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To evaluate the role of cerebral ultrasonography studies (CUSS) in detecting intracerebral and cranial pathologies (hemorrhages, ischemia, skull fractures) in near-term and term neonates following assisted vaginal delivery. Prospective single-center study (11/2017-11/2018) at the University Children's Hospital of Saarland, Homburg, Germany including newborns with a gestational age ≥ 36 weeks born by assisted vaginal delivery. In all newborns, a standardized CUSS was performed within the first three days of life prior to discharge. 200 neonates (43.0 % female, 57.0 % male; gestational age 39.6 ± 1.3 weeks) were included in this study (birth weight 3345.6 ± 450.6 g, body length 51.7 ± 2.5 cm, head circumference 35.0 ± 1.5 cm). 67 (33.5 %) neonates had minor external injuries of the scalp. 5 children showed clinical neurologic abnormalities: 4 (2.0 %) seizures and 1 facial palsy (0.5 %). In 34 (17.0 %) patients, minor incidental intracranial abnormalities unrelated to mode of delivery were detected on CUSS. No intracerebral, cranial pathologies or skull fractures were seen on routine CUSS. Routine CUSS in newborns after assisted vaginal delivery did not yield clinically relevant results in our cohort. Clinical observation and selective CUSS in symptomatic newborns might be more efficient than routine CUSS.ZIEL: Bewertung der Rolle von zerebralen Ultraschalluntersuchungen (cUS) bei der Erkennung von intrazerebralen und kranialen Pathologien (Blutungen, Ischämie, Schädelfrakturen) bei Neugeborenen nach vaginal-operativer Entbindung kurz vor oder am Termin. Prospektive Studie an einem einzigen Zentrum (11/2017–11/2018) am Universitätskinderklinikum, Homburg, Deutschland, die Neugeborene mit einem Gestationsalter von ≥ 36 Wochen nach vaginal-operativer Entbindung einschließt. Bei allen Neugeborenen wurde innerhalb der ersten drei Lebenstage vor Entlassung ein standardisierter cUS durchgeführt. 200 Neugeborene (43,0 % weiblich, 57,0 % männlich; Gestationsalter 39,6 ± 1,3 Wochen) wurden in diese Studie eingeschlossen (Geburtsgewicht 3345,6 ± 450,6 g, Körperlänge 51,7 ± 2,5 cm, Kopfumfang 35,0 ± 1,5 cm). 67 Neugeborene (33,5 %) hatten leichte, äußere Verletzungen der Kopfhaut. 5 Kinder wiesen klinische neurologische Anomalien auf: 4 Krampfanfälle (2,0 %) und 1 Faszialisparese (0,5 %). Bei 34 Patienten (17,0 %) wurden im cUS geringfügige zufällige intrakraniale Anomalien festgestellt, die nicht mit dem Entbindungsmodus zusammenhingen. Beim Routine-cUS wurden keine intrazerebralen oder kranialen Pathologien oder Schädelfrakturen festgestellt. Routine-cUS bei Neugeborenen nach vaginal-operativer Entbindung erbrachte in unserer Kohorte keine klinisch relevanten Ergebnisse. Klinische Beobachtung und selektiver cUS sind bei symptomatischen Neugeborenen möglicherweise effizienter als routinemäßiger cUS.

Objective This study aimed to measure health-related quality of life (HRQOL) in children and adolescents with tuberous sclerosis complex (TSC) and quality of life (QOL) and depressive symptoms among caregivers. Methods Adequate metrics were used to assess HRQOL in children and adolescents with TSC (4-18 years, KINDLR) as well as QOL (EQ-5D) and symptoms of depression (BDI-II) among caregivers. Predictors for reduced HRQOL and depressive symptoms were identified by variance analysis, ordinal regression, and bivariate correlation. Results The mean HRQOL score was 67.9 ± 12.7, and significantly lower values were associated with increasing age, attending special needs education, TSC-associated psychiatric symptoms, and drug-related adverse events. The mean QOL of caregivers was 85.4 ± 15.7, and caregiver's sex, TSC mutation locus, familial TSC clustering, special needs education, degree of disability, care dependency, presence of TSC-associated psychiatric symptoms, and TSC severity were significant predictors of lower QOL. Depressive symptoms were identified in 45.7% of caregivers, associated with female sex of the caregiver, familial TSC clustering, special needs education, and presence of TSC-associated psychiatric symptoms of the child. Multivariate regression analysis revealed adolescence and drug-related adverse events as significant predictors for lower HRQOL in TSC children, and TSC2 variants predicted lower QOL and depressive symptoms in caregivers. Conclusion Compared with other chronic diseases, such as headache, diabetes or obesity, children with TSC have significantly lower HRQOL, which further decreases during adolescence. A decreased HRQOL of patients correlates with a lower QOL and increased symptoms of depression of their caregivers. These results may improve the comprehensive therapy and care of children and adolescents with TSC and their families and caregivers. Trial registration DRKS, DRKS00016045. Registered 01 March 2019, http://www.drks.de/DRKS00016045.

Seizures are a primary and early disease manifestation of Tuberous Sclerosis Complex (TSC). We aimed to describe the age-stratified patterns of antiseizure drug (ASD) treatments among children, adolescents, and adults with TSC in Germany. Additionally, we reviewed real-world and clinical study evidence regarding ASD utilization in patients with TSC.We evaluated the pattern of routine ASD use and everolimus prescriptions based on a 2019 multicenter survey of 268 individuals with TSC-associated epilepsy. We contextualized the results with a structured review of real-world and clinical study evidence.TSC-associated epilepsy treatment comprises a wide variety of ASDs. In this German sample, the majority of patients were treated with polytherapy, and lamotrigine (34.7%), valproate (32.8%), oxcarbazepine (28.7%), vigabatrin (19.0%), and levetiracetam (17.9%) were identified as the most-commonly used ASDs. In addition, everolimus was used by 32.5% of patients. In adherence to current TSC guidelines, the disease-modifying ASD vigabatrin was widely used in children (58% below the age of 5 years), whereas treatment in adults did not necessarily reflect guideline preference for (partial) GABAergic ASDs.The selection of ASDs for patients with TSC-associated epilepsy follows well-evaluated recommendations, including the guidelines regarding vigabatrin use in children. Several characteristics, such as the comparatively high frequency of valproate use and polytherapy, reflect the severity of TSC-associated epilepsy.

In diesem Beitrag werden einige Besonderheiten der Infektionspravention bei intensivmedizinisch behandelten Fruh und Neugeborenen dargestellt. Erganzend finden sich Hinweise zum krankenhaushygienischen Management der SARS-CoV-2(„severe acute respiratory syndrome coronavirus 2“)-Pandemie und zur Antibiotic Stewardship in der neonatologischen Intensivmedizin.

