Clinical characteristics and outcomes of children with WAGR syndrome and Wilms tumor and/or nephroblastomatosis: The 30-year SIOP-RTSG experience - Hol, Janna A.; Jongmans, Marjolijn C. J.; Sudour-Bonnange, Helene; Ramirez-Villar, Gema L.; Chowdhury, Tanzina; Rechnitzer, Catherine; Pal, Niklas; Schleiermacher, Gudrun; Karow, Axel; Kuiper, Roland P.; De Camargo, Beatriz; Avcin, Simona; et al. (Cancer, 2020)
Background WAGR syndrome (Wilms tumor, aniridia, genitourinary anomalies, and range of developmental delays) is a rare contiguous gene deletion syndrome with a 45% to 60% risk of developing Wilms tumor (WT). Currently, surveillance and treatment recommendations are based on limited evidence.
CRIS-Team WoS Importer:2020-11-20

Clinical Characteristics of Necrotizing Enterocolitis in Preterm Patients With and Without Persistent Ductus Arteriosus and in Patients With Congenital Heart Disease - Diez, Sonja; Tielesch, Lea; Weiss, Christel; Halbfass, Julia; Mueller, Hanna; Besendörfer, Manuel (Frontiers in Pediatrics, 2020)
Background: Diagnosis and management of NEC is based on clinical, radiological, and laboratory findings. Discrimination of pathogens for an improved understanding of NEC in preterm infants and NEC in infants with congenital heart disease has been previously discussed and enables evaluation of further NEC biomarkers. Patients and Methods: Within a study period of 11 years (2008–2019), we identified 107 patients with a diagnosis of NEC at our primary care center. Thirty-six out of 54 patients suffering from NEC in high Bell stages who underwent surgery met inclusion criteria. These patients were classified according to their cardiac status, and analyses of clinical factors influencing NEC were conducted. Additionally, clinical factors associated with a fulminant course of NEC were examined. Univariable and multivariable analyses were performed. Results: The study populations consisted of 12 preterm infants with NEC but without patent ductus arteriosus (PT-NEC), seven preterm infants with NEC and patent ductus arteriosus (PDA-NEC), and 17 infants with NEC and congenital heart disease (CHD-NEC). Blood flow in intestinal vessels was impaired in infants with PDA-NEC and CDH-NEC. Therefore, we used logistic regression to compare PDA-NEC and CDH-NEC infants with PT-NEC infants: positive bacterial culture of intraoperative swabs (p = 0.0199; odds ratio: 21.9) and macroscopic intestinal necrosis (p = 0.0033; odds ratio: 43.5) were observed more frequently in the first group. Furthermore, multiple regression analysis determined the NEC localization (p = 0.0243) as a significant factor correlated with a fulminant course. Compared to a NEC exclusively localized in the colon, there is a 5.8-fold increased risk of a fulminant course when the small intestine is affected and a 42-fold increase of risk when both small intestine and colon were affected. Conclusion: An early diagnosis and timely surgical intervention of NEC, especially in infants with PDA and CDH may be considered to avoid major bowel necrosis (resulting in loss of intestinal tissue) and multiple operations.
CRIS-Team Scopus Importer:2020-07-10
Keywords: congenital heart disease; fulminant NEC; NEC; necrotizing enterocolitis; patent ductus arteriosus

Clinical Characteristics of the End-of-Life Phase in Children with Life-Limiting Diseases: Retrospective Study from a Single Center for Pediatric Palliative Care - Baumann, Fanni; Hébert, Steven; Rascher, Wolfgang; Wölfle, Joachim; Gravou-Apostolatou, Chara (Children, 2021)
Background: Data on the end-of-life phase of children receiving palliative care are limited. The purpose of this study is to investigate the spectrum of symptoms of terminally ill children, adolescents, and young adults, depending on their underlying disease. Methods: Findings are based on a 4.5-year retrospective study of 89 children who received palliative care before they died, investigating the symptomatology of the last two weeks before death. Results: In this study, the most common clinical symptomatology present in children undergoing end-of-life care includes pain, shortness of breath, anxiety, nausea, and constipation. Out of 89 patients included in this study, 47% suffered from an oncological disease. Oncological patients had a significantly higher symptom burden at the end of life (p < 0.05) compared to other groups, and the intensity of symptoms increased as the underlying disease progressed. The likelihood of experiencing pain and nausea/vomiting was also significantly higher in oncological patients (p = 0.016). Conclusions: We found that the underlying disease is associated with marked differences in the respective leading clinical symptom. Therefore, related to these differences, symptom management has to be adjusted according to the underlying disease, since the underlying disorder seems to exert an influence on the severity of symptoms and thereby on the modality and choice of treatment. This study is intended to aid underlying disease-specific symptom management at the end-of-life care for children, adolescents, and young adults, with a specific focus on end-of-life care in a home environment.
CRIS-Team WoS Importer:2021-07-09

Clinical characteristics, resource utilization, quality of life and care situation for patients with Dravet syndrome in Germany - Kalski, Malin; Schubert-Bast, Susanne; Kieslich, Matthias; Leyer, Anne-Christine; Polster, Tilman; Herting, Arne; Mayer, Thomas; Trollmann, Regina; Neubauer, Bernd A.; Bettendorf, Ulrich; Bast, Thomas; Wiemer-Kruel, Adelheid; et al. (Zeitschrift für Epileptologie, 2019)
Introduction and objective Dravet syndrome (DS) is a rare epileptic and developmental encephalopathy associated with cognitive impairment and delayed development due to genetic mutations predominantly in the SCN1A gene. This multicenter, prospective survey-based study collected data about the clinical characteristics, health care resource utilization, costs and quality of life (QoL) of patients with DS and their caregivers in Germany. Methods A retrospective questionnaire covering the previous 3-12 months was used in addition to a prospective diary over 3 months to confirm the retrospective data and to obtain detailed information about indirect costs, QoL, medication, seizures and health care resource utilization. The questionnaires and the diary were handed out to the parents via Dravet-Syndrome e.& x202f;V. and participating centers. Results The questionnaire and diary were completed by 93 and 77 caregivers of DS patients, respectively. Patient mean age was 10 years (range: 15 months-33.7 years), whereby the time to diagnosis was significantly lower in the last two decades. In the previous 12 months, 95% of patients experienced at least one epileptic seizure. Fever (93.4%), excitement (56%), sleep deprivation (51.6%) and physical exertion (50.5%) were reported as the factors that triggered seizures. The lifetime prevalence of status epilepticus was 77%, with 28% having had at least one episode of status epilepticus within the last year. Patient QoL was lower compared with the general population, with 46% of the parents reporting symptoms of depression. The 3-month direct healthcare costs were 6043 & x202f;euro per patient, the largest components of which were inpatient costs (1702 & x202f;euro) followed by nursing care services (1130 & x202f;euro), anticonvulsant drugs (892 & x202f;euro) and ancillary treatment (559 & x202f;euro). The 3-month total indirect cost for mothers was 4399 & x202f;euro and for fathers 391 & x202f;euro. Conclusion The DS is associated with frequent and often treatment refractory seizures, including status epilepticus as well as various comorbidities. This study shows the substantial associated socioeconomic impact of the disease, with high direct and indirect costs and reduced QoL for patients and the caregivers. In order to achieve an improvement in the QoL for patients with DS and caregivers, new treatment and care concepts are necessary.
CRIS-Team WoS Importer:2019-10-22

Clinical characterization of respiratory large droplet production during common airway procedures using high-speed imaging - Müller, Sarina Katrin; Veltrup, Reinhard; Jakubaß, Bernhard; Kniesburges, Stefan; Hübner, Matthias; Kempfle, J. S.; Dittrich, Sven; Dittrich, Sven; Iro, Heinrich; Döllinger, Michael (Scientific Reports, 2021)
During the COVID-19 pandemic, a significant number of healthcare workers have been infected with SARS-CoV-2. However, there remains little knowledge regarding large droplet dissemination during airway management procedures in real life settings. 12 different airway management procedures were investigated during routine clinical care. A high-speed video camera (1000 frames/second) was for imaging. Quantitative droplet characteristics as size, distance traveled, and velocity were computed. Droplets were detected in 8/12 procedures. The droplet trajectories could be divided into two distinctive patterns (type 1/2). Type 1 represented a ballistic trajectory with higher speed large droplets whereas type 2 represented a random trajectory of slower particles that persisted longer in air. The use of tracheal cannula filters reduced the amount of droplets. Respiratory droplet patterns generated during airway management procedures follow two distinctive trajectories based on the influence of aerodynamic forces. Speaking and coughing produce more droplets than non-invasive ventilation therapy confirming these behaviors as exposure risks. Even large droplets may exhibit patterns resembling the fluid dynamics smaller airborne aerosols that follow the airflow convectively and may place the healthcare provider at risk.
CRIS-Team Scopus Importer:2021-06-04

