Genetic landscape of pediatric acute liver failure of indeterminate origin.

BACKGROUND AND AIMS: 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. APPROACH AND RESULTS: 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. RESULTS: 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. CONCLUSIONS: 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.

Muscle hypertrophy and neuroplasticity in the small bowel in short bowel syndrome.

Short bowel syndrome (SBS) is a severe, life-threatening condition and one of the leading causes of intestinal failure in children. Here we were interested in changes in muscle layers and especially in the myenteric plexus of the enteric nervous system (ENS) of the small bowel in the context of intestinal adaptation. Twelve rats underwent a massive resection of the small intestine to induce SBS. Sham laparotomy without small bowel transection was performed in 10 rats. Two weeks after surgery, the remaining jejunum and ileum were harvested and studied. Samples of human small bowel were obtained from patients who underwent resection of small bowel segments due to a medical indication. Morphological changes in the muscle layers and the expression of nestin, a marker for neuronal plasticity, were studied. Following SBS, muscle tissue increases significantly in both parts of the small bowel, i.e., jejunum and ileum. The leading pathophysiological mechanism of these changes is hypertrophy. Additionally, we observed an increased nestin expression in the myenteric plexus in the remaining bowel with SBS. Our human data also showed that in patients with SBS, the proportion of stem cells in the myenteric plexus had risen by more than twofold. Our findings suggest that the ENS is tightly connected to changes in intestinal muscle layers and is critically involved in the process of intestinal adaptation to SBS.

[Interdisciplinary endoscopy in children]. / Interdisziplinäre Endoskopie bei Kindern.

INTRODUCTION: Endoscopic diagnostics and interventions in children require a high level of expertise from different fields. The small dimensions, the vulnerability of the patients and the rarity of the diseases and problems as well as the necessity for the most modern endoscopic technology can only be mastered by an adequately constructed team. METHODS: We describe the typical indications, personnel and technical requirements and make suggestions for process organization. The necessity for an interdisciplinary approach is described using three illustrative examples. RESULT: No single specialty alone can cope with the manifold challenges of pediatric endoscopy. The organization should therefore favor low-threshold collaborations. OUTLOOK: Further development of techniques is needed especially in the field of premature infant care and children with intestinal failure and motility disorders.

Environmental factors drive language density more in food-producing than in hunter-gatherer populations.

Linguistic diversity is a key aspect of human population diversity and shapes much of our social and cognitive lives. To a considerable extent, the distribution of this diversity is driven by environmental factors such as climate or coast access. An unresolved question is whether the relevant factors have remained constant over time. Here, we address this question at a global scale. We approximate the difference between pre- versus post-Neolithic populations by the difference between modern hunter-gatherer versus food-producing populations. Using a novel geostatistical approach of estimating language and language family densities, we show that environmental-chiefly climate factors-have driven the language density of food-producing populations considerably more strongly than the language density of hunter-gatherer populations. Current evidence suggests that the population dynamics of modern hunter-gatherers is very similar to that of what can be reconstructed from the Palaeolithic record. Based on this, we cautiously infer that the impact of environmental factors on language densities underwent a substantial change with the transition to agriculture. After this transition, the environmental impact on language diversity in food-producing populations has remained relatively stable since it can also be detected-albeit in slightly weaker form-in models that capture the reduced linguistic diversity during large-scale language spreads in the Mid-Holocene.

Differential effect of a patient-education transition intervention in adolescents with IBD vs. diabetes.

Patient education programs (PEPs) to improve disease management are part of standard and regular treatment in adolescents with diabetes. In Germany, youth with inflammatory bowel disease (IBD) receive individual counseling but not PEPs in group settings. Generic PEPs have been developed in order to improve transition from child-centered to adolescent health services. The aim of the study was to investigate the effects of a transition-oriented PEP on quality of life (QoL) and self-management in young patients with IBD (PEP naive), compared to patients with diabetes (familiar with PEPs). A 2-day transition workshop was oriented at improving psychosocial skills and addressed both generic as well as specific aspects of the condition. A controlled trial on the outcomes of a generic transition-oriented PEP was conducted in 14- to 20-year-old patients with IBD (n = 99) and diabetes (n = 153). Transition competence and QoL were assessed at baseline and 6-month follow-up. Results show that the intervention lead to a significant increase in QoL only in patients with IBD. The PEP significantly improved transition competence in both groups, however to a higher extent in subjects with IBD. CONCLUSION: Transition-oriented PEPs can have differential effects in different patient groups. However, this needs further longitudinal investigations. What is Known: • To date, evidence has accumulated concerning the effectiveness of patient education programs (PEPs) in pediatric health care for chronic conditions such as type 1 diabetes, asthma, atopic dermatitis, or obesity but is less documented in inflammatory bowel disease (IBD). In particular, PEPs in the transition period have not been investigated in youth with IBD. • The current study focuses on evaluating a PEP for transition preparation and management designed to be generically used across different chronic conditions since many aspects of managing chronic conditions share commonalities across conditions. The 2-day workshop included condition-specific modules adapted to the specific medical needs but was otherwise similar in quality and organization among different conditions. What is New: • The transition-oriented PEP was effective in enhancing self-management and transition management skills in both patients with IBD and diabetes; however, effects were higher in youth with IBD. A significant impact of the intervention on patients' QoL compared to the control group was only identified in youth with IBD. • We recommend that patients with IBD have access to PEP as a standard treatment as well as to a transition program during the course of illness.