Duchenne muscular dystrophy (DMD) is the most frequent genetic neuromuscular disease in childhood with loss of ambulation usually occurring around the age of 9-11 years.Based on current guidelines and clinical trials, neuropediatric and neurological experts developed recommendations for the treatment of nonambulatory DMD patients focusing on drug treatment of adults. This advisory board was sponsored by PTC Therapeutics, the distributers of the substance ataluren.Loss of ambulation is heterogeneously defined across clinical trials. Among others, the need of a wheelchair, ambulation without mobility aids or maximum walking distance can be suitable parameters for assessment. Treatment of DMD patients at any stage of the disease is based on supportive and symptomatic measures, which should be continued after loss of ambulation. In addition, disease-modifying drugs are available for the treatment of DMD and glucocorticoids are the usual standard of care treatment even beyond the loss of ambulation. Ataluren, a potentially dystrophin restorative, disease-modifying treatment, has been approved for patients with DMD due to a nonsense mutation (nmDMD), which applies to approximately 13% of DMD patients and is usually combined with steroids. Clinical data from the STRIDE registry demonstrated a delayed disease progression even after loss of ambulation. Currently, no reliable data are available for exon skipping approaches in adult DMD patients. The antioxidant idebenone could be an option in nonambulant adolescent patients not treated with glucocorticoids and without other therapeutic options. A combination treatment of idebenone and glucocorticoids is currently being investigated in a clinical trial. Add-on treatment with idebenone in addition to ataluren may be considered for nonambulant nmDMD patients. Some of the discussed treatment options are still in clinical trials or there are not enough data for older DMD patients; therefore, these expert recommendations correspond to evidence class IV.HINTERGRUND: Die Muskeldystrophie Duchenne (DMD) ist die häufigste genetische neuromuskuläre Krankheit im Kindesalter, bei der es meist im Alter von 9 bis 11 Jahren zum Verlust der Gehfähigkeit kommt.Auf der Grundlage aktueller Leitlinien und Studien erarbeiteten neuropädiatrische und neurologische Experten im Rahmen eines von der Firma PTC Therapeutics GmbH (Frankfurt am Main, Deutschland), die die Substanz Ataluren vertreibt, gesponserten Advisory Boards Empfehlungen zur Behandlung nichtgehfähiger Patienten mit DMD mit Schwerpunkt medikamentöse Therapien von Erwachsenen.Der Verlust der Gehfähigkeit wird in Studien sehr unterschiedlich definiert und bezieht sich u. a. auf die Rollstuhlpflicht, das selbständige Gehen ohne Hilfsmittel oder die maximale Gehstrecke. Grundlage der Therapie von Patienten mit DMD in jedem Krankheitsstadium sind supportive und symptomatische Maßnahmen, die in der Regel auch nach dem Verlust der Gehfähigkeit intensiv weitergeführt werden sollten. Zusätzlich stehen den Patienten medikamentöse Therapien mit dem Ziel der Modifikation des Krankheitsverlaufes zur Verfügung. Glukokortikoide bilden den Stützpfeiler der medikamentösen Therapie auch über den Verlust der Gehfähigkeit hinaus, dann meist in reduzierter Dosis. Für Patienten mit DMD aufgrund einer Nonsense-Mutation (nmDMD), ca. 13 % aller DMD-Patienten, steht Ataluren als potenziell dystrophinwiederherstellende, krankheitsmodifizierende Therapie zur Verfügung; klinische Daten aus dem STRIDE-Register zeigen eine verzögerte Krankheitsprogression auch nach Verlust der Gehfähigkeit. Zum Exon-Skipping liegen für erwachsene Patienten derzeit noch keine belastbaren Daten vor. Das Antioxidans Idebenon kommt bei nichtgehfähigen, jugendlichen Patienten ohne therapeutische Alternative, die nicht mit Glukokortikoiden behandelt werden können, infrage. Ataluren eignet sich zur kombinierten Behandlung mit Glukokortikoiden, eine Kombination von Idebenon und Glukokortikoiden wird derzeit in einer klinischen Studie überprüft. Eine Add-on-Therapie mit Idebenon zusätzlich zu Ataluren ist bei nichtgehfähigen nmDMD-Patienten zu erwägen. Bedingt durch die Tatsache, dass sich einige der diskutierten Therapieoptionen noch in der Phase der klinischen Prüfung befinden oder noch keine oder nur begrenzte Daten für ältere Patienten mit DMD vorliegen, handelt es sich um Expertenempfehlungen entsprechend der Evidenzklasse IV.

Multisystem inflammatory syndrome in children (MIS-C or PIMS) is a rare but serious complication after an infection with SARS-CoV-2. A possible involvement of pathogenetically relevant autoantibodies has been discussed. Recently neutralizing autoantibodies against anti-inflammatory receptor antagonists progranulin (PGRN) and IL-1-receptor antagonist (IL-1-Ra) were discovered in adult patients with critical COVID-19.Plasma of an index case with severe PIMS/MIS-C was analyzed for autoantibodies against IL-1-Ra and PGRN. The study was extended by a case series of 12 additional patients. In addition to ELISA for of antibodies, IL-1-Ra plasma levels were determined and IL-1-Ra was analyzed by Western-blot and isoelectric focusing. Functional activity of the autoantibodies was examined in vitro with IL-1ß reporter assays.Antibodies against IL-1-Ra could be detected in 10 of 13 (76.9%) patients with PIMS/MIS-C, but not in controls. In contrast to critical COVID-19 in adults, no IL-1-Ra antibodies of the IgM class were detected in PIMS/MIS-C. IL-1-Ra-antibodies exclusively belonged to IgG1. No antibodies directed against PGRN were detected. Western blots and ELISA showed a concomitant reduction of free IL-1-Ra plasma levels in the presence of IL-1-Ra-antibodies. The antibodies inhibited IL-1-Ra function in IL-1ß reporter cell assays. Notably, an additional, hyperphosphorylated, transiently occurring atypical isoform of IL-1-Ra was observed in all IL-1-Ra autoantibody-positive patients.To conclude, IL-1-Ra autoantibodies were observed in high frequency in children with PIMS/MIS-C. They may represent a diagnostic and pathophysiologically relevant marker for PIMS/MIS-C. Their generation is likely to be triggered by an atypical, hyperphosphorylated isoform of IL-1-Ra.

Background: Histologic chorioamnionitis is only diagnosed postnatally which prevents interventions. We hypothesized that volatile organic compounds (VOCs) in the amniotic fluid might be useful biomarkers for chorioamnionitis and that VOC profiles differ between amnionitis of different origins.Methods: Time-mated ewes received intra-amniotic injections of media or saline (controls), or live Ureaplasma parvum serovar 3 (Up) 14, 7 or 3d prior to c-section at day 124 gestational age (GA). 100 μg recombinant ovine IL-1α was instilled at 7, 3 or 1d prior to delivery. Headspace VOC profiles were measured from amniotic fluids at birth using ion mobility spectrometer coupled with multi-capillary columns.Results: 127 VOC peaks were identified. 27 VOCs differed between samples from controls and Up- or IL-1α induced amnionitis. The best discrimination between amnionitis by Up vs. IL-1α was reached by 2-methylpentane, with a sensitivity/specificity of 96/95% and a positive predictive value/negative predictive values of 96 and 95%. The concentration of 2-methylpentane in VOCs peaked 7d after intra-amniotic instillation of Up.Discussion: We established a novel method to study headspace VOC profiles of amniotic fluids. VOC profiles may be a useful tool to detect and to assess the duration of amnionitis induced by Up. 2-methylpentane was previously described in the exhalate of women with pre-eclampsia and might be a volatile biomarker for amnionitis. Amniotic fluids analyzed by ion mobility spectrometry coupled with multi-capillary columns may provide bedside diagnosis of amnionitis and understanding inflammatory mechanisms during pregnancy.