Clinical courses and complications of young adults with Autosomal Recessive Polycystic Kidney Disease (ARPKD) - Burgmaier, Kathrin; Kilian, Samuel; Bammens, Bert; Benzing, Thomas; Billing, Heiko; Buescher, Anja; Galiano, Matthias; Grundmann, Franziska; Klaus, Guenter; Mekahli, Djalila; Michel-Calemard, Laurence; Milosevski-Lomic, Gordana; et al. (Scientific Reports, 2019)
Autosomal recessive polycystic kidney disease (ARPKD) is a severe pediatric hepatorenal disorder with pronounced phenotypic variability. A substantial number of patients with early diagnosis reaches adulthood and some patients are not diagnosed until adulthood. Yet, clinical knowledge about adult ARPKD patients is scarce. Here, we describe forty-nine patients with longitudinal follow-up into young adulthood that were identified in the international ARPKD cohort study ARegPKD. Forty-five patients were evaluated in a cross-sectional analysis at a mean age of 21.4 (±3.3) years describing hepatorenal findings. Renal function of native kidneys was within CKD stages 1 to 3 in more than 50% of the patients. Symptoms of hepatic involvement were frequently detected. Fourteen (31%) patients had undergone kidney transplantation and six patients (13%) had undergone liver transplantation or combined liver and kidney transplantation prior to the visit revealing a wide variability of clinical courses. Hepatorenal involvement and preceding complications in other organs were also evaluated in a time-to-event analysis. In summary, we characterize the broad clinical spectrum of young adult ARPKD patients. Importantly, many patients have a stable renal and hepatic situation in young adulthood. ARPKD should also be considered as a differential diagnosis in young adults with fibrocystic hepatorenal disease.
CRIS-Team Scopus Importer:2019-06-25

Clinical Effectiveness of Newborn Screening for Spinal Muscular Atrophy: A Nonrandomized Controlled Trial - Schwartz, Oliver; Vill, Katharina; Pfaffenlehner, Michelle; Behrens, Max; Weiß, Claudia; Johannsen, Jessika; Friese, Johannes; Hahn, Andreas; Ziegler, Andreas; Illsinger, Sabine; Smitka, Martin; Von Moers, Arpad; et al. (JAMA Pediatrics, 2024)
Importance: There is increasing evidence that early diagnosis and treatment are key for outcomes in infants with spinal muscular atrophy (SMA), and newborn screening programs have been implemented to detect the disease before onset of symptoms. However, data from controlled studies that reliably confirm the benefits of newborn screening are lacking. Objective: To compare data obtained on patients with SMA diagnosed through newborn screening and those diagnosed after clinical symptom onset. Design, Setting, and Participants: This nonrandomized controlled trial used data from the SMARTCARE registry to evaluate all children born between January 2018 and September 2021 with genetically confirmed SMA and up to 3 SMN2 copies. The registry includes data from 70 participating centers in Germany, Austria, and Switzerland. Data analysis was performed in February 2023 so that all patients had a minimal follow-up of 18 months. Exposure: Patients born in 2 federal states in Germany underwent screening in a newborn screening pilot project. All other patients were diagnosed after clinical symptom onset. All patients received standard care within the same health care system. Main Outcomes: The primary end point was the achievement of motor milestones. Results: A total of 234 children (123 [52.6%] female) were identified who met inclusion criteria and were included in the analysis: 44 (18.8%) in the newborn screening cohort and 190 children (81.2%) in the clinical symptom onset cohort. The mean (SD) age at start of treatment with 1 of the approved disease-modifying drugs was 1.3 (2.2) months in the newborn screening cohort and 10.7 (9.1) months in the clinical symptom onset cohort. In the newborn screening cohort, 40 of 44 children (90.9%) gained the ability to sit independently vs 141 of 190 (74.2%) in the clinical symptom onset cohort. For independent ambulation, the ratio was 28 of 40 (63.6%) vs 28 of 190 (14.7%). Conclusions and Relevance: This nonrandomized controlled trial demonstrated effectiveness of newborn screening for infants with SMA in the real-world setting. Functional outcomes and thus the response to treatment were significantly better in the newborn screening cohort compared to the unscreened clinical symptom onset group. Trial Registration: German Clinical Trials Register: DRKS00012699.
CRIS-Team Scopus Importer:2024-04-26

Clinical, Imaging, Genetic, and Disease Course Characteristics in Patients with GM2 Gangliosidosis: Beyond Age of Onset - Kern, Jan; Böhringer, Judith; Timmann, Dagmar; Trollmann, Regina; Stendel, Claudia; Kamm, Cristoph; Röbl, Markus; Santhanakumaran, Vidiyaah; Groeschel, Samuel; Beck-Wödl, Stefanie; Göricke, Sophia; Krägeloh-Mann, Ingeborg; et al. (Neurology, 2024)
Background and ObjectivesGM2 gangliosidoses, a group of autosomal-recessive neurodegenerative lysosomal storage disorders, result from β-hexosaminidase (HEX) deficiency with GM2 ganglioside as its main substrate. Historically, GM2 gangliosidoses have been classified into infantile, juvenile, and late-onset forms. With disease-modifying treatment trials now on the horizon, a more fine-grained understanding of the disease course is needed.MethodsWe aimed to map and stratify the clinical course of GM2 gangliosidoses in a multicenter cohort of pediatric and adult patients. Patients were stratified according to age at onset and age at diagnosis. The 2 resulting GM2 disease clusters were characterized in-depth for respective disease features (detailed standardized clinical, laboratory, and MRI assessments) and disease evolution.ResultsIn 21 patients with GM2 gangliosidosis (17 Tay-Sachs, 2 GM2 activator deficiency, 2 Sandhoff disease), 2 disease clusters were discriminated: an early-onset and early diagnosis cluster (type I; n = 8, including activator deficiency and Sandhoff disease) and a cluster with very variable onset and long interval until diagnosis (type II; n = 13 patients). In type I, rapid onset of developmental stagnation and regression, spasticity, and seizures dominated the clinical picture. Cherry red spot, startle reactions, and elevated AST were only seen in this cluster. In type II, problems with balance or gait, muscle weakness, dysarthria, and psychiatric symptoms were specific and frequent symptoms. Ocular signs were common, including supranuclear vertical gaze palsy in 30%. MRI involvement of basal ganglia and peritrigonal hyperintensity was seen only in type I, whereas predominant infratentorial atrophy (or normal MRI) was characteristic in type II. These types were, at least in part, associated with certain genetic variants.DiscussionAge at onset al.one seems not sufficient to adequately predict different disease courses in GM2 gangliosidosis, as required for upcoming trial planning. We propose an alternative classification based on age at disease onset and dynamics, predicted by clinical features and biomarkers, into type I - an early-onset, rapid progression cluster - and type II - a variable onset, slow progression cluster. Specific diagnostic workup, including GM2 gangliosidosis, should be performed in patients with combined ataxia plus lower motor neuron weakness to identify type II patients.
CRIS-Team Scopus Importer:2024-01-05

Clinical outcomes and immunogenicity analysis over 6 months following a switch from originator infliximab (Remicade (R)) to the biosimilar SB2 (Flixabi (R)) in inflammatory bowel disease patients - Fischer, Sven Moritz; Klenske, E.; Schmitt, H.; Vitali, Francesco; Hirschmann, S.; Koch, F.; Ramming, A.; Zundler, Sebastian; Nagore, D.; Uter, Wolfgang; Neurath, Markus; Atreya, Raja (2018)
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Clinical Outcomes in Pediatric Patients With Type 1 Diabetes With Early Versus Late Diagnosis: Analysis From the DPV Registry - Hammersen, Johanna; Tittel, Sascha R.; Kamrath, Clemens; Warncke, Katharina; Galler, Angela; Menzel, Ulrike; Hess, Melanie; Meißner, Thomas; Karges, Beate; Holl, Reinhard W. (Diabetes Care, 2024)
OBJECTIVE This study was conducted to evaluate the effects of early clinical diagnosis of type 1 diabetes by comparison of clinical parameters at diagnosis and during follow-up in patients with pediatric type 1 diabetes with early, intermediate, and late diagnosis. RESEARCH DESIGN AND METHODS In a population-based analysis, data on 14,292 pediatric patients with type 1 diabetes diagnosed between 2015 and 2019 were retrieved from the Diabetes Prospective Documentation (DPV) registry in March 2023. Patients were divided into four groups: one with diabetic ketoacidosis (DKA) at diagnosis and three with early, intermediate, or late diagnosis based on age-dependent HbA1c terciles. Laboratory-measured HbA1c values and those estimated from continuous glucose monitoring were aggregated as a combined glucose indicator (CGI). Insulin dose– adjusted CGI values <9% were defined as partial remission. RESULTS At diagnosis, patients had a median age of 9.8 years (IQR 6.8; 13.0). Three years later, patients with early diagnosis had lower CGI than patients with late diagnosis or DKA (mean [95% CI] 7.46% [7.40; 7.53] vs. 7.81% [7.75; 7.87] or 7.74% [7.68; 7.79], respectively; each P < 0.001). More patients experienced partial remission (12.6% [11.0; 14.4] vs. 9.1% [7.7; 10.7] or 8.6% [7.3; 10.0]; each P < 0.001), and 11.7% [10.2; 13.5] of patients with intermediate diagnosis were in partial remission. CONCLUSIONS Early clinical diagnosis of type 1 diabetes may be beneficial for metabolic control and remission after 3 years of follow-up. Patients diagnosed early may represent a distinct group with better resources or with a different disease biology and slower b-cell destruction, which needs further evaluation.
CRIS-Team Scopus Importer:2024-12-13

