Pediatric acute liver failure (PALF) is a life-threatening condition. In Europe, the main causes are viral infections (12%-16%) and inherited metabolic diseases (14%-28%). Yet, in up to 50% of cases ...the underlying etiology remains elusive, challenging clinical management, including liver transplantation. We systematically studied indeterminate PALF cases referred for genetic evaluation by whole-exome sequencing (WES), and analyzed phenotypic and biochemical markers, and the diagnostic yield of WES in this condition.
With this international, multicenter observational study, patients (0-18 y) with indeterminate PALF were analyzed by WES. Data on the clinical and biochemical phenotype were retrieved and systematically analyzed.
In total, 260 indeterminate PALF patients from 19 countries were recruited between 2011 and 2022, of whom 59 had recurrent PALF. WES established a genetic diagnosis in 37% of cases (97/260). Diagnostic yield was highest in children with PALF in the first year of life (41%), and in children with recurrent acute liver failure (64%). Thirty-six distinct disease genes were identified. Defects in NBAS (n=20), MPV17 (n=8), and DGUOK (n=7) were the most frequent findings. When categorizing, the most frequent were mitochondrial diseases (45%), disorders of vesicular trafficking (28%), and cytosolic aminoacyl-tRNA synthetase deficiencies (10%). One-third of patients had a fatal outcome. Fifty-six patients received liver transplantation.
This study elucidates a large contribution of genetic causes in PALF of indeterminate origin with an increasing spectrum of disease entities. The high proportion of diagnosed cases and potential treatment implications argue for exome or in future rapid genome sequencing in PALF diagnostics.
Tuberous sclerosis complex is associated with the occurrence of cardiac rhabdomyomas that may result in life‐threatening arrhythmia unresponsive to standard antiarrhythmic therapy. We report the case ...of an infant with multiple cardiac rhabdomyomas who developed severe refractory supraventricular tachycardia (SVT) that was successfully treated with everolimus. Pharmacological mTOR inhibition rapidly improved arrhythmia within few weeks after treatment initiation and correlated with a reduction in tumor size. Intermediate attempts to discontinue everolimus resulted in rhabdomyoma size rebound and recurrence of arrhythmic episodes, which resolved on resumption of therapy. While everolimus treatment led to successful control of arrhythmia in the first years of life, episodes of SVT reoccurred at the age of 6 years. Electrophysiologic testing confirmed an accessory pathway that was successfully ablated, resulting in freedom of arrhythmic events. In summary we present an in‐depth evaluation of the long‐term use of everolimus in a child with TSC‐associated SVT, including the correlation between drug use and arrhythmia outcome. This case report provides important information on the safety and efficacy of an mTOR inhibitor for the treatment of a potentially life‐threatening cardiac disease manifestation in TSC for which the optimal treatment strategy is still not well established.
Data on cross‐neutralization of the SARS‐CoV‐2 omicron variant more than 1 year after SARS‐CoV‐2 infection are urgently needed, especially in children, to predict the likelihood of reinfection and to ...guide vaccination strategies. In a prospective observational cohort study, we evaluated live‐virus neutralization of the SARS‐CoV‐2 omicron (BA.1) variant in children compared with adults 14 months after mild or asymptomatic wild‐type SARS‐CoV‐2 infection. We also evaluated immunity to reinfection conferred by previous infection plus COVID‐19 mRNA vaccination. We studied 36 adults and 34 children 14 months after acute SARS‐CoV‐2 infection. While 94% of unvaccinated adults (16/17) and children (32/34) neutralized the delta (B.1.617.2) variant, only 1/17 (5.9%) unvaccinated adults, 0/16 (0%) adolescents and 5/18 (27.8%) children <12 years of age had neutralizing activity against omicron (BA.1). In convalescent adults, one or two doses of mRNA vaccine increased delta and omicron neutralization 32‐fold, similar to a third mRNA vaccination in uninfected adults. Neutralization of omicron was 8‐fold lower than that of delta in both groups. In conclusion, our data indicate that humoral immunity induced by previous SARS‐CoV‐2 wild‐type infection more than 1 year ago is insufficient to neutralize the current immune escape omicron variant.