Background The approval of everolimus (EVE) for the treatment of angiomyolipoma (2013), subependymal giant cell astrocytoma (2013) and drug-refractory epilepsy (2017) in patients with tuberous sclerosis complex (TSC) represents the first disease-modifying treatment option available for this rare and complex genetic disorder. Objective The objective of this study was to analyse the use, efficacy, tolerability and treatment retention of EVE in patients with TSC in Germany from the patient’s perspective. Methods A structured cross-age survey was conducted at 26 specialised TSC centres in Germany and by the German TSC patient advocacy group between February and July 2019, enrolling children, adolescents and adult patients with TSC. Results Of 365 participants, 36.7% (n = 134) reported the current or past intake of EVE, including 31.5% (n = 115) who were taking EVE at study entry. The mean EVE dosage was 6.1 ± 2.9 mg/m2 (median: 5.6 mg/m2, range 2.0–15.1 mg/m2) in children and adolescents and 4 ± 2.1 mg/m2 (median: 3.7 mg/m2, range 0.8–10.1 mg/m2) in adult patients. An early diagnosis of TSC, the presence of angiomyolipoma, drug-refractory epilepsy, neuropsychiatric manifestations, subependymal giant cell astrocytoma, cardiac rhabdomyoma and overall multi-organ involvement were associated with the use of EVE as a disease-modifying treatment. The reported efficacy was 64.0% for angiomyolipoma (75% in adult patients), 66.2% for drug-refractory epilepsy, and 54.4% for subependymal giant cell astrocytoma. The overall retention rate for EVE was 85.8%. The retention rates after 12 months of EVE therapy were higher among adults (93.7%) than among children and adolescents (88.7%; 90.5% vs 77.4% after 24 months; 87.3% vs 77.4% after 36 months). Tolerability was acceptable, with 70.9% of patients overall reporting adverse events, including stomatitis (47.0%), acne-like rash (7.7%), increased susceptibility to common infections and lymphoedema (each 6.0%), which were the most frequently reported symptoms. With a total score of 41.7 compared with 36.8 among patients not taking EVE, patients currently being treated with EVE showed an increased Liverpool Adverse Event Profile. Noticeable deviations in the sub-items ‘tiredness’, ‘skin problems’ and ‘mouth/gum problems’, which are likely related to EVE-typical adverse effects, were more frequently reported among patients taking EVE. Conclusions From the patients’ perspective, EVE is an effective and relatively well-tolerated disease-modifying treatment option for children, adolescents and adults with TSC, associated with a high long-term retention rate that can be individually considered for each patient. Everolimus therapy should ideally be supervised by a centre experienced in the use of mechanistic target of rapamycin inhibitors, and adverse effects should be monitored on a regular basis.

Background Tuberous sclerosis complex (TSC) is a monogenetic, multisystemic disease characterised by the formation of benign tumours that can affect almost all organs, caused by pathogenic variations in TSC1 or TSC2. In this multicentre study from Germany, we investigated the influence of sociodemographic, clinical, and therapeutic factors on quality of life (QoL) among individuals with TSC. Methods We assessed sociodemographic and clinical characteristics and QoL among adults with TSC throughout Germany using a validated, three-month, retrospective questionnaire. We examined predictors of health-related QoL (HRQoL) using multiple linear regression analysis and compared the QoL among patients with TSC with QoL among patients with other chronic neurological disorders. Results We enrolled 121 adults with TSC (mean age: 31.0 ± 10.5 years; range: 18–61 years, 45.5% [n = 55] women). Unemployment, a higher grade of disability, a higher number of organ manifestations, the presence of neuropsychiatric manifestations or active epilepsy, and a higher burden of therapy-related adverse events were associated with worse QoL, as measured by two QoL instruments (EuroQoL-5 dimensions [EQ-5D] and Quality of Life in Epilepsy Patients [QOLIE-31]). Neuropsychiatric and structural nervous system manifestations, the number of affected organs, and therapy-related adverse events were also associated with higher depression, as measured by the Neurological Disorders Depression Inventory for Epilepsy (NDDI-E). In multiple regression analysis, more severe therapy-related adverse events (large effect, p p p = 0.003) were independently associated with worse HRQoL, explaining 65% of the variance (p p Conclusions Active epilepsy, neuropsychiatric manifestations (such as anxiety and depression), and therapy-related adverse events are important independent predictors of worse quality of life among adults with TSC. Generic quality of life in TSC with several manifestations is similar to uncontrolled severe chronic diseases and significantly negatively correlates with TSC severity. Trial registration DRKS, DRKS00016045. Registered 01 March 2019.

In patients with neurosurgical interventions requiring dura reconstruction, the use of bovine graft material may be required. Case report. We present a 12-year-old girl with a profound graft reaction with severe neurologic symptoms mimicking post-neurosurgical bacterial meningitis after resection of an infra-tentorial brain tumour. It is important to take into consideration this rare clinical entity in children and adults after dura reconstruction using allogenic graft (bovine) material in order to avoid the unnecessary use of antibiotics and antiviral drugs.

Objective: The goal of this study was to evaluate whether symptoms are reduced and emotion regulation improves when patients with borderline personality disorder (BPD) receive a 5-week course of inpatient dialectical behavioral therapy (DBT) and if changes in emotion regulation are associated with changes in symptoms. Methods: Forty-four patients with BPD receiving a 5-week course of DBT in a German psychiatry clinic participated. The short version of the "Borderline Symptom List" (BSL-23) was the patient-reported outcome. To measure emotion regulation, the "Self-Report Measure for the Assessment of Emotion Regulation Skills" (SEK-27) was administered. Wilcoxon tests were performed to evaluate whether pre-post changes in the BSL-23 and SEK-27 reached statistical significance. Effect sizes (d) were calculated and correlations between the pre-post differences for both measures were computed to test associations between changes in emotion regulation and changes in symptoms. Completer (n=33) and intention-to-treat (n=43) analyses were performed. Results: Symptoms (BSL-23) were reduced and emotion regulation (SEK-27) improved during the 5-week inpatient DBT treatment (completer and intention-to-treat analysis: P

Umbilical venous and peripherally inserted central venous catheters are often used in preterm infants, but complications include late-onset catheter-associated infections. Conversely, other sites of infection have to be taken into account in the case of clinical deterioration. In this Image in Science and Medicine paper, we report on a preterm infant with a rare cause of neonatal sepsis.

We report on an 11-year old pediatric cancer patient with T-lymphoblastic lymphoma who acquired a severe SARS-CoV-2 pneumonia immediately after the start of oral maintenance treatment with mercaptopurine. He was admitted to our hospital on day 7 after onset of symptoms (day 5 after diagnosis). Due to respiratory failure, he was transferred to the pediatric intensive care unit (from day 8 for 5 days) for high-flow-nasal cannula respiratory support. Treatment consisted of intravenous methylprednisolone and ceftriaxone. Because anti-SARS-CoV-2 antibodies were not detectable, he received two units of COVID-19 convalescence plasma containing high-titer neutralizing anti-SARS-CoV-2 antibodies (day 8 and day 9). Anti-SARS-CoV-2 antibodies increased to a maximum of 725 IU/L on day 10. Clinically, this was accompanied by a gradual decrease in oxygen demand and an overall clinical improvement. Remarkably, the patient started to mount a humoral immune response with continuously increasing anti-SARS-CoV-2 antibodies from day 15 up to 35.698 AU/ml on day 51 with extremely low (< 0.4%; < 0.01 x 109/L) detectible CD19-positive B-lymphocytes in his peripheral blood. Moreover, a strong SARS-CoV-2 specific CD4 and CD8 T cell response was induced with a predominance of CD8 T cells towards NCAP. This finding indicates that passive immunization facilitated active induction of both humoral and cellular immunity. This also suggests that active immunization may be feasible and effective in pediatric cancer patients despite B-lymphocytopenia.