Clinical practice guidelines for the care of girls and women with Turner syndrome Proceedings from the 2023 Aarhus International Turner Syndrome Meeting - Gravholt, Claus H.; Andersen, Niels H.; Christin-Maitre, Sophie; Davis, Shanlee M.; Duijnhouwer, Anthonie; Gawlik, Aneta; Maciel-Guerra, Andrea T.; Gutmark-Little, Iris; Fleischer, Kathrin; Hong, David; Klein, Karen O.; Prakash, Siddharth K.; et al. (European Journal of Endocrinology, 2024)
Turner syndrome (TS) affects 50 per 100 000 females. TS affects multiple organs through all stages of life, necessitating multidisciplinary care. This guideline extends previous ones and includes important new advances, within diagnostics and genetics, estrogen treatment, fertility, comorbidities, and neurocognition and neuropsychology. Exploratory meetings were held in 2021 in Europe and United States culminating with a consensus meeting in Aarhus, Denmark in June 2023. Prior to this, eight groups addressed important areas in TS care: (1) diagnosis and genetics, (2) growth, (3) puberty and estrogen treatment, (4) cardiovascular health, (5) transition, (6) fertility assessment, monitoring, and counselling, (7) health surveillance for comorbidities throughout the lifespan, and (8) neurocognition and its implications for mental health and well-being. Each group produced proposals for the present guidelines, which were meticulously discussed by the entire group. Four pertinent questions were submitted for formal GRADE (Grading of Recommendations, Assessment, Development and Evaluation) evaluation with systematic review of the literature. The guidelines project was initiated by the European Society for Endocrinology and the Pediatric Endocrine Society, in collaboration with members from the European Society for Pediatric Endocrinology, the European Society of Human Reproduction and Embryology, the European Reference Network on Rare Endocrine Conditions, the Society for Endocrinology, and the European Society of Cardiology, Japanese Society for Pediatric Endocrinology, Australia and New Zealand Society for Pediatric Endocrinology and Diabetes, Latin American Society for Pediatric Endocrinology, Arab Society for Pediatric Endocrinology and Diabetes, and the Asia Pacific Pediatric Endocrine Society. Advocacy groups appointed representatives for pre-meeting discussions and the consensus meeting.
CRIS-Team Scopus Importer:2024-09-13
Keywords: cardiovascular health; co-morbidity; hypogonadism; infertility; neurocognition; transition; Turner syndrome

Clinical presentation and long-term outcome of patients with KCNJ11/ABCC8 variants: Neonatal diabetes or MODY in the DPV registry from Germany and Austria - Warncke, Katharina; Eckert, Alexander; Kapellen, Thomas; Kummer, Sebastian; Raile, Klemens; Dunstheimer, Desiree; Grulich-Henn, Jurgen; Wölfle, Joachim; Wenzel, Sandra; Hofer, Sabine E.; Dost, Axel; Holl, Reinhard W. (Pediatric Diabetes, 2022)
Objective: To describe clinical presentation/longterm outcomes of patients with ABCC8/KCNJ11 variants in a large cohort of patients with diabetes. Research Design and Methods We analyzed patients in the Diabetes Prospective Follow-up (DPV) registry with diabetes and pathogenic variants in the ABCC8/KCNJ11 genes. For patients with available data at three specific time-points-classification as K+-channel variant, 2-year follow-up and most recent visit-the longitudinal course was evaluated in addition to the cross-sectional examination.
CRIS-Team WoS Importer:2022-08-05

Clinical translation of photoacoustic imaging - Park, Jeongwoo; Choi, Seongwook; Knieling, Ferdinand; Clingman, Bryan; Bohndiek, Sarah; Wang, Lihong V.; Kim, Chulhong (Nature Reviews Bioengineering, 2025)
Photoacoustic imaging (PAI), also known as optoacoustic imaging, is a promising biomedical imaging technique that combines the benefits of rich optical contrast and high ultrasonic spatial resolution to overcome the limited penetration depth of light in living subjects. Basic biomedical research conducted with PAI in preclinical studies has generated much interest and shown outstanding potential for clinical and commercial translation. PAI has captured morphological, functional and molecular information in studies of living animals and humans, providing intrinsic clinical indicators from early diagnosis through to treatment monitoring. This Review presents the fundamentals of PAI technology and various clinical PAI systems and addresses key findings from pilot and clinical patient studies of human organ systems. The Review also discusses technical and non-technical challenges in clinical scenarios, emphasizes the importance of standardization in accelerating clinical translation, and summarizes the current state of the PAI regulatory process.
CRIS-Team Scopus Importer:2025-02-14

Closing the gap - Detection of clinically relevant von Willebrand disease in emergency settings through an improved algorithm based on rotational Thromboelastometry 11 Medical and Health Sciences 1103 Clinical Sciences 11 Medical and Health Sciences 1102 Cardiorespiratory Medicine and Haematology - Topf, H. -G.; Strasser, Erwin; Breuer, Georg; Rascher, Wolfgang; Rauh, Manfred; Fahlbusch, F. B. (BMC Anesthesiology, 2019)
Background: Hemorrhage and blood loss are still among the main causes of preventable death. Global hemostatic assays are useful point-of-care test (POCT) devices to rapidly detect cumulative effects of plasma factors and platelets on coagulation. Thromboelastography (TEG) and Thromboelastometry (ROTEM) are established methods in many anesthesiological departments for guided hemostatic treatment. However, von Willebrand disease remains undetected by standard ROTEM, especially during emergency care, despite being the most prevalent congenital hemostatic disorder. Methods: In our monocentric cohort pilot study we focused on hemostatic challenges associated with von Willebrand disease. Twenty-seven patients with suspected von Willebrand disease were included. We modified the routine ROTEM assay by adding a preincubation with ristocetin and commercially available plasma-derived von Willebrand factor to identify clinically relevant von Willebrand disease (VWD). Results: Addition of von Willebrand factor to the ristocetin assay of a VWD type 3 patient restored the reaction of the whole blood probe to match the response of a healthy person. Our modified ROTEM assay with ristocetin (Ricotem) showed that all high responders (n = 7) had VWD. In the low responder group (n = 16) - 10 of 16 had VWD and in the normal responder group (n = 5), 2 of 5 had mild type 1 VWD. Conclusions: This new modification of the standard ROTEM assay enables the detection of otherwise unnoticed critical von Willebrand disease based on alterations in clot formation and might serve as a novel approach to reliably assess severe VWD patients by platelet-mediated blood clotting in an emergency setting. We recommend incorporating this new VWD-focused screening tool into the current ROTEM-based management algorithm of acute microvascular bleeding.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Bleeding; Emergency; ROTEM; Thromboelastometry; Von Willebrand disease; VWD