Resolving the role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission in households with members from different generations is crucial for containing the current pandemic. ...We conducted a large-scale, multicenter, cross-sectional seroepidemiologic household transmission study in southwest Germany during May 11-August 1, 2020. We included 1,625 study participants from 405 households that each had ≥1 child and 1 reverse transcription PCR-confirmed SARS-CoV-2-infected index case-patient. The overall secondary attack rate was 31.6% and was significantly higher in exposed adults (37.5%) than in children (24.6%-29.2%; p = <0.015); the rate was also significantly higher when the index case-patient was >60 years of age (72.9%; p = 0.039). Other risk factors for infectiousness of the index case-patient were SARS-CoV-2-seropositivity (odds ratio OR 27.8, 95% CI 8.26-93.5), fever (OR 1.93, 95% CI 1.14-3.31), and cough (OR 2.07, 95% CI 1.21-3.53). Secondary infections in household contacts generate a substantial disease burden.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Hyperammonemia is the common biochemical hallmark of urea cycle disorders, activating neurotoxic pathways. If untreated, affected individuals have a high risk of irreversible brain damage and ...mortality. Here we show that acute hyperammonemia strongly enhances transamination-dependent formation of osmolytic glutamine and excitatory glutamate, thereby inducing neurotoxicity and death in ammoniotelic zebrafish larvae via synergistically acting overactivation of NMDA receptors and bioenergetic impairment induced by depletion of 2-oxoglutarate. Intriguingly, specific and irreversible inhibition of ornithine aminotransferase (OAT) by 5-fluoromethylornithine rescues zebrafish from lethal concentrations of ammonium acetate and corrects hyperammonemia-induced biochemical alterations. Thus, OAT inhibition is a promising and effective therapeutic approach for preventing neurotoxicity and mortality in acute hyperammonemia.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This book is designed as a source of practical information of use in the diagnosis and management of patients with inherited diseases of metabolism. We have kept the focus, as did Garrod, on the ...inborn errors. This permits a unity of theme. At the same time, the reality is that genetically determined human variation in metabolism leads to an enormous variety of clinical expression crossing most of the boundaries of clinical subspecialty.
E-learning and blended learning approaches gain more and more popularity in emergency medicine curricula. So far, little data is available on the impact of such approaches on procedural learning and ...skill acquisition and their comparison with traditional approaches.
This study investigated the impact of a blended learning approach, including Web-based virtual patients (VPs) and standard pediatric basic life support (PBLS) training, on procedural knowledge, objective performance, and self-assessment.
A total of 57 medical students were randomly assigned to an intervention group (n=30) and a control group (n=27). Both groups received paper handouts in preparation of simulation-based PBLS training. The intervention group additionally completed two Web-based VPs with embedded video clips. Measurements were taken at randomization (t0), after the preparation period (t1), and after hands-on training (t2). Clinical decision-making skills and procedural knowledge were assessed at t0 and t1. PBLS performance was scored regarding adherence to the correct algorithm, conformance to temporal demands, and the quality of procedural steps at t1 and t2. Participants' self-assessments were recorded in all three measurements.
Procedural knowledge of the intervention group was significantly superior to that of the control group at t1. At t2, the intervention group showed significantly better adherence to the algorithm and temporal demands, and better procedural quality of PBLS in objective measures than did the control group. These aspects differed between the groups even at t1 (after VPs, prior to practical training). Self-assessments differed significantly only at t1 in favor of the intervention group.
Training with VPs combined with hands-on training improves PBLS performance as judged by objective measures.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Long COVID in children and adolescents remains poorly understood due to a lack of well-controlled studies with long-term follow-up. In particular, the impact of the family context on persistent ...symptoms following SARS-CoV-2 infection remains unknown. We examined long COVID symptoms in a cohort of infected children, adolescents, and adults and their exposed but non-infected household members approximately 1 year after infection and investigated clustering of persistent symptoms within households.
1267 members of 341 households (404 children aged <14 years, 140 adolescents aged 14-18 years and 723 adults) were categorized as having had either a SARS-CoV-2 infection or household exposure to SARS-CoV-2 without infection, based on three serological assays and history of laboratory-confirmed infection. Participants completed questionnaires assessing the presence of long COVID symptoms 11-12 months after infection in the household using online questionnaires.