SummaryDescribed herein is a case of distended abdomen in a 4-year-old boy with a ventriculoperitoneal (VP) shunt due to bilateral intraventricular hemorrhage following premature birth. Physical examination and laboratory tests revealed tenderness in the lower quadrants, with mild leukocytosis and normal C‑reactive protein levels. X‑ray demonstrated an intact VP shunt catheter but cranial displacement of the large intestine. Ultrasonography confirmed a large pseudocyst around the VP shunt, with extension from the symphysis to the sternum. The distal part of the VP shunt was surgically revised and 2.5 l of cerebrospinal fluid were evacuated. The boy made a full clinical recovery. Conventional X‑rays, routinely used to confirm or exclude VP shunt continuity, may provide important clues regarding to the etiology of VP shunt dysfunction.

SummaryCongenital heart disease comprises one of the largest groups of congenital defects, affecting approximately 1% of births. Advances in pre- and postoperative critical care treatment as well as surgery and interventional procedures have improved survival rates, but treatment and long-term care of children with complex congenital heart disease remains challenging, and is associated with a number of complications.Here, we report on a 17-month-old infant with congenital univentricular heart disease who devloped post-operatively inferior vena cava (IVC) thrombosis. IVC thrombosis was confirmed by a bedside contrast media study (X-ray) demonstrating collateral paravertebral circulation along the paravertebral sinuses bilaterally into the azygos and hemiazygos vein (“rope ladder sign“), with no contrast media detected in the IVC. The infant was subsequently started on aspirin and clopidogrel.

Aims Tuberous sclerosis complex (TSC) is a multisystem genetic disorder caused by a mutation in the TSC1 or TSC2 gene with a broad spectrum of physical and psychological manifestations. The aim of the study was to examine incontinence, psychological problems, and adaptive behavior skills in patients with TSC. Methods Through a worldwide TSC support group, 26 children (4-17 years) and 15 adults (18-50 years) with TSC were recruited (38.1% male, mean age 16.4 years). Parents or care-givers completed the Developmental Behavior Checklist (DBC), the Parental Questionnaire: Enuresis/urinary Incontinence, and the Vineland Adaptive Behavior Scales (3rd edition). Results A total of 60.0% of the participants had nocturnal enuresis (NE), 51.3% daytime urinary incontinence (DUI) and 52.4% fecal incontinence (FI). 65.4% of children and 50.0% of adults had a clinically relevant DBC score. Psychological symptoms were associated with at least one subtype of incontinence. The mean adaptive behavior composite (ABC) score of the patients was 57.2 (SD = 26.1), with 38.1% in the average or below-average range (IQ >70), 26.2% with a mild, 11.9% with a moderate and 23.8% with a severe/profound intellectual disability. The incontinence rate was significantly higher in the groups with a lower ABC score. Conclusion A substantial proportion of patients with TSC are affected by incontinence and psychological symptoms. Incontinence was higher in persons with lower adaptive skills and those with at least one type of incontinence showed a significantly higher DBC score. As incontinence and psychological problems affect daily functioning and well-being, assessment, and treatment are recommended.

EClinicalMedicine 39, 101082 (2021). doi:10.1016/j.eclinm.2021.101082, Published by Elsevier, Amsterdam

Nusinersen, an antisense oligonucleotide enhancing the production of the survival motor neuron protein, is approved for the treatment of spinal muscular atrophy (SMA) but requires repetitive lumbar punctures. Application via a subcutaneous port connected to a permanent intrathecal catheter has been proposed as an alternative for patients with severe scoliosis, spinal fusion, or comorbidities, rendering serial interlaminar punctures complicated and risky. Since experience with this technique is sparse and follow-up data are lacking, we assessed feasibility, safety, and tolerability of this approach in eight patients with SMA II/SMA III receiving Nusinersen in a multicenter study. Median age at port implantation was 21 years (range: 10–30 years), and median follow-up time thereafter was 19 months (range: 7–24 months). Leakage of the port catheter occurred in two patients, promptly resolving after resuturing. No further complications such as infection, dislocation, kinking, or obstruction of the port were noted in any of the patients. These findings suggest that application via an intrathecal port and catheter system represents a safe and feasible option for Nusinersen treatment in subjects with SMA. However, to detect rare adverse events longer term follow-up in a larger study cohort is warranted.

Aim: To provide data on the inadequate use of emergency medical transports services (EMTS) in children and underlying contributing factors. Methods: This was a prospective single-center cohort study (01/2017-12/2017) performed at the Saarland University Children's Hospital, Homburg, Germany. Patients ≤20 years of age transported by EMTS for suspected acute illness/trauma were included and proportion of inadequate/adequate EMTS use, underlying contributing factors, and additional costs were analyzed. Results: Three hundred seventy-nine patients (mean age: 9.0 ± 6.3 years; 55.7% male, 44.3% female) were included in this study. The three most common reasons for EMTS use were: central nervous system (30.6%), respiratory system affection (14.0%), and traumas (13.2%). ETMS use was categorized as inadequate depending on physician's experience: senior physician (58.8%), pediatrician (54.9%), resident (52.7%). All three physicians considered 127 (33.5%) cases to be medically indicated for transportation by EMTS, and 177 (46.7%) to be medically not indicated. The following parameters were significantly associated with inadequate EMTS use: non-acute onset of symptoms (OR 2.5), parental perception as non-life-threatening (OR 1.7), and subsequent out-patient treatment (OR 4.0). Conversely, transport by an emergency physician (OR 3.5) and first time parental EMTS call (OR 1.7) were associated with adequate use of EMTS. Moreover, a significant relation existed between maternal, respectively, paternal educational status and inadequate EMTS use (each p = 0.01). Using multiple logistic regression analysis, non-acute onset of symptoms (OR 2.2) was associated with inadequate use of EMTS while first time parental EMTS call (OR 1.8), transport by an emergency physician (OR 3.3), and need for in-patient treatment (OR 4.0) were associated with adequate use of EMTS. Conclusion: A substantial number of pediatric EMTS is medically not indicated. Possibly, specific measures including multifaceted educational efforts may be helpful in reducing unnecessary EMTS use.