Clustering of genomic breakpoints at the MLL locus in therapy-related acute leukemia with t(4;11)(q21;q23) - Hasan, Syed Khizer; Barba, Gianluca; Metzler, Markus; Divona, Mariadomenica; Ottone, Tiziana; Cicconi, Laura; Falini, Brunangelo; Mecucci, Cristina; Lo-Coco, Francesco (Genes Chromosomes & Cancer, 2014)
Genomic characterization of translocation breakpoints is relevant to identify possible mechanisms underlying their origin. The consistent association of anthracylines (e.g., epirubicin and idarubicin) in inducing therapy-related acute leukemias (t-AL) with mixed lineage leukemia (MLL) gene rearrangement suggests that MLL translocations are causative events for t-AL. Using asymmetric multiplex PCR strategy followed by direct DNA sequencing, we characterized the genomic breakpoints of the MLL and AFF1 genes in two patients who developed t-AL with t(4;11)(q21;q23). Chemotherapeutic treatment of the primary disease in both patients included topoisomerase II (topo II) targeting agents. In one case, the MLL breakpoint was located in intron 9 at nucleotide position chr11:118354284 while the AFF1 breakpoint was in intron 3 at nucleotide position chr4:87992070. The breakpoint junction sequences revealed an insertion of two nucleotides at the MLL-AFF1 junction. In the other patient, the MLL breakpoint was located in intron 11 at nucleotide position chr11:118359130-32 and the AFF1 break was in intron 3 at nucleotide position chr4:87996215-17. The MLL breakpoint found in the latter patient was identical to that of two previously reported cases, strongly suggesting the presence of a preferential site of DNA cleavage in the presence of topo II inhibitor. In addition, microhomologies at the breakpoint junctions were indicative of DNA repair by the non-homologous end joining (NHEJ) pathway. This study further supports the evidence that MLL breakpoints in therapy-related acute leukemia with MLL-AFF1 are clustered in the telomeric half of the breakpoint cluster region that contains topo II recognition sites.
EVALuna2:18880

Collaborative evaluation study on 18 candidate diseases for newborn screening in 1.77 million samples - Maier, Esther M.; Mütze, Ulrike; Janzen, Nils; Steuerwald, Ulrike; Nennstiel, Uta; Odenwald, Birgit; Schuhmann, Elfriede; Lotz-Havla, Amelie S.; Weiss, Katharina J.; Hammersen, Johanna; Weigel, Corina; Thimm, Eva; et al. (Journal of Inherited Metabolic Disease, 2023)
Analytical and therapeutic innovations led to a continuous but variable extension of newborn screening (NBS) programmes worldwide. Every extension requires a careful evaluation of feasibility, diagnostic (process) quality and possible health benefits to balance benefits and limitations. The aim of this study was to evaluate the suitability of 18 candidate diseases for inclusion in NBS programmes. Utilising tandem mass spectrometry as well as establishing specific diagnostic pathways with second-tier analyses, three German NBS centres designed and conducted an evaluation study for 18 candidate diseases, all of them inherited metabolic diseases. In total, 1 777 264 NBS samples were analysed. Overall, 441 positive NBS results were reported resulting in 68 confirmed diagnoses, 373 false-positive cases and an estimated cumulative prevalence of approximately 1 in 26 000 newborns. The positive predictive value ranged from 0.07 (carnitine transporter defect) to 0.67 (HMG-CoA lyase deficiency). Three individuals were missed and 14 individuals (21%) developed symptoms before the positive NBS results were reported. The majority of tested candidate diseases were found to be suitable for inclusion in NBS programmes, while multiple acyl-CoA dehydrogenase deficiency, isolated methylmalonic acidurias, propionic acidemia and malonyl-CoA decarboxylase deficiency showed some and carnitine transporter defect significant limitations. Evaluation studies are an important tool to assess the potential benefits and limitations of expanding NBS programmes to new diseases.
CRIS-Team Scopus Importer:2023-09-22
Keywords: dried blood spot; evaluation study; Germany; inborn errors of metabolism; newborn screening; public health; tandem mass spectrometry

Combined antifungal therapy is superior to monotherapy in pulmonary scedosporiosis in cystic fibrosis - Schwarz, Carsten; Brandt, Claudia; Melichar, Volker; Runge, Christoph; Heuer, Eberhard; Sahly, Hany; Schebek, Martin; Koester, Holger; Bouchara, Jean-Philippe; Biedermann, Thomas; Meissner, Peter; Grosse-Onnebrink, Joerg; et al. (Journal of Cystic Fibrosis, 2019)
Cystic fibrosis (CF) is characterised by chronic airway infection with bacteria and fungi. Infections caused by Scedosporium/Lomentospora species can occur and are difficult to treat. Moulds belonging to the genus Scedosporium/Lomentospora are detected most frequently in respiratory samples of patients with CF, next to Aspergillus spp. Our aim was to define pulmonary fungal infections due to Scedosporium/Lomentospora in CF and to study the antimycotic treatment. In this multicentre study (12 centres; duration January 2008 to December 2014) 31 patients with a lung infection caused by moulds of the genus Scedosporium/Lomentospora were included. 36 courses of antifungal treatment were documented. Scedosporium apiospermum sensu stricto accounted for 48.4% of cases. In 20/31 patients a therapeutic response under antimycotics (median duration 3.9 months) was achieved. Triple and double therapy was significantly more effective compared to monotherapy regarding FEV 1 , radiology, and symptoms. This data suggests that combined treatment is superior to monotherapy in patients with CF.
CRIS-Team Scopus Importer:2020-02-21
Keywords: Anti-fungal treatment; Mycosis; Pneumonia

Combining Congenital Heart Surgical and Interventional Cardiology Outcome Data in a Single Database: The Development of a Patient-Centered Collaboration of the European Congenital Heart Surgeons Association (ECHSA) and the Association for European Paediatric and Congenital Cardiology (AEPC). - Jacobs, Jeffrey P.; Krasemann, Thomas; Herbst, Claudia; Tobota, Zdzislaw; Maruszewski, Bohdan; Fragata, Jose; Ebels, Tjark; Vida, Vladimiro L.; Mattila, Ilkka; Kansy, Andrzej; Asfour, Boulos; Hörer, JÜrgen; et al. (Cardiology in the Young, 2023)
The European Congenital Heart Surgeons Association (ECHSA) Congenital Database (CD) is the second largest clinical pediatric and congenital cardiac surgical database in the world and the largest in Europe, where various smaller national or regional databases exist. Despite the dramatic increase in interventional cardiology procedures over recent years, only scattered national or regional databases of such procedures exist in Europe. Most importantly, no congenital cardiac database exists in the world that seamlessly combines both surgical and interventional cardiology data on an international level; therefore, the outcomes of surgical and interventional procedures performed on the same or similar patients cannot easily be tracked, assessed, and analyzed. In order to fill this important gap in our capability to gather and analyze information on our common patients, ECHSA and The Association for European Paediatric and Congenital Cardiology (AEPC) have embarked on a collaborative effort to expand the ECHSA-CD with a new module designed to capture data about interventional cardiology procedures. The purpose of this manuscript is to describe the concept, the structure, and the function of the new AEPC Interventional Cardiology Part of the ECHSA-CD, as well as the potentially valuable synergies provided by the shared interventional and surgical analyses of outcomes of patients. The new AEPC Interventional Cardiology Part of the ECHSA-CD will allow centers to have access to robust surgical and transcatheter outcome data from their own center, as well as robust national and international aggregate outcome data for benchmarking. Each contributing center or department will have access to their own data, as well as aggregate data from the AEPC Interventional Cardiology Part of the ECHSA-CD. The new AEPC Interventional Cardiology Part of the ECHSA-CD will allow cardiology centers to have access to aggregate cardiology data, just as surgical centers already have access to aggregate surgical data. Comparison of surgical and catheter interventional outcomes could potentially strengthen decision processes. A study of the wealth of information collected in the database could potentially also contribute toward improved early and late survival, as well as enhanced quality of life of patients with pediatric and/or congenital heart disease treated with surgery and interventional cardiac catheterization across Europe and the world.
EVALuna2:540968