XIAP variants in male Crohn's disease.

OBJECTIVE: The genetic basis of inflammatory bowel disease (IBD) is incompletely understood. The aim of this study was to identify rare genetic variants involved in the pathogenesis of IBD. DESIGN: Exome sequencing and immunological profiling were performed in a patient with early onset Crohn's disease (CD). The coding region of the gene encoding X-linked inhibitor of apoptosis protein (XIAP) was sequenced in samples of 275 paediatric IBD and 1047 adult-onset CD patients. XIAP genotyping was performed in samples of 2680 IBD patients and 2864 healthy controls. Functional effects of the variants identified were investigated in primary cells and cultured cell lines. RESULTS: Our results demonstrate the frequent occurrence of private variants in XIAP in about four percent of male patients with paediatric-onset CD. While XIAP mutations are known to be associated with the primary immunodeficiency (PID) X-linked lymphoproliferative disease type 2 (XLP2), CD patients described here exhibited intestinal inflammation in the absence of XLP2 and harboured a spectrum of mutations partially distinct from that observed in XLP2. The majority of XIAP variants identified was associated with a selective defect in NOD1/2 signalling, impaired NOD1/2-mediated activation of NF-κB, and altered NF-κB-dependent cytokine production. CONCLUSIONS: This study reveals the unanticipated, frequent occurrence of XIAP variants in male paediatric-onset CD. The link between XIAP and NOD1/2, and the association of XIAP variants with XLP2, support the concept of PID in a subset of IBD patients. Moreover, these studies provide a rationale for the implementation of XIAP sequencing in clinical diagnostics in male patients with severe CD.

Chronic intestinal failure in children.

BACKGROUND: Chronic intestinal failure (CIF) in childhood is caused by congenital malformations and inflammatory diseases of the gut. Its reported prevalence is 13.7 per million population. Long-term home parenteral nutrition has dramatically improved the life expectancy and quality of life of children with CIF. The affected children are now treated with parenteral nutrition at home as soon as their medical state and family circumstances allow. METHODS: The authors present data from a patient registry and review publications retrieved by a selective literature search. RESULTS AND CONCLUSION: Children with CIF can now be expected to survive beyond adolescence, at the very least, and enjoy good quality of life. This goal can only be achieved if nutritional therapy is carried out safely and the affected children's development is closely monitored by an interdisciplinary team that consists of primary care physicians/family doctors, neonatologists, pediatric gastroenterologists, and pediatric surgeons. Moreover, the prevention, early detection, and appropriate treatment of complications such as infection, liver disease, renal dysfunction, and disturbances of bone metabolism is of vital importance. The patients' families must be supported by specially qualified ambulatory nurses and social workers. Treatment with parenteral, enteral, and oral nutrition and surgery enables most infants with CIF to meet all their nutritional needs orally by the time they start going to school. For children who suffer from intractable complications, intestinal transplantation provides a real and increasing chance of survival.

Implications for the usage of the left lateral liver graft for infants ≤10 kg, irrespective of a large-for-size situation--are monosegmental grafts redundant?

Organ donor shortage for infant liver transplant recipients has lead to an increase in splitting and living donation. For cases in which even transplantation of the left lateral graft (Couinaud's segments II + III) results in a "large for size situation" with an estimated graft body weight ratio (GBWR) of >4%, monosegmental liver transplantation was developed. This, however, bears complications because of greater parenchymal surface and suboptimal vascular flow. We exclusively use the left lateral graft from living donors or split grafts. Temporary abdominal closure is attempted in cases of increased pressure. We report of 41 pediatric transplants in 38 children ≤10 kg. Within this group, there were 23 cases with a GBWR of ≥4, and 15 cases with a GBWR <4. There was no statistical difference in vascular or biliary complications. Despite a more frequent rate of temporary abdominal closure, we did not find a higher rate of intra-abdominal infections. Overall, patient and graft survival was excellent in both groups (one death, three re-transplants). We noticed, however, that the ventro-dorsal diameter of the graft appears to be more relevant to potential graft necrosis than the actual graft size. In conclusion, the usage of monosegmental grafts seems unnecessary if transplantation of left lateral grafts is performed by an experienced multidisciplinary team, and temporary abdominal closure is favored in cases of increased abdominal pressure.