Since 2012, a colonization screening (CoS) for multidrug-resistant Gram-negative bacteria (MRGN) in very low birth weight infants (VLWBI) was implemented in order to provide a basis for an effective empiric therapy of subsequent nosocomial infections (NI). According to antibiotic stewardship, carbapenems should be reserved for NI caused by MRGN or severe NI. We examined whether the CoS increased the first-line use of carbapenems. In this retrospective cohort analysis, we enrolled all VLBWI before (2009–2011) and after (2012–2014) the introduction of CoS (2012) at a tertiary university neonatal intensive care and neonatal intermediate care unit (NIMC) in Germany. Rectal swabs were used to detect MRGN colonization (on admission and weekly until discharge from the NIMC). The use of carbapenems was measured by days of therapy (DoT). To exclude the replacement of carbapenems by other antibiotics, antibiotic therapy for late-onset sepsis (LOS) was assessed by DoT and length of therapy (LoT). In 55/201 (27.4%) VLBWI, CoS detected MRGN colonization. Compared to the cohort prior to the introduction of CoS (n = 191), a significant decrease in LoT (p < 0.001) and total DoT (p < 0.001) was seen (n = 201). This was due to a significant decrease in LoT (p < 0.001) and total DoT (p < 0.001) in the birth weight category of 1,000–1,499 g. In these infants, DoT for carbapenems (p = 0.009) was significantly lower, possibly caused by a significant decline of LOS (25 episodes vs. 39 episodes, p = 0.025). Conversely, no significant differences in LoT and total DoT were seen in infants with a birth weight

Background: PHACE syndrome is a rare inborn condition characterized by large facial hemangiomas and variable malformations of the arterial system, heart, central nervous system, and eyes. According to Orphanet estimates, the prevalence is Objectives: We conducted the present study to provide population-based estimates of the disease prevalence of PHACE syndrome in children in Germany, Switzerland, and Austria. We compared these first systematic data on PHACE syndrome from Europe to published data from the PHACE Syndrome International Clinical Registry and Genetic Repository (USA). Clinical features in our cohort with PHACE syndrome were assessed in detail, including the need for early supportive measures. Methods: We used a population-based approach by means of a previously well-established network of child neurologists from Germany, Switzerland, and Austria (“ESNEK”) to identify potential patients. The patients’ guardians and child neurologists were asked to fill in questionnaires developed in collaboration with the International PHACE Registry. Results: We identified 19 patients with PHACE syndrome. Estimated prevalence rates were 6.5 per million in Switzerland, 0.59 per million in Germany, and 0.65 per million in Austria. A subset of 10 patients from Germany and Switzerland participated in our study, providing detailed clinical assessment (median age: 2.5 years; 9 females, 1 male). Cerebrovascular involvement was frequent (80%). Facial hemangioma extent correlated significantly with the number of organs involved (p = 0.011). In 9 out of 10 patients, facial hemangiomas were treated successfully with oral propranolol. Baseline demographic data as well as the rate of cerebrovascular and cardiovascular anomalies were in line with those from the US International PHACE Registry and other published PHACE cohorts. Conclusions: Our study provides population-based estimates for PHACE syndrome in 3 German-speaking countries. The data from Switzerland indicate that PHACE syndrome may be more prevalent than demonstrated by previous reports. Underreporting of PHACE syndrome in Germany and Austria likely accounts for the differences in prevalence rates. The clinical observation of a potential association between the size of facial hemangioma and extent of organ involvement warrants further investigation.

Aim We assessed the risk factors for transient acute kidney injury in very low birth weight (VLBW) infants treated for patent ductus arteriosus (PDA) using the serum creatinine-based criteria in Kidney Disease: Improving Global Outcomes. Method This retrospective study of infants requiring ibuprofen and, or, surgery for haemodynamic relevant PDAs was performed at the University Children's Hospital of Saarland, Homburg, Germany, from January 2009 to December 2015. Results We studied 422 infants with a mean birth weight of 1059 ± 308.2 g. Acute kidney injuries developed in 150/295 infants (50.9%) with spontaneous PDA closure, in 46/82 (56.1%) who received intravenous ibuprofen treatment, in 18/24 (75.0%) who had surgery and in 15/21 infants (71.4%) who received both medical and surgical treatment. Acute kidney injuries were associated with birth weight and gestational age, Apgar scores at 10 minutes, the PDA size corrected for birth weight, a PDA with three affected circulatory territories, PDA surgery and gentamicin. Multiple logistic regression analysis showed particular associations between acute kidney injury and birth weight (p = 0.001), the 10-minute Apgar score (p = 0.02) and gentamicin (p = 0.043). Conclusion Birth weight, the 10-minute Apgar score and gentamicin were particularly associated with acute kidney injuries in our cohort.

Zusammenfassung Hintergrund Die Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland (ESPED) wurde 1992 mit dem Ziel gegründet, Daten zur Inzidenzbestimmung und zum Krankheitsverlauf seltener pädiatrischer Erkrankungen zu erheben. Methoden und Fragestellung Retrospektive Analyse der von 1992–2017 durch ESPED erhobenen epidemiologischen Daten bezüglich untersuchter Krankheitsbilder und -gruppen sowie systematische Analyse sämtlicher nationaler und internationaler ESPED-Publikationen. Zudem wurden die Kriterien zur Evaluation von Surveillance-Systemen des Center of Disease Control and Prevention (CDC) auf ESPED bzgl. Einfachheit, Flexibilität, Rechtzeitigkeit, Qualität der Daten, Repräsentanz und Vollständigkeit, Akzeptanz und Stabilität angewandt. Ergebnisse Im Zeitraum 1992–2017 wurden prospektiv 96 seltene Krankheitsentitäten untersucht. Die 3 größten Krankheitsgruppen waren: Infektiologie (n=30), Neuropädiatrie (n=14) und Hämatologie/Hämostaseologie (n=10). Es wurden 337 Publikationen in Kooperation mit ESPED in nationalen und internationalen Fachzeitschriften veröffentlicht. Bei den 192 Publikationen mit Impact-Faktor (IF) betrug der mediane IF 2,587 (Range 0,032–28,409). Die höchsten IF wurden in den Bereichen Endokrinologie/Stoffwechsel (n=130; medianer IF=3,534), Infektiologie (n=83; medianer IF=3,131) und Hämatologie/Hämostaseologie (n=37; medianer IF=2,497) erzielt. Unsere Untersuchung zeigte, dass ESPED die definierten CDC-Qualitätskriterien erfüllt. Schlussfolgerung ESPED ist ein sinnvolles, qualitativ hochwertiges Instrument zur Erfassung der Inzidenz sowie zur Beschreibung klinischer Erscheinungsformen von seltenen pädiatrischen Erkrankungen. Dies spiegelt sich in Publikationen in hochkarätigen nationalen und internationalen Fachzeitschriften wider.

ZusammenfassungObschon die intrauterine Exposition gegenüber Drogen vom Typ Opioide, Cannabinoide sowie Kokain eine nicht ganz seltene Entität ist, liegen nur wenige systematische Arbeiten zu deren langfristigen Konsequenzen für die Entwicklung Betroffener vor. Wesentliche Konsequenzen der Exposition gegenüber Opioiden sind innerhalb der ersten 2 Lebensjahre eine Reduktion der motorischen Entwicklungs-Scores, die sich bis zum Schulkindesalter und Adoleszenz verbessern. In diesen Altersabschnitten finden sich für kognitive und Verhaltensuntersuchungen in Metaanalysen deutliche, allerdings nicht signifikante Trends zu verminderten Leistungen nach Exposition. Die Nachuntersuchungen nach intrauteriner Exposition gegenüber Cannabinoiden zeigen in einem Teil der Studien verminderte kognitive Leistungen und eine verschlechterte Lesefunktion sowie Störungen der Exekutivfunktionen der komplexen Planung. Bei Jungen zeigen sich in der Verhaltensanalyse vermehrt externalisierende Störungen. Die pränatale Kokainexposition führt hinsichtlich der Variablen Kognition, Sprache sowie Verhalten zu einer schwach signifikanten Verminderung der Leistungen Betroffener bis zur Adoleszenz. Insgesamt ist bei der Interpretation der Nachsorgedaten zu beachten, dass widersprüchliche Resultate publiziert wurden, die zumindest partiell durch differente Umgebungsbedingungen während der Kindheit zu erklären sind. Die aufgeführten Daten sollten ein Grund mehr sein, primäre und sekundäre Präventivbemühungen zu intensivieren.