Combining Congenital Heart Surgical and Interventional Cardiology Outcome Data in a Single Database: The Development of a Patient-Centered Collaboration of the European Congenital Heart Surgeons Association (ECHSA) and the Association for European Paediatric and Congenital Cardiology (AEPC) - Jacobs, Jeffrey P.; Krasemann, Thomas; Herbst, Claudia; Tobota, Zdzislaw; Maruszewski, Bohdan; Fragata, Jose; Ebels, Tjark; Vida, Vladimiro L.; Mattila, Ilkka; Kansy, Andrzej; Asfour, Boulos; Hörer, Jürgen; et al. (World Journal for Pediatric and Congenital Heart Surgery, 2023)
The European Congenital Heart Surgeons Association (ECHSA) Congenital Database (CD) is the second largest clinical pediatric and congenital cardiac surgical database in the world and the largest in Europe, where various smaller national or regional databases exist. Despite the dramatic increase in interventional cardiology procedures over recent years, only scattered national or regional databases of such procedures exist in Europe. Most importantly, no congenital cardiac database exists in the world that seamlessly combines both surgical and interventional cardiology data on an international level; therefore, the outcomes of surgical and interventional procedures performed on the same or similar patients cannot easily be tracked, assessed, and analyzed. In order to fill this important gap in our capability to gather and analyze information on our common patients, ECHSA and The Association for European Paediatric and Congenital Cardiology (AEPC) have embarked on a collaborative effort to expand the ECHSA-CD with a new module designed to capture data about interventional cardiology procedures. The purpose of this manuscript is to describe the concept, the structure, and the function of the new AEPC Interventional Cardiology Part of the ECHSA-CD, as well as the potentially valuable synergies provided by the shared interventional and surgical analyses of outcomes of patients. The new AEPC Interventional Cardiology Part of the ECHSA-CD will allow centers to have access to robust surgical and transcatheter outcome data from their own center, as well as robust national and international aggregate outcome data for benchmarking. Each contributing center or department will have access to their own data, as well as aggregate data from the AEPC Interventional Cardiology Part of the ECHSA-CD. The new AEPC Interventional Cardiology Part of the ECHSA-CD will allow cardiology centers to have access to aggregate cardiology data, just as surgical centers already have access to aggregate surgical data. Comparison of surgical and catheter interventional outcomes could potentially strengthen decision processes. A study of the wealth of information collected in the database could potentially also contribute toward improved early and late survival, as well as enhanced quality of life of patients with pediatric and/or congenital heart disease treated with surgery and interventional cardiac catheterization across Europe and the world.
CRIS-Team Scopus Importer:2023-07-21
Keywords: cardiac surgery; congenital heart disease; database; interventional cardiology; nomenclature; pediatric; pediatric heart disease

Comeback of Renal Denervation As Treatment Option in Patients with Hypertension - Jung, Susan; Schmieder, Roland (Aktuelle Kardiologie, 2019)
The effectiveness of renal denervation to reduce blood pressure has been controversially discussed. After a few uncontrolled pilot studies had shown promising results with respect to the effectiveness of this method, the results of the Symplicity HTN-3 study were discouraging: no significant difference in blood pressure reduction between denervation and sham group could be observed. The results of three sham-controlled studies were finally able to prove the effectiveness of renal denervation: in comparison to sham-procedure, a significant office and 24-h ambulatory blood pressure reduction could be achieved. The findings obtained from these studies provide interesting future perspectives with respect to the application of the technique in other diseases and patients that profit most from renal denervation.
CRIS-Team WoS Importer:2019-10-29

Common arterial trunk: current implementation of the primary and staged repair strategies - Sandrio, Stany; Rueffer, Andre; Purbojo, Ariawan; Glöckler, Martin; Dittrich, Sven; Cesnjevar, Robert (Interactive Cardiovascular and Thoracic Surgery, 2015)
In this study, we report our experience on the primary and staged surgical approaches for common arterial trunk (CAT) repair.Between August 2003 and February 2015, 16 consecutive patients underwent CAT repair in our institution. Two different approaches have been followed: group 'primary repair' (PR) consists of patients suitable for straightforward CAT repair, who underwent surgery electively at 1-3 months of age (n = 13); group 'staged repair' (SR) consists of critically ill neonates with CAT and poor preoperative status or coexisting interrupted aortic arch (n = 3). They underwent staged CAT repair with aortic arch repair and right ventricular-to-pulmonary artery (RV-PA) shunt within the neonatal period, followed by an intracardiac repair later in infancy.Median age at initial surgical treatment was 8 days (range: 7-21 days) in group SR and 34 days (range: 14-91 days) in group PR (P = 0.03). Mean Aristotle Comprehensive Complexity score was 11 ± 0.6 (range: 11-13) in group PR and 18 ± 3.1 (range: 15-21) in group SR (P < 0.01). Follow-up was completed with a median duration of 3.6 years (range: 8 months to 11 years). There was neither early nor late mortality in both groups. In group SR, the median interval to second stage surgery was 216 days (range: 216-260 days). Seven patients (54%) in group PR required reoperation for RV-PA conduit failure (n = 4), truncal valve repair/replacement (n = 2) or both (n = 1). After initial surgery, Kaplan-Meier freedom from reoperation after 1, 2 and 8 years was 77 ± 12, 68 ± 13 and 20 ± 17% in group PR, and 0% in group SR (log-rank P < 0.01). Although all patients in group SR required reoperation to complete the anatomical correction (second stage procedure), there was no surgical reintervention of truncal valve and aortic arch thereafter.Routine elective CAT repair could be safely performed at 1-3 months of age. However, neonatal CAT repair could be associated with a higher mortality especially in the presence of an interrupted aortic arch. In such cases, a staged CAT repair seems to be associated with favourable postoperative course and improved hospital survival, despite the inevitable need for reoperation, which can be performed at a relatively low risk.
EVALuna2:25116

Common Genetic Variants Contribute to Risk of Transposition of the Great Arteries - Skoric-Milosavljevic, Doris; Tadros, Rafik; Bosada, Fernanda M.; Tessadori, Federico; Van Weerd, Jan Hendrik; Woudstra, Odilia; Tjong, Fleur V. Y.; Lahrouchi, Najim; Bajolle, Fanny; Cordell, Heather J.; Agopian, A. J.; Blue, Gillian M.; et al. (Circulation Research, 2022)
Rationale: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored. Objective: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA. Methods and Results: We conducted a genome-wide association study in an international set of 1,237 patients with D-TGA and identified a genome-wide significant susceptibility locus on chromosome 3p14.3, which was subsequently replicated in an independent case-control set (rs56219800, meta-analysis P=8.6x10(-10), OR=0.69 per C allele). SNP-based heritability analysis showed that 25% of variance in susceptibility to D-TGA may be explained by common variants. A genome-wide polygenic risk score derived from the discovery set was significantly associated to D-TGA in the replication set (P=4x10(-5)). The genome-wide significant locus (3p14.3) co-localizes with a putative regulatory element that interacts with the promoter of WNT5A, which encodes the Wnt Family Member 5A protein known for its role in cardiac development in mice. We show that this element drives reporter gene activity in the developing heart of mice and zebrafish and is bound by the developmental transcription factor TBX20. We further demonstrate that TBX20 attenuates Wnt5a expression levels in the developing mouse heart. Conclusions: This work provides support for a polygenic architecture in D-TGA and identifies a susceptibility locus on chromosome 3p14.3 near WNT5A. Genomic and functional data support a causal role of WNT5A at the locus.
CRIS-Team WoS Importer:2022-02-04

Common variants increase risk for congenital diaphragmatic hernia within the context of de novo variants - Qiao, Lu; Welch, Carrie L.; Hernan, Rebecca; Wynn, Julia; Krishnan, Usha S.; Zalieckas, Jill M.; Buchmiller, Terry; Khlevner, Julie; De, Aliva; Farkouh-Karoleski, Christiana; Wagner, Amy J.; Heydweiller, Andreas; et al. (American Journal of Human Genetics, 2024)
Congenital diaphragmatic hernia (CDH) is a severe congenital anomaly often accompanied by other structural anomalies and/or neurobehavioral manifestations. Rare de novo protein-coding variants and copy-number variations contribute to CDH in the population. However, most individuals with CDH remain genetically undiagnosed. Here, we perform integrated de novo and common-variant analyses using 1,469 CDH individuals, including 1,064 child-parent trios and 6,133 ancestry-matched, unaffected controls for the genome-wide association study. We identify candidate CDH variants in 15 genes, including eight novel genes, through deleterious de novo variants. We further identify two genomic loci contributing to CDH risk through common variants with similar effect sizes among Europeans and Latinx. Both loci are in putative transcriptional regulatory regions of developmental patterning genes. Estimated heritability in common variants is ∼19%. Strikingly, there is no significant difference in estimated polygenic risk scores between isolated and complex CDH or between individuals harboring deleterious de novo variants and individuals without these variants. The data support a polygenic model as part of the CDH genetic architecture.
CRIS-Team Scopus Importer:2024-11-08
Keywords: common variants; congenital diaphragmatic hernia; de novo variants; genome-wide association study; single-nucleotide polymorphism; WNT5A