The prevalence of moderate or severe persistent symptoms was statistically significantly higher in infected than in exposed women (36.4% 95% CI: 30.7–42.4% vs 14.2% 95% CI: 8.7–21.5%), infected men (22.9% 95% CI: 17.9–28.5% vs 10.3% 95% CI: 5.8–16.9%) and infected adolescent girls (32.1% 95% CI: 17.2–50.5% vs 8.9% 95%CI: 3.1–19.8%). However, moderate or severe persistent symptoms were not statistically more common in infected adolescent boys aged 14–18 (9.7% 95% CI: 2.8–23.6% or in infected children <14 years (girls: 4.3% 95% CI: 1.2–11.0%; boys: 3.7% 95% CI: 1.1–9.6%) than in their exposed counterparts (adolescent boys: 0.0% 95% CI: 0.0–6.7%; girls < 14 years: 2.3% 95% CI: 0·7–6·1%; boys < 14 years: 0.0% 95% CI: 0.0–2.0%). The number of persistent symptoms reported by individuals was associated with the number of persistent symptoms reported by their household members (IRR=1·11, p=·005, 95% CI 1.03–1.20).
In this controlled, multi-centre study, infected men, women and adolescent girls were at increased risk of negative outcomes 11-12 months after SARS-CoV-2 infection. Amongst non-infected adults, prevalence of negative outcomes was also high. Prolonged symptoms tended to cluster within families, suggesting family-level interventions for long COVID could prove useful.
Ministry of Science, Research and the Arts, Baden-Württemberg, Germany.
The explosion of insights in the field of metabolic disease has shed new light on diagnostic as well as treatment options. `Inherited Metabolic Disease - A Clinical Approach` is written with a ...reader-friendly consistent structure. It helps the reader to find the information in an easily accessible and rapid way when needed. Starting with an overview of the major groups of metabolic disorders it includes algorithms with questions and answers as well as numerous graphs, metabolic pathways, and an expanded index. Clinical and diagnostic details with a system and symptom based are given to facilitate an efficient and yet complete diagnostic work-up of individual patients. TOC:Introduction to Inborn Errors of Metabolism.- Disorders of Intermediary Metabolism.- Disorders of the Biosynthesis and Breakdown of Complex Molecules.- Neurotransmitter Defects and Related Disorders.- Other Inborn Errors of Metabolism.- Approach to the Patient with Metabolic Disease.- Pathological Neonatal Screening Results.- Metabolic Emergencies.- Cardiovascular Abnormalities.- Hepatic Abnormalities.- Gastrointestinal and General Abdominal Symptoms.- Renal and Electrolyte Disturbances.- Neurological Symptoms.- Myopathies.- Psychiatric Problems.- Eye Disorders.- Skin and Hair Disorders.- Sceletal Abnormalities.- Congenital Malformations.- Hematological Abnormalities.- Immunological Problems.- Peculiar Odour.- Investigations for Metabolic Disease.- Biochemical Studies.- Enzyme Studies.- DNA Studies.- Function Tests.- Other Investigations.- Postmodern Investigations.- Work-up for an Unclassified Multisystem Disease.- Work-up for a Possible Mitochondrial Disorder.- Indications for Lumbar Puncture.- Prenatal Diagnosis.- Family Analyses - Carrier Analysis.- Appendix.
Pediatric emergencies challenge professional teams by demanding substantial cognitive effort, skills and effective teamwork. Educational designs for team trainings must be aligned to the needs of ...participants in order to increase effectiveness. To assess these needs, a survey among physicians and nurses of a tertiary pediatric center in Germany was conducted, focusing on previous experience, previous training in emergency care, and individual training needs.
Fifty-three physicians and 75 nurses participated. Most frequently experienced emergencies were respiratory failure, resuscitation, seizure, shock/sepsis and arrhythmia. Resuscitations were perceived as being particularly precarious. Team collaboration and communication were major issues arising from previous emergency situations, but perceptions differed between physicians and nurses. Regarding previous training, physicians were accustomed to self-directed learning, whereas nurses usually attended practical courses. Both physicians and nurses rated themselves as having moderate levels of knowledge and skills for pediatric emergencies, though residents reported the significantly lowest preparedness. Both professions reported a high need for training of basic procedures and emergency algorithms, physicians even more than nurses.
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