To report a rare case of bilateral subretinal granulomas with choroidal neovascularization after Mycoplasma pneumoniae atypical pneumonia.Presentation of a 7-year-old girl, who showed bilateral atypical subretinal granulomas with choroidal neovascularization. Visual acuity was 20/20 oculus dexter and 20/200 oculus sinister. Evaluation revealed a systemic Mycoplasma pneumoniae infection with pulmonary involvement. Successful ocular treatment was performed by intravitreal injection of Bevacizumab and laser photocoagulation.Visual acuity was unchanged 36 months after treatment. No further subretinal lesions were seen oculus uterque.To the best of their knowledge and according to literature this patient report is the first one of subretinal granuloma formation after pneumonia due to mycoplasma infection. Since Mycoplasma pneumoniae is a common pathogen, especially in children and young adults, it should be considered in the differential diagnosis of any febrile illness accompanied by ocular signs.

SummarySignificant progress in prenatal care has decreased the incidence of rhesus incompatibility, which may result in hemolytic disease of the fetus and newborn (HDFN). This case report describes an unusual presentation of HDFN in a preterm infant delivered by caesarean section with isolated massive abdominal fluid collection as the leading clinical sign in addition to severe anemia. The immediate drainage of ascites provided transient clinical stabilization with improved pulmonary function in the delivery suite. After admission to the neonatal intensive care unit (NICU), HDFN treatment was initiated. This case report shows the importance of adequately trained staff including neonatologists, pediatricians and NICU nurses in the delivery suite to provide neonatal intensive care for HDFN.

Eine wichtige Voraussetzung fur das Wachstum sowie die korperliche Entwicklung von Fruhgeborenen ist eine adaquate Nahrungszufuhr. Basierend auf den Ergebnissen zahlreicher Studien werden sowohl die Geschwindigkeit des Nahrungsaufbaus als auch die parenteral zugefuhrten Substratmengen z. T. kontrovers diskutiert. Ziel dieser Arbeit war es, das parenterale Ernahrungsregime bei sehr und extrem unreifen Fruhgeborenen („Very-low-birth-weight“(VLBW)-Neonaten: Geburtsgewicht

Die seltene Multisystemerkrankung tuberose Sklerose (TSC) kann nahezu jedes Organ – haufig Haut, Zentralnervensystem, Herz, Lungen und Nieren – betreffen. Ursachlich sind autosomal-dominant vererbte TSC1- oder TSC2-Mutationen. Oft treten bereits in fruher Kindheit Entwicklungsverzogerung, epileptische Anfalle und andere schwere neurologische Manifestationen auf, die entscheidend zu Morbiditat und Mortalitat beitragen. Die TSC kann jedoch auch in einer milden und schwierig zu diagnostizierenden Form verlaufen. Die Kenntnis typischer Merkmale ist nicht nur fur den Neuropadiater bedeutsam, sondern aufgrund der erforderlichen interdisziplinaren Therapie insbesondere fur den betreuenden Kinder- und Jugendmediziner. Therapeutisch stehen neben etablierten symptomatischen Ansatzen nun die „Mechanistic-target-of-rapamycin“(mTOR)-Inhibitoren als „targeted therapy“ zur Verfugung. Die fruhzeitige und sichere Diagnosestellung kann zur Reduktion von Morbiditat und Mortalitat fuhren.

Zusammenfassung Die tuberose Sklerose (tuberous scerlosis complex, TSC) ist eine genetische Multisystemerkrankung mit auffalliger Hautbeteiligung, die haufig in der fruhen Kindheit eintritt. Zu den dermatologischen Manifestationen gehoren faziale Angiofibrome, hypomelanotische Maculae, fibrose Stirnplaques, Shagreen-Fleck (shagreen patches) und unguale Fibrome. Die Internationale TSC-Konsensuskonferenz (International TSC Consensus Conference) von 2012 hat Leitlinien fur die standardisierte Erstuntersuchung und die Nachsorge zur Verfugung gestellt. Sowohl fur Kinder als auch fur Erwachsene werden eine eingehende klinisch-dermatologische Untersuchung zum Zeitpunkt der Diagnose sowie eine jahrliche Hautuntersuchung empfohlen. Das erstmalige Auftreten der dermatologischen Manifestationen ist offensichtlich altersabhangig. Allerdings mussen Dermatologen die klinischen Manifestationen auch uber ihr eigenes Fachgebiet hinaus beurteilen. Durch Fortschritte in der Genetik und die Einfuhrung von TORC1-Inhibitoren stehen neue, spezifische Therapieoptionen fur TSC-Patienten mit Hautmanifestationen zur Verfugung. Im Allgemeinen wird bei symptomatischen, sich schnell entwickelnden, entstellenden oder behindernden Lasionen ein fruhes Eingreifen empfohlen. Die Konsensus-Leitlinien empfehlen eine „der Lasion und dem klinischen Kontext angemessene Behandlung“ und schlagen die Anwendung chirurgischer Exzision, Lasertherapie oder topischer mTORC1-Inhibitoren vor. Topische mTORC1-Inhibitoren sind eine sinnvolle Option fur TSC-assoziierte Hautlasionen, insbesondere bei medizinisch komplexen Patienten. Sie konnen nachfolgende chirurgische Eingriffe sowie dauerhafte Narbenbildung verhindern oder ihr Risiko verringern.

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder with prominent skin involvement that frequently occurs in early childhood. Dermatologic manifestations include facial angiofibromas, hypomelanotic macules, fibrous cephalic plaques, shagreen patches, and ungual fibromas. The International TSC Consensus Conference in 2012 provided guidelines for standardized baseline evaluation and follow-up. Detailed clinical dermatological evaluation at the time of diagnosis and annual skin examination is recommended for both pediatric and adult populations. The onset of dermatological manifestations is clearly age-related. However, dermatologists also have to assess for clinical manifestations beyond their own specialty. With advances in genetics and the advent of mTORC1 inhibitors, new specific therapeutic options have become available for TSC patients with skin manifestations. Early intervention is commonly recommended for symptomatic, rapidly evolving, disfiguring, or debilitating lesions. The consensus guidelines recommend "treatment as appropriate for the lesion and clinical context" and suggest the use of surgical excision, laser therapy, or topical mTORC1 inhibitors. Topical mTORC1 inhibitors present a useful option for TSC-associated skin lesions, particularly in medically complex patients. They may prevent or reduce the risks of subsequent surgeries and permanent scarring.