Comparable Cerebral Blood Flow in Both Hemispheres During Regional Cerebral Perfusion in Infant Aortic Arch Surgery - Rueffer, Andre; Tischer, Philip; Münch, Frank; Purbojo, Ariawan; Toka, Okan; Rascher, Wolfgang; Cesnjevar, Robert; Juengert, Joerg (Annals of Thoracic Surgery, 2017)
Cerebral protection during aortic arch repair can be provided by regional cerebral perfusion (RCP) through the innominate artery. This study addresses the question of an adequate bilateral blood flow in both hemispheres during RCP.Fourteen infants (median age 11 days [range, 3 to 108]; median weight, 3.6 kg [range, 2.8 to 6.0 kg]) undergoing RCP (flow rate 54 to 60 mL · kg(-1) · min(-1)) were prospectively included. Using combined transfontanellar/transtemporal two- and three-dimensional power/color Doppler sonography, cerebral blood flow intensity in the main cerebral vessels was displayed. Mean time average velocities were measured with combined pulse-wave Doppler in the basilar artery, and both sides of the internal carotid, anterior, and medial cerebral arteries. In addition, bifrontal regional cerebral oximetry (rSO2) was assessed. Comparing both hemispheres, measurements were performed at target temperature (28°C) during full-flow total body perfusion (TBP) and RCP.A regular circle of Willis with near-symmetric blood flow intensity to both hemispheres was visualized in all infants during both RCP and TBP. In the left internal carotid artery, blood flow direction was mixed (retrograde, n = 5; antegrade, n = 8) during TBP and retrograde during RCP. Comparison between sides showed comparable cerebral time average velocities and rSO2, except for higher time average velocities in the right internal carotid artery (TBP p = 0.019, RCP p = 0.09). Unilateral comparison between perfusion methods revealed significantly higher rSO2 in the right hemisphere during TBP (82% ± 9%) compared with RCP (74% ± 11%, p = 0.036).Bilateral assessment of cerebral rSO2 and time average velocity in the main great cerebral vessels suggests that RCP is associated with near-symmetric blood flow intensity to both hemispheres. Further neurodevelopmental studies are necessary to verify RCP for neuroprotection during aortic arch repair.
EVALuna2:25812

COMPARATIVE ANALYSIS OF INTEGRIN ALPHA 8 EXPRESSION AND ITS LIGANDS FIBRONECTIN AND OSTEOPONTIN IN HUMAN, RAT AND MOUSE PLACENTA - Fahlbusch, Fabian; Herdl, Sebastian; Volkert, Gudrun; Marek, Ines; Menendez-Castro, Carlos; Nögel, Stephanie; Rübner, Matthias; Hübner, Hanna; Hartner, Andrea; Rascher, Wolfgang (2016)
EVALuna2:33461

Comparative Socioeconomic Study Of Patients In Germany With Dravet Syndrome, Refractory Epilepsy Or Epilepsy In Seizure Remission, And Their Caregivers - Strzelczyk, A.; Schubert-Bast, S.; Bast, T.; Bettendorf, U.; Hamer, Hajo; Herting, A.; Kalski, M.; Kay, L.; Kieslich, M.; Klein, K. M.; Kluger, G.; Kurlemann, G.; et al. (EPILEPSIA, 2019)
CRIS-Team WoS Importer:2019-11-15

Comparison of automated differential blood cell counts from abbott sapphire, siemens advia 120, beckman coulter DxH 800, and sysmex XE-2100 in normal and pathologic samples - Meintker, Lisa; Ringwald, Juergen; Rauh, Manfred; Krause, Stefan (American Journal of Clinical Pathology, 2013)
Reliable automated blood cell characterization and quantification remain challenging in pathologic samples, whereas slide reviews due to unnecessary flagging should be avoided. We compared 4 modern hematology analyzers-Abbott Sapphire, Siemens Advia 120, Sysmex XE-2100, and Beckman Coulter DxH 800-regarding complete blood cell count (CBC), leukocyte differential count, and flagging efficacy in a total of 202 samples from hematology patients and normal controls. Manual differential count was used as reference. The analyzers exhibited very good correlation for CBC parameters. Neutrophils and eosinophils also showed very good correlations, whereas lymphocytes and monocytes correlated fairly. The Advia 120 displayed notably lower measurements for both parameters, which is attributable to classification of some events as large unstained cells. Basophil counts were unreliable with all analyzers. Flagging for blasts and immature granulocytes showed moderate sensitivity and specificity. Operators must not rely on blast flagging alone to detect leukemic samples with any analyzer. © American Society for Clinical Pathology.
Created from Fastlane, Scopus look-up
Keywords: Automated blood cell count; Blasts; Flag; Immature granulocytes; Leukocyte differential count

Comparison of stress and stress–strain approaches for the active contraction in a rat cardiac cycle model - Martonová, Denisa; Holz, David; Seufert, Julia; Duong, Minh Tuan; Alkassar, Muhannad; Leyendecker, Sigrid (Journal of Biomechanics, 2022)
In the last decades, different strategies to model the active electromechanically coupled behaviour of the cardiac tissue were proposed in order to simulate electromechanics of the heart under healthy and pathological conditions. The main objective of this work is to compare two approaches for modelling the active contraction during the electromechanically coupled rat cardiac cycle —- the stress and the stress–strain approach. Firstly, a cylindrical benchmark is considered and secondly, for a generic model of a rat left ventricle, a simulation including the Windkessel model, excitation via Purkinje fibre network and mechano-electrical feedback is performed. The model is calibrated with experimental data for rats, partly from own measurements via cardiac ultrasound, partly from the literature. Further, possibilities to reach higher ejection fractions are discussed and considered for an exemplary rat left ventricle. Within each approach, we observe regionally different active stresses and fibre stretches. Moreover, the transmural active stress and fibre stretch distribution is influenced by the pressure load on the endocardial surface. The active stress approach is not sensitive to the fibre stretch and transmurally varying fibre stretch in the left ventricular domain is observed. The active stress–strain approach leads to transmurally more homogeneous fibre stretch at the end-systolic state.
CRIS-Team Scopus Importer:2022-02-25
Keywords: Active stress; Cardiac cycle; Cardiac electromechanics; Finite element method; Rat left ventricle

Comparison of the Ramirez technique for the closure of large open myelomeningocele defects with alternative methods - Kneser, Ulrich; Bigdeli, Amir K.; Himmler, Joerg P.; Eyüpoglu, Ilker Yasin; Ganslandt, Oliver Thomas; Hirsch, Almut; Schmidt, Volker J.; Beier, Justus; Horch, Raymund E. (Journal of Plastic Reconstructive and Aesthetic Surgery, 2015)
To compare the Ramirez technique for the operative closure of large open myelomeningocele defects with conventional closure techniques in newborns. We hypothesized that the immediate surgical treatment with the Ramirez technique is superior to prior used operative techniques.From 2003 to 2010, 23 children (8 female, 15 male) underwent closure of large open myelomeningocele defects using the Ramirez technique (group A), while from 1993 to 2002, 23 children (6 female, 17 male) underwent conventional closure techniques (group B). All children were included in the retrospective analysis with a mean follow-up period of 3.4 years.Perioperative variables were similar in both groups (P = ns). There were no hospital deaths in both groups. The operation time was significantly higher in group A (228.7 ± 76.8 versus 157.8 ± 70.3 min, P = 0.003). Mean length of hospital stay was significantly lower in group A (30.7 ± 16.4 days versus 52.0 ± 38.5; P = 0.02). Postoperative complication rate was significantly lower in group A (P = 0.01). Beyond postoperative day 10, liquor fluid leakage was significantly lower in group A (P = 0.05). During follow-up, there were no complications in group A. In group B, 2 children developed liquor fistulas.The Ramirez technique allows efficient and safe closure of large open myelomeningocele defects and reduces incidence of postoperative liquor fistulae. The increased operation time and surgical efforts seem to be justified. Treatment of large myelomeningocele defects requires an interdisciplinary team including paediatrician-neonatologists, neurosurgeons and plastic surgeons.
EVALuna2:15600

Complex lipid globules in early-life nutrition improve long-term metabolic phenotype in intra-uterine growth-restricted rats - Teller, Inga C.; Hoyer-Kuhn, Heike; Broenneke, Hella; Nosthoff-Horstmann, Pia; Oosting, Annemarie; Lippach, Gregor; Wohlfarth, Maria; Rauh, Manfred; Van Der Beek, Eline M.; Doetsch, Joerg; Nuesken, Kai D. (British Journal of Nutrition, 2018)
Intra-uterine growth restriction (IUGR) is associated with adverse metabolic outcome later in life. Healthy mice challenged with a Western-style diet (WSD) accumulated less body fat when previously fed a diet containing large lipid globules (complex lipid matrix (CLM)). This study was designed to clarify whether an early-life CLM diet mitigates 'programmed' visceral adiposity and associated metabolic sequelae after IUGR. In rats, IUGR was induced either by bilateral uterine vessel ligation (LIG) or sham operation (i.e. intra-uterine stress) of the dam on gestational day 19. Offspring from non-operated (NOP) dams served as controls. Male offspring of all groups were either fed CLM or 'normal matrix' control diet (CTRL) from postnatal days (PND) 15 to 42. Thereafter, animals were challenged with a mild WSD until dissection (PND 98). Fat mass (micro computer-tomograph scan; weight of fat compartments), circulating metabolic markers and expression of 'metabolic' genes (quantitative real-time PCR) were assessed. CLM diet significantly reduced visceral fat mass in LIG at PND 40. At dissection, visceral fat mass, fasted blood glucose, TAG and leptin concentrations were significantly increased in LIG-CTRL v. NOP-CTRL, and significantly decreased in LIG-CLM v. LIG-CTRL. Gene expression levels of leptin (mesenteric fat) and insulin-like growth factor 1 (liver) were significantly reduced in LIG-CLM v. LIG-CTRL. In conclusion, early-life CLM diet mitigated the adverse metabolic phenotype after utero-placental insufficiency. The supramolecular structure of dietary lipids may be a novel aspect of nutrient quality that has to be considered in the context of primary prevention of obesity and metabolic disease in at-risk populations.
EVALuna2:35819