Influence of different intravenous lipid emulsions on hepatobiliary dysfunction in a rabbit model.

OBJECTIVES: Long-term total parenteral nutrition (TPN) in children is often complicated by the development of cholestasis, liver fibrosis, and liver failure. High doses of intravenous lipids may be involved in the pathogenesis of hepatobiliary dysfunction. The purpose of this study was to determine whether the use of 2 newly developed lipid emulsions could reduce liver damage. MATERIALS AND METHODS: Three groups of prepubescent rabbits received TPN including a lipid emulsion either based on soybean oil, olive oil, or soybean oil with n-3 fatty acids added. Enterally fed animals served as controls. After 21 d the animals were killed. Serum samples were obtained at the beginning and end of the study period. Specimens were processed for histological evaluation using a specific score to assess the severity of liver damage. RESULTS: Biochemical parameters did not predict the extent of liver damage. Hydropic degeneration as an indicator of toxic liver injury was the predominant histological alteration regardless of the type of lipids infused. The extent of fibrosis did not significantly differ among treatment groups except for animals infused with n-3 fatty acids exhibiting increased fibrotic transformation as compared with controls. CONCLUSION: In our animal model, the use of a lipid emulsion with a reduced amount of polyunsaturated fatty acids was not superior to a lipid emulsion based on soybean oil. Long-term application of n-3 fatty acids was associated with more extensive fibrosis. Therefore, intravenous n-3 fatty acids containing lipid preparations (fish oil) should not be used in patients for long-term TPN.

Cisapride may improve feeding tolerance of preterm infants: a randomized placebo-controlled trial.

To evaluate the efficacy of cisapride in improving tolerance of enteral feeding, 59 premature infants were randomized into a blinded placebo-controlled study. Treatment was initiated with the introduction of enteral feeding and continued until 150 ml/kg/day of milk were tolerated. Only in extremely low birth weight (ELBW) infants, was the time to tolerate full enteral feeding shorter in the treatment group, whereas ECG recordings showed a significantly prolonged QTc interval during treatment. Two children developed cardiac rhythm disturbances. In conclusion premature infants may not benefit from routine use of the drug to improve enteral feeding, and seem to be more vulnerable to its side effects.

Gender-based differences in children with sepsis and ARDS: the ESPNIC ARDS Database Group.

Male gender predisposes to severe sepsis and septic shock. This effect has been ascribed to higher levels of testosterone. The ESPNIC ARDS database was searched, to determine if there was evidence of a similar male preponderance in severe sepsis in prepubertal patients in spite of low levels of male sex hormones at this age. A total of 72 patients beyond neonatal age up to 8 years of age with sepsis were identified. The male/female (M/F) ratio was 1.7 (1.0;2.7) and differed significantly from non-septic ARDS patients in this age group [n = 209; M/F = 1.0 (0.8;1.3)]. The highest M/F-ratio was observed in the first year of life. The gender-ratio was the same as reported in adult patients with sepsis. In infants between 1 month and 12 months of age, the ratio was 2.8 (1.2;6.1) (Chi2= 5.6; P< 0.01), in children from 1 year to 8 years of age it was 1.2 (0.7;2.2) (n.s.). In a subgroup of patients with severe sepsis or septic shock, caused by other bacteria than Neisseria meningitidis, the M/F-ratio was 2.1 (1.2;3.6) (Chi2= 4.9; P<0.05), while in patients with meningococcal sepsis (n=20) the M/F-ratio was 1.0 (0.4;2.3). In prepubertal ARDS patients with sepsis an increased frequency of male patients is found, comparable to adults. No male preponderance exists in patients with ARDS due to meningococcal septic shock. Since levels of testosterone and other sex hormones are extremely low at this age, we conclude that factors others than testosterone are involved in the male preponderance in severe sepsis.

Treatment with bovine surfactant in severe acute respiratory distress syndrome in children: a randomized multicenter study.