Cochrane meta-analyses provide the physician at the bedside with the most relevant, up-to-date clinical information. However, implementation of evidence-based medicine (EBM) at the bedside may be difficult for a variety of reasons. The aim of this study was to assess relevant issues and obstacles related to implementing EBM in pediatrics in real life at the bedside/cotside. We performed five systematic literature reviews of all published Cochrane reviews in neonatology (1996–2010), pediatric neurology (1996–2010), pediatric gastroenterology (1993–2012), pediatric cardiology (2001–2015), and complementary and alternative medicine (1996–2012; CAM) in children and neonates. In all five analyses, the main outcome variables were percentage of reviews concluding that a certain intervention provides a benefit, percentage of reviews concluding that a certain intervention should not be performed, and percentage of studies concluding that the current level of evidence is inconclusive. In all five areas of pediatrics, a substantial number of Cochrane reviews yielded inconclusive data (neonatology: 46.6%; neuropediatrics: 26.8%; pediatric gastroenterology: 27.9%; pediatric cardiology: 42.9%; complementary and alternative medicine: 66.9%). Our up-dated systematic synopsis reiterates the need for high-quality, sophisticated research to reduce the number of inconclusive meta-analyses in the field of pediatrics—most importantly in the field of complementary and alternative medicine (CAM), neonatology, and pediatric cardiology. The realization of high-quality, clinically driven research will in turn yield more systematic reviews with a clear conclusion (e. g., in favor or against a certain intervention, or treatment modality), thus, substantively decreasing the proportion of inconclusive reviews.

Tuberous sclerosis complex (TSC) is a genetic multisystem disorder with prominent skin involvement including facial angiofibromas that often appear in early childhood. Here we report the case of a 12-year-old girl with widespread disfiguring facial angiofibromas that were successfully treated with topical rapamycin, a mTOR inhibitor. A sustained remission of skin lesions was documented in detail over a 3-year follow-up. This case highlights the fact that topical rapamycin is a useful option in treating TSC-associated skin lesions. Especially in medically complex patients topical treatment may lessen the need for surgical interventions, reducing the risks of surgery, its adverse effects and permanent scarring. However, there is no standard dose or formulation at present. Topical rapamycin appears safe, but long-term maintenance therapy is necessary to prevent facial lesions from regrowth.

Grasselli G, Zangrillo A, Zanella A, Antonelli M, Cabrini L, Castelli A, et al. Baseline characteristics and outcomes of 1591 patients infected with SARS-coV‑2 admitted to ICus of the Lombardy region, Italy. JAMA. 2020; https://doi.org/10.1001/jama.2020.5394. Article PubMed PubMed Central Google Scholar Ji T, Chen HL, Xu J, Wu LN, Li JJ, Chen K, et al. Lockdown contained the spread of 2019 novel coronavirus disease in Huangshi city, China: early epidemiological findings. Clin Infect Dis. 2020; https://doi.org/10.1093/cid/ciaa390. Article PubMed PubMed Central Google Scholar Stuckler D, Reeves A, Loopstra R, Karanikolos M, McKee M. Austerity and health: the impact in the UK and Europe. Eur J Public Health. 2017;27(4):18–21. https://doi.org/10.1093/eurpub/ckx167. Article PubMed PubMed Central Google Scholar Bennett JE, Pearson-Stuttard J, Kontis V, Capewell S, Wolfe I, Ezzati M. Contributions of diseases and injuries to widening life expectancy inequalities in England from 2001 to 2016: a population-based analysis of vital registration data. Lancet Public Health. 2018;3:e586–97. Article Google Scholar Allam Z, Jones DS. On the coronavirus (COVID-19) outbreak and the smart city network: universal data sharing standards coupled with artificial intelligence (AI) to benefit Urban health monitoring and management. Healthcare (Basel). 2020;8(1):E46. https://doi.org/10.3390/healthcare8010046. Article Google Scholar Kupferschmidt K, Cohen J. Race to find COVID-19 treatments accelerates. Science. 2020;367(6485):1412–3. https://doi.org/10.1126/science.367.6485.1412. CAS Article PubMed Google Scholar Bartosch U, Gansczyk K. Weltinnenpolitik fur das 21. Jahrhundert. Carl-Friedrich von Weizacker verpflichtet. Weltinnenpolitische Colloquien, Vol. 1. Berlin: LIT-Verlag; 2009. Google Scholar Ayittey FK, Ayittey MK, Chiwero NB, Kamasah JS, Dzuvor C. Economic impacts of Wuhan 2019-nCoV on China and the world. J Med Virol. 2020;92(5):473–5. https://doi.org/10.1002/jmv.25706. CAS Article PubMed PubMed Central Google Scholar Download references Department of Pediatrics and Neonatology, Unversity Hospital of Saarland, 66421, Homburg, Germany Professor Dr. Sascha Meyer Center for Infectious Diseases, Institute of Medical Microbiology and Hygiene, University Hospital of Saarland, Homburg, Germany Cihan Papan & Katharina Last You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar You can also search for this author in PubMed Google Scholar The comment was conceptualized by all three authors. Correspondence to Professor Dr. Sascha Meyer. S. Meyer, C. Papan and K. Last declare that they have no competing interests. Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Reprints and Permissions Meyer, S., Papan, C. & Last, K. A global health perspective on SARS-CoV-2—hazards, disaster and hope. Wien Med Wochenschr (2020). https://doi.org/10.1007/s10354-020-00769-8 Download citation Received: 07 May 2020 Accepted: 18 June 2020 Published: 14 September 2020 DOI: https://doi.org/10.1007/s10354-020-00769-8

BACKGROUND: Acute kidney injury (AKI) and intraventricular hemorrhage (IVH) are common in premature infants. We previously demonstrated that infants with AKI have a higher hazards ratio to develop grade ≥2 IVH when controlling for confounders. However, that single-center study was unable to show an overall association. OBJECTIVES: To test the hypothesis that infants diagnosed with AKI have an increased risk of IVH independent of variables associated with both AKI and IVH, we performed a study on 825 infants from the Assessment of Worldwide Acute Kidney Injury Epidemiology in Neonates (AWAKEN) study (a 24-center multinational retrospective cohort). METHOD: A neonatal modified KDIGO definition of AKI was used based on serum creatinine (SCr) and/or urine output criteria. Baseline SCr was defined as the lowest previous value. IVH was diagnosed with head ultrasounds. RESULTS: AKI was documented in 183/825 (22.2%) infants and IVH in 118/825 (14.3%). Infants with AKI (n=183) were more likely to have IVH [26.8% (49/183)] than those without AKI (n=642) who had IVH [10.7% (69/642), p

Aim To assess the role of the TAND (tuberous sclerosis complex [TSC] associated neuropsychiatric disorders) checklist as a screening tool for neuropsychiatric pathology, to evaluate behavioral and psychiatric symptoms and related parental stress in children with TSC, and to analyze associations between parental stress, TAND findings, and TSC pathology. Method This is a prospective cohort study including 22 individuals from a national TSC surveillance study in Germany using demographic and clinical data, the TAND checklist, the Child Behavior Checklist (CBCL), and the Parenting Stress Index (PSI). Results Mean (standard deviation) age at follow-up was 4 years (3 years 9 months), and 13/22 of patients were male. Seventeen children had epilepsy (focal: 9; generalized: 4; infantile spasms: 4). Developmental delay was diagnosed in 12/22 patients. The most prevalent TAND items were anxiety and mood swings in 10/22 children. At least one TAND item was reported by 17/22 patients, internalizing symptoms by 10/22, and externalizing symptoms by 11/22. In contrast, only one patient had a clinically relevant score in the CBCL scales. Of 22 parents, 12 reported clinically relevant parental stress due to both child and parenting factors. Higher total parental stress was associated with a higher TAND externalizing score (r = 0.49; p = 0.028) and TAND total score (r = 0.51; p = 0.016), a higher CBCL total score (r = 0.59; p = 0.005), and the number of antiepileptic drugs (r = 0.50; p = 0.017). Developmental delay was correlated with child stress factors (r = 0.48; p = 0.023). Interpretation The TAND checklist appears to be a promising screening tool for neuropsychiatric problems in very young children with TSC. Parental stress in children with TSC is modified by TSC-related pathology, both neuropsychiatric and neurological.

