broadband magnetoencephalogram was simultaneously measured with time-resolved near-infrared spectroscopy during a motor activity paradigm. The raw MEG and NIRS data were denoised separately using independent component analysis. RESULTS: After averaging the resulting signals showed motor activity-related changes. The temporal correspondence between MEG and NIRS was assessed plotting a combined trajectory and calculating a cross-correlation. Compared to the MEG signal, at movement onset the NIRS signal showed an onset delay in the range of seconds. CONCLUSIONS: Multi-variate signal pre-processing followed by temporal delay estimates demonstrated the extraction of neurovascular coupling parameters.

Time-delayed decorrelation for the identification of cardiac artifact components in MEG data.

The time-delayed decorrelation (TDD) Independent Component Analysis (ICA) applied to continuous multichannel magnetoencephalographic (MEG) recordings is a straightforward calculation in the time domain: Its main ingredient is a calculation of the correlation between signals having different time shifts with respect to each other. The equivalent mathematical representation in the frequency domain and a simple simulation show that TDD exploits different complex frequency spectra of the sources. Applying ICA to 80-channel whole head MEG data obtained under visual stimulation we can assign five of the 80 source components to the cardiac artifact. Their complex spectra exhibit a randomly distributed phase showing that TDD is capable of isolating quasi-periodic signals even for the case of an unspecified phase.

Spontaneous disproportionation of rhodium(I) bisoxazolinates to rhodium(II).

[RhI(t-Bu2-boxate)(C2H4)2] spontaneously disproportionates to the mononuclear [RhII(t-Bu2-boxate)2], whereas [RhI(Ph2-boxate)(C2H4)2] is stable against disproportionation.

Coordination and oxidative addition at a low-coordinate rhodium(I) beta-diiminate centre.

The reaction of 14e [L(Me)Rh(coe)] (1; L(Me)[double bond]ArNC(Me)CHC(Me)NAr, Ar[double bond]2,6-Me(2)C(6)H(3); coe[double bond]cis-cyclooctene) with phenyl halides and thiophenes was studied to assess the competition between sigma coordination, arene pi coordination and oxidative addition of a C-X bond. Whereas oxidative addition of the C-Cl and C-Br bonds of chlorobenzene and bromobenzene to L(Me)Rh results in the dinuclear species [[L(Me)Rh(Ph)(micro-X)](2)] (X=Cl, Br), fluorobenzene yields the dinuclear inverse sandwich complex [[L(Me)Rh](2)(anti-micro-eta(4):eta(4)-PhF)]. Thiophene undergoes oxidative addition of the C-S bond to give a dinuclear product. The reaction of 1 with dibenzo[b,d]thiophene (dbt) in the ratio 1:2 resulted in the formation of the sigma complex [L(Me)Rh(eta(1)-(S)-dbt)(2)], which in solution dissociates into free dbt and a mixture of the mononuclear complex [L(Me)Rh(eta(4)-(1,2,3,4)-dbt)] and the dinuclear complex [[L(Me)Rh](2)(micro-eta(4)-(1,2,3,4):eta(4)-(6,7,8,9)-dbt)]. The latter could be obtained selectively by the 2:1 reaction of 1 and dbt. Reaction of 1 with diethyl sulfide produces [L(Me)Rh(Et(2)S)(2)], which in the presence of hydrogen loses a diethyl sulfide ligand to give [L(Me)Rh(Et(2)S)(H(2))] and catalyses the hydrogenation of cyclooctene.