OBJECTIVE: To determine whether bovine surfactant given in cases of severe pediatric acute respiratory distress syndrome (ARDS) improves oxygenation. DESIGN: Single-center study with 19 patients, followed by a multicenter randomized comparison of surfactant with a standardized treatment algorithm. Primary endpoint PaO(2)/FIO(2) at 48 h, secondary endpoints: PaO(2)/FIO(2) at 2, 4, 12, and 24 h, survival, survival without rescue, days on ventilator, subgroups analyzed by analysis of variance to identify patients who might benefit from surfactant. SETTING: Multicenter study in 19 reference centers for ARDS. PATIENTS: Children after the 44th postconceptional week and under 14 years old, admitted for at least 4 h, ventilated for 12-120 h, and without heart failure or chronic lung disease. In the multicenter study 35 patients were recruited; 20 were randomized to the surfactant group and 15 to the nonsurfactant group. Decreasing recruitment of patients led to a preliminary end of this study. INTERVENTIONS: Administration of 100 mg/kg bovine surfactant intratracheally under continuous ventilation and PEEP, as soon as the PaO(2)/FIO(2) ratio dropped to less than 100 for 2 h (in the pilot study increments of 50 mg/kg as long as the PaO(2)/FIO(2) did not increase by 20%). A second equivalent dose within 48 h was permitted. RESULTS: In the pilot study the PaO(2)/FIO(2) increased by a mean of 100 at 48 h (n=19). A higher PaO(2)/FIO(2) ratio was observed in the surfactant group 2 h after the first dose (58 from baseline vs. 9), at 48 h there was a trend towards a higher ratio (38 from baseline vs. 22). The rate of rescue therapy was significantly lower in the surfactant group. Outcome criteria were not affected by a second surfactant dose (n=11). A significant difference in PaO(2)/FIO(2) in favor of surfactant at 48 h was found in the subgroup with an initial PaO(2)/FIO(2) ratio higher than 65 and in patients without pneumonia. CONCLUSIONS. Surfactant therapy in severe ARDS improves oxygenation immediately after administration. This improvement is sustained only in the subgroup of patients without pneumonia and that with an initial PaO(2)/FIO(2) ratio higher than 65

Evaluation of the performance of general emergency physicians in pediatric emergencies: Obstructive airway diseases, seizures, and trauma.

BACKGROUND: In the Lübeck region, as is usual in Germany, hospital-based emergency physicians are called for outside emergencies. They evaluate and stabilize patients and transfer them to hospital facilities of their choice (no emergency department system). These physicians are mainly anesthesiologists, surgeons, and internists-not pediatricians. Numerous quality management studies have shown an overall excellent performance of this system, but it has not been evaluated for pediatric emergencies. PATIENTS AND METHODS: In a prospective, observational study conducted over a 1-year period, all pediatric emergencies (patient age < 15 y) treated by the emergency physician service were studied. A syllabus with standards of care for children with trauma, obstructive airway disease, and seizures was distributed. In accordance with this syllabus, the actions taken were documented by the emergency physicians, and the cases were documented as life threatening or not and were classified as "trauma," "obstructive airway disease," "seizures," or "other" by the admitting pediatric intensivists and surgeons. The admitting attending physician compared these data and evaluated whether the standard management required by the syllabus was followed. RESULTS: A total of 422 pediatric cases out of 11,605 emergencies (3.5%) were recorded (147 [34.8%] trauma patients, 41 [9.7%] patients with obstructive airway disease, and 108 [25.6%] patients with seizures). Of the pediatric patients, 20.5% had life-threatening conditions; three children died before arrival, and the others required treatment in the intensive care unit. In 25% of trauma patients, deficiencies in primary treatment were observed: no documentation of neurologic status in 10.6%, no cervical immobilization in 15% of head trauma patients, and no adequate analgesia in 7%. In 25% of seizure patients, neurologic status was not documented, although treatment was in accordance with the standard of care. The worst results were observed in infants with obstructive airway disease: no documentation of oxygen saturation in 71.4%, no oxygen therapy despite hypoxemia in seven of 12 patients, and overall therapy not in accordance with the standard of care in 50%. CONCLUSIONS: The high quality of the emergency physician service documented for adults is not reproduced in the pediatric population. Trauma and seizures with similarities to adult cases are handled in a fair manner. However, the most important pediatric diagnostic entity of obstructive airway disease is often not treated adequately. Intensified educational programs for emergency physicians are warranted.

HPA-1 carrier status and thrombocytopenia in preterm infants with a birth weight below 1500 grams.

OBJECTIVE: In cohorts of infants with proven neonatal alloimmune thrombocytopenia (NAIT) an unusual high rate of preterm infants has been reported, raising the question of whether NAIT contributes to the high rate of intracranial hemorrhage in preterm infants. METHODS: We genotyped the HPA-1-allele in a large cohort of term (n = 205) and very low birth weight infants (VLBW-infants, n = 299) with polymerase-chain-reaction and restriction enzyme digestion. RESULTS: HPA-1a/b is the only fetal HPA-1-genotype in which alloimmunization and NAIT could occur. Genotype distribution did not differ between term and VLBW-infants (p = 0.26). Furthermore, neither HPA-1a/b genotype nor platelet count at birth were of significant prognostic value in predicting subsequent intracranial haemorrhage or death in VLBW-infants (p = 0.93 and p = 0.19 respectively). CONCLUSION: Our data did not support the hypothesis that routine screening of preterm infants or their mothers for HPA-1-genotype is of additional value in the care of these infants.