About 15% of Duchenne muscular dystrophy (DMD) cases are caused by point mutations leading to premature stop codons and disrupted synthesis of the dystrophin protein. Stop codon read-through therapy is available with the drug Ataluren (Translarna® by PTC Therapeutics). Following positive results in ambulatory nmDMD (non-sense mutation Duchenne muscular dystrophy) patients, Ataluren received conditional approval in ambulant nmDMD patients by the EMA in 2014. However, there are limited data on non-ambulatory nmDMD patients treated with Ataluren. Here, we report our experience in four non-ambulatory nmDMD patients. Routine investigations included cardiac function, pulmonary function tests and muscle strength. We compared changes in left ventricular fractional shorting, forced volume vital capacity and BMI from two defined time periods (18-26-month period prior to and after Ataluren start). Mean age at loss of ambulation was 10.1 ±0.5 years, mean age when initiating Ataluren treatment 14.1 ±1.4 years. Serial echocardiography, pulmonary lung function tests, and assessment of muscle strength indicated mild attenuation of disease progression after initiation of Ataluren treatment. A possible side effect of Ataluren was a reduction in BMI. There were no adverse clinical effects or relevant abnormalities in routine laboratory values. We conclude that Ataluren appears to mildly ameliorate the clinical course in our patients with a good safety profile. However, larger clinical trials are required to assess the role of Ataluren and its long-term impact on disease progression in non-ambulant nmDMD patients.

Background: Early and non-invasive diagnosis of common diseases is of great importance in the care of preterm infants. We hypothesized that volatile organic compounds (VOC) can be successfully measured in the neonatal incubator atmosphere. Methods: This is a feasibility study to investigate whether the discrimination of occupied and unoccupied neonatal incubators is possible by bedside measurement of volatile organic compounds (VOCs) on the neonatal intensive care unit. VOC profiles were measured in the incubator air using ion mobility spectrometry coupled to multi-capillary columns (BreathDiscovery B&S Analytik GmbH, Dortmund, Germany). Results: 17 incubators occupied by preterm infants (50 measurements) and nine unoccupied neonatal incubators were sampled, using 37 room air measurements as controls. Three VOC signals that allow the discrimination between occupied and unoccupied incubators were identified. The best discrimination was reached by peak P20 exhibiting a sensitivity, specificity, positive predictive value and negative predictive value of 94.0 %, 88.9 %, 97.3 % and 72.3 %, respectively. Use of a decision tree improved these values to 100.0 %, 88.9 %, 98.0 % and 100.0 %, respectively. Discussion: A bedside method that allows the characterization of VOC profiles in the neonatal incubator atmosphere using ion mobility spectrometry was established. Occupied and unoccupied incubators could be discriminated by characterizing VOC profiles. This technique has the potential to yield results within minutes. Thus, future studies are recommended to test the hypothesis that VOCs within neonatal incubators are useful biomarkers for non-invasive diagnostics in preterm neonates.

An universal coagulation test that reliably detects prolonged coagulation times in patients, regardless of which anticoagulant is administered, is not yet available. The authors developed a novel, miniaturized device utilizing surface acoustic waves (SAW) to detect clotting, and used it to develop a novel universal microfluidic coagulation test. Results from this assay were compared with results from standard coagulation assays to detect classical anticoagulants (unfractionated heparin, argatroban) and direct oral anticoagulants (dabigatran, rivaroxaban). The SAW-clotting time (SAW-CT) of this novel device was prolonged in a dose-dependent manner for heparin, argatroban, dabigatran, and rivaroxaban, comparable to standard assays. The authors confirmed the clinical utility of this device in a small patient population admitted to a stroke unit. Preliminary clinical data prove the suitability of the SAW-CT in patients receiving warfarin, rivaroxaban, or dabigatran. The device could be particularly useful as a point-of-care test to assess whole blood coagulation (e.g., in stroke units or in other emergency settings).

Grundlagen Bei der Tuberosen Sklerose Complex-Erkrankung (TSC) handelt sich um eine seltene, genetisch bedingte Multisystemerkrankung, die charakterisiert ist durch das Auftreten von Hamartomen.

Chemotherapy-induced peripheral neuropathic pain (CIPNP) is a severe dose- and therapy-limiting side effect of widely used cytostatics that is particularly difficult to treat. Here, we report increased expression of the cytochrome-P450-epoxygenase CYP2J6 and increased concentrations of its linoleic acid metabolite 9,10-EpOME (9,10-epoxy-12Z-octadecenoic acid) in dorsal root ganglia (DRGs) of paclitaxel-treated mice as a model of CIPNP. The lipid sensitizes TRPV1 ion channels in primary sensory neurons and causes increased frequency of spontaneous excitatory postsynaptic currents in spinal cord nociceptive neurons, increased CGRP release from sciatic nerves and DRGs, and a reduction in mechanical and thermal pain hypersensitivity. In a drug repurposing screen targeting CYP2J2, the human ortholog of murine CYP2J6, we identified telmisartan, a widely used angiotensin II receptor antagonist, as a potent inhibitor. In a translational approach, administration of telmisartan reduces EpOME concentrations in DRGs and in plasma and reverses mechanical hypersensitivity in paclitaxel-treated mice. We therefore suggest inhibition of CYP2J isoforms with telmisartan as a treatment option for paclitaxel-induced neuropathic pain.

The aim of the NeoVitaA Trial is to assess the role of postnatal additional high-dose oral vitamin A supplementation for 28 days in reducing Bronchopulmonary dysplasia (BPD) or death in extremely low birth weight (ELBW) infants at 36 weeks postmenstrual age (PMA). All infants (both intervention and control group) will be provided with basic vitamin A (1000 IU/kg/day) in addition to trial intervention. In this short communication, we will give an up-date on obstacles, challenges as well as perspectives and potential solutions when putting into place a multicenter, double-blind, randomized trial in this cohort of extremely susceptible infants.

Summary Background The aim of this study was to assess multiplex PCR analysis in detecting causative viruses in children with febrile seizures. Methods The study was a retrospective analysis comparing data from a pre-multiplex era (2009) with a period after the introduction of routine respiratory multiplex analysis (2010–2013) in children with febrile seizures. Results We included 200 children with febrile seizures (mean age: 29.5 ± 1.4.months; 104 male) in the study. In 2009, in 10 out of 49 (20 %) children, microbiology testing (bacterial/fungal) was positive compared with a rate of 74 out of 151 (49 %) children during 2010–2013 (p < 0.01). The rate of positive virological studies increased from 10 (20 %) in 2009 to 73 (48.3 %) in the period 2010–2013 (p < 0.01). Multiplex PCR analysis confirmed viral infections in 52 of 73 cases (71.2 %). Conclusion Routine multiplex PCR analysis fosters the detection of respiratory viruses in children with febrile seizure. The precise role of multiplex analysis in the management of these children awaits further clarification.