Compound heterozygous RYR1 mutations in a preterm with arthrogryposis multiplex congenita and prenatal CNS bleeding - Brackmann, Florian; Türk, Matthias; Gratzki, Nils; Rompel, Oliver; Jungbluth, Heinz; Schröder, Rolf; Trollmann, Regina (Neuromuscular Disorders, 2018)
RYR1 mutations, the most common cause of non-dystrophic neuromuscular disorders, are associated with the malignant hyperthermia susceptibility (MHS) trait as well as congenital myopathies with widely variable clinical and histopathological manifestations. Recently, bleeding anomalies have been reported in association with certain RYR1 mutations. Here we report a preterm infant born at 32 weeks gestation with arthrogryposis multiplex congenita due to compound heterozygous, previously MHS-associated RYR1 mutations, with additional signs of prenatal hemorrhage. The patient presented at birth with multiple joint contractures, scoliosis, severe thoracic rigidity and respiratory failure. He continued to depend on mechanical ventilation and tube feeding. Muscle histopathology showed a marked myopathic pattern with eccentric cores. Interestingly, the patient had additional unusual prenatal intraventricular hemorrhage, resulting in post-hemorrhagic hydrocephalus as well as epidural hemorrhage affecting the spinal cord. This report adds to the phenotypic variability associated with RYR1 mutations, and highlights possible bleeding complications in affected individuals.
EVALuna2:34599

Comprehensive assessments and related interventions to enhance the long-term outcomes of child, adolescent and young adult cancer survivors - presentation of the CARE for CAYA-Program study protocol and associated literature review - Salchow, J.; Mann, J.; Koch, B.; von Grundherr, J.; Jensen, W.; Elmers, S.; Straub, L. A.; Vettorazzi, E.; Escherich, G.; Rutkowski, S.; Dwinger, S.; Bergelt, C.; et al. (BMC Cancer, 2020)
BACKGROUND: Improved, multimodal treatment strategies have been shown to increase cure rates in cancer patients. Those who survive cancer as a child, adolescent or young adult (CAYA), are at a higher risk for therapy-, or disease-related, late or long-term effects. The CARE for CAYA-Program has been developed to comprehensively assess any potential future problems, to offer need-based preventative interventions and thus to improve long-term outcomes in this particularly vulnerable population. METHODS: The trial is designed as an adaptive trial with an annual comprehensive assessment followed by needs stratified, modular interventions, currently including physical activity, nutrition and psycho-oncology, all aimed at improving the lifestyle and/or the psychosocial situation of the patients. Patients, aged 15-39 years old, with a prior cancer diagnosis, who have completed tumour therapy and are in follow-up care, and who are tumour free, will be included. At baseline (and subsequently on an annual basis) the current medical and psychosocial situation and lifestyle of the participants will be assessed using a survey compiled of various validated questionnaires (e.g. EORTC QLQ C30, NCCN distress thermometer, PHQ-4, BSA, nutrition protocol) and objective parameters (e.g. BMI, WHR, co-morbidities like hyperlipidaemia, hypertension, diabetes), followed by basic care (psychological and lifestyle consultation). Depending on their needs, CAYAs will be allocated to preventative interventions in the above-mentioned modules over a 12-month period. After 1 year, the assessment will be repeated, and further interventions may be applied as needed. During the initial trial phase, the efficacy of this approach will be compared to standard care (waiting list with intervention in the following year) in a randomized study. During this phase, 530 CAYAs will be included and 320 eligible CAYAs who are willing to participate in the interventions will be randomly allocated to an intervention. Overall, 1500 CAYAs will be included and assessed. The programme is financed by the innovation fund of the German Federal Joint Committee and will be conducted at 14 German sites. Recruitment began in January 2018. DISCUSSION: CAYAs are at high risk for long-term sequelae. Providing structured interventions to improve lifestyle and psychological situation may counteract against these risk factors. The programme serves to establish uniform regular comprehensive assessments and need-based interventions to improve long-term outcome in CAYA survivors. TRIAL REGISTRATION: Registered at the German Clinical Trial Register (ID: DRKS00012504, registration date: 19th January 2018).
CRIS-Team Scopus Importer:2020-01-21
Keywords: AYA; CAYA; Children adolescents and young adults after cancer; Follow-up care; Lifestyle intervention; Long-term side effects; Long-term toxicity; Prevention programme

Comprehensive bone marrow analysis integrating deep learning-based pattern discovery (BMDeep) - Pontones, Martina; Hoefener, H.; Kock, F.; Schwen, L.; Westphal, M.; Dickel, Nicholas; Kunz, Meik; Metzler, Markus (KLINISCHE PADIATRIE, 2022)
Bone marrow morphology forms the basis for the assessment of hematopoiesis. The currently established approach is dependent on manual microscopic counting of a limited number of cells by specially trained personnel, which is inherently associated with substantial intra- and inter-individual variability. The aim of our project is to automatize and improve the evaluation of bone marrow smears and to identify pathological patterns in pediatric leukemia.<br
CRIS-Team WoS Importer:2022-07-08

Computational model of a rat left ventricle - Holz, David; Duong, Minh Tuan; Alkassar, Muhannad; Dittrich, Sven; Leyendecker, Sigrid (8th Summer School on Biomechanics, from Protein to Tissue to Organ: Modeling and Computation, 2018)

Computational study of ventricular fibrillation by considering a strongly coupled electromechanical rat heart model - Holz, David; Duong, Minh Tuan; Alkassar, Muhannad; Dittrich, Sven; Leyendecker, Sigrid (Procc. App. Math. Mech. (PAMM), 2019)

Computed Tomography-Guided Wire-Marking for Thoracoscopic Resection of Small Lung Nodules in Children - Seitz, Sigurd T.; Schellerer, Vera; Schmid, Axel; Metzler, Markus; Besendörfer, Manuel (Journal of Laparoendoscopic & Advanced Surgical Techniques, 2019)
Introduction: In pediatric patients, thoracoscopic wedge-resection of pulmonary nodules is an established therapy. However, intraoperative localization of small lesions is still challenging. Purpose of this study was to evaluate the efficacy of preoperative computed tomography (CT)-guided wire-marking of small lung nodules. Materials and Methods: Between 2012 and 2017 a total of six cases receiving thoracoscopic resection of CT-marked lung nodules were analyzed. The nodules were preoperatively tagged by a wire, which was attached to the thoracic wall by sterile dressing. Characteristics of interest were stability of wire, complete resection, and prevention of open thoracotomy. Results: Six procedures were performed on five patients, including four men and one woman. Median age at intervention was 16 years (range 11-19 years). All patients had a history of primary malignancies, including osteosarcoma (n = 4) and synovial sarcoma (n = 1). A total of 10 nodules were visualized in CT of which 9 were marked by wire. The median expected size of nodules was 6 mm (range 2-23 mm). Two patients had bilateral, two left-sided and two right-sided lung lesions. There was no wire slippage. In five procedures wedge resection was possible; one case needed a near total lobe resection. In one case a mini-thoracotomy at port insertion site was performed to extract the specimen. There was no conversion to thoracotomy. Histopathology showed R0 resection in all patients. Malignancy was found in all specimens. In one patient postoperative hemorrhagic anemia necessitated transfusion. Conclusions: Preoperative wire-localization of small lung nodules is a safe and effective tool to enable thoracoscopic resection in children and to avoid thoracotomic interventions.
CRIS-Team WoS Importer:2019-04-18

Conditional Alox12b Knockout: Degradation of the Corneocyte Lipid Envelope in a Mouse Model of Autosomal Recessive Congenital Ichthyoses - Krieg, P.; Dick, Angela; Latzko, Susanne; Rosenberger, Sabine; Meyer, J.; Crumrine, D.; Hielscher, Thomas; Elias, Peter M.; Rauh, Manfred; Schneider, Holm (Journal of Investigative Dermatology, 2019)
CRIS-Team Scopus Importer:2019-09-17

CONFOCAL LASER ENDOMICROSCOPY CAN PREDICT MAJOR CLINICAL EVENTS WITH VERY HIGH SENSITIVITY IN PATIENTS WITH INFLAMMATORY BOWEL DISEASES - Klenske, Entcho; Atreya, Raja; Zundler, Sebastian; Fischer, Sven Moritz; Neurath, Markus; Rath, Timo (GASTROINTESTINAL ENDOSCOPY, 2019)
CRIS-Team WoS Importer:2019-06-21

Congenital disorders of glycosylation with defective fucosylation - Huellen, Andreas; Falkenstein, Kristina; Weigel, Corina; Huidekoper, Hidde; Naumann-Bartsch, Nora; Spenger, Johannes; Feichtinger, Rene G.; Schaefers, Jacqueline; Frenz, Stephanie; Kotlarz, Daniel; Momen, Tooba; Khoshnevisan, Razieh; et al. (Journal of Inherited Metabolic Disease, 2021)
Fucosylation is essential for intercellular and intracellular recognition, cell-cell interaction, fertilization, and inflammatory processes. Only five types of congenital disorders of glycosylation (CDG) related to an impaired fucosylation have been described to date: FUT8-CDG, FCSK-CDG, POFUT1-CDG SLC35C1-CDG, and the only recently described GFUS-CDG. This review summarizes the clinical findings of all hitherto known 25 patients affected with those defects with regard to their pathophysiology and genotype. In addition, we describe five new patients with novel variants in the SLC35C1 gene. Furthermore, we discuss the efficacy of fucose therapy approaches within the different defects.
CRIS-Team Scopus Importer:2021-09-24
Keywords: CDG; coarse facial features; developmental delay; epilepsy; fucosylation; intellectual disability; neutrophilia

Congenital Nail Disorders among Children with Suspected Ectodermal Dysplasias - Maier-Wohlfart, Sigrun; Aicher, Carmen; Willershausen, Ines; Peschel, Nicolai; Meißner, Udo; Gölz, Lina; Schneider, Holm (Genes, 2022)
We report on a cohort of 204 children referred between January 2017 and January 2022 to the German Center for Ectodermal Dysplasias, Erlangen. The most frequent reasons for referral were tooth malformations and lack of multiple teeth leading to the suspicion of an ectodermal dysplasia. Many patients also suffered from being unable to perspire. Nail abnormalities, in contrast, represented a much rarer finding, albeit the impact on some individuals was large. As ectodermal dysplasias are congenital genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands, we analyzed congenital nail disorders detected in these patients. Dystrophic or otherwise abnormal nails were evident in 17 of 18 subjects with pathogenic WNT10A or GJB6 variants but in none of 161 children with EDA variants underlying X-linked hypohidrotic ectodermal dysplasia. However, 2 of 17 children who carry mutations in EDAR or EDARADD, two other genes involved in the ectodysplasin A signaling pathway, showed nail abnormalities, such as brittle or hypoplastic nails. TP63 variants were regularly associated with nail disorders. In one girl, anonychia congenita caused by a compound heterozygous variant of the R-spondin-4 gene (RSPO4) was diagnosed. Thus, nail dysplasia is rarer among patients with ectodermal dysplasia than commonly thought.
CRIS-Team Scopus Importer:2022-12-09
Keywords: anonychia/hyponychia congenita; congenital nail disorders; ectodermal dysplasia; R-spondin 4 (RSPO4)

Considerations for Continuing Semielective and Emergency Otolaryngological Procedures During the COVID-19 Pandemic - Müller, Sarina Katrin; Traxdorf, Maximilian; Mantsopoulos, Konstantinos; Gostian, Antoniu Oreste; Sievert, Matti; Koch, Michael; Hübner, Matthias; Iro, Heinrich (Ent-Ear Nose & Throat Journal, 2020)
Introduction: During the COVID-19 pandemic, worldwide over 600,000 human beings died due to the cause of the disease. In order to deescalate the transmission rate and to avoid crush loading the countries medical health systems social distancing, face masks, and lockdowns have been considered essential by the majority of governments. Whereas some countries have highly reduced or completely stopped otorhinolaryngological procedures, other countries have continued selected surgeries. The objective of this study was to analyze procedures and outcomes of continuing semielective and emergency surgeries during the COVID-19 pandemic. Methods: Retrospective analysis of n = 750 patients who received semi-elective or emergency surgery between March 26 and June 16, 2020, in the Otolaryngology Department of the Friedrich-Alexander-University of Erlangen-Nürnberg. All patients were screened for COVID symptoms and swabbed for SARS-CoV-2 prior to surgery. Results: Of the n = 750 patients, n = 699 patients received semielective surgery and n = 51 emergency surgery. For 27 patients, the swab result could not be awaited due to a life-threatening condition. In these cases, surgery was performed in full protective equipment. No patient was tested positive during or after the surgery (follow-up 45 to 127 days). No member of the medical personnel showed symptoms or was tested positive after contact with patients. Due to the continuation of surgeries, patients’ lives were saved and improvement of long-term quality-of-life and outcomes is anticipated. Conclusions: Continuing selected otorhinolaryngological surgeries is crucial for patients’ health, survival, and long-time quality of life, yet, the protection of the medical personnel has to be granted.
CRIS-Team Scopus Importer:2020-09-18
Keywords: COVID-19; false-negative; otorhinolaryngological procedures; patient’s health; SARS-CoV-2 test

Consider further differential diagnoses - Schneider, Holm (Deutsches Ärzteblatt international, 2014)
EVALuna2:18897

CONTINUOUS GLUCOSE MONITORING IN CSII THERAPY IN DIFFERENT AGE GROUPS (0.5- - Van Den Boom, L.; Auzanneau, M.; Wölfle, Joachim; Sindichakis, M.; Herbst, A.; Meraner, D.; Hake, K.; Klinkert, C.; Gohlke, B.; Holl, R. (DIABETES TECHNOLOGY & THERAPEUTICS, 2022)
CRIS-Team WoS Importer:2022-05-20

Continuous monitoring of SARS-CoV-2 seroprevalence in children using residual blood samples from routine clinical chemistry - Wachter, Felix; Regensburger, Adrian; Peter, Antonia Sophia; Knieling, Ferdinand; Wagner, Alexandra; Simon, David; Hörning, André; Wölfle, Joachim; Überla, Klaus; Neubert, Antje; Rauh, Manfred (Clinical Chemistry and Laboratory Medicine, 2022)
Objectives The assessment of SARS-CoV-2 infections in children is still challenging, but essential for appropriate political decisions. The aim of this study was to investigate whether residual blood samples can be used for SARS-CoV-2 seroprevalence monitoring in pediatrics. Methods In this repeated cross-sectional cohort study, anonymous residual blood samples from pediatric patients aged 0-17 years were collected in three time-periods (Oct.-Nov. 2020, April 2021, and June-July 2021) and analyzed for SARS-CoV-2 Spike protein (anti-S) and nucleocapsid (anti-N) antibodies using commercial antibody assays. 28 reactive samples were used to compare antibody levels with a pseudotyped neutralization assay. The results were further compared to the official national COVID-19 surveillance data to calculate the number of unreported cases. Results In total, n=2,626 individual blood samples were analyzed. In this unvaccinated pediatric cohort anti-S and anti-N antibody seroprevalence increased over the three time periods (anti-S: 1.38-9.16%, and 14.59%; anti-N: 1.26%, to 6.19%, and 8.56%). Compared to the national surveillance data this leads to a 3.93-5.66-fold increase in the number of unreported cases. However, a correlation between the cumulative incidence of the individual provinces and our assigned data was found (r=0.74, p=0.0151). In addition, reactive samples with anti-S and anti-N and samples with only anti-S showed neutralization capabilities (11/14 and 8/14, respectively). Anti-S levels were not significantly different between age groups and sexes (all p>0.05). Conclusions The present study suggests that residual blood samples from routine laboratory chemistry could be included in the estimation of the total SARS-CoV-2 seroprevalence in children.
CRIS-Team WoS Importer:2022-03-11
Keywords: COVID-19; pediatrics; prevalence; SARS-CoV-2

Continuous Non-Invasive Blood Pressure Measurement Using Pulse Transit Time in Children and Adolescents - Zagrada, Elena; Krickau, Tobias; Rascher, Wolfgang (Klinische Pädiatrie, 2019)
Background As an alternative to ambulatory 24-h blood pressure monitors, the continuous, non-invasive blood pressure recording using pulse transit time (PTT) was compared with both oscillometric and intra-arterial measurement. Methods In 144 pediatric patients (9.4 +/- 5.2 years) acute blood pressure was determined using three different methods of measurement. In 57 patients (11.4 +/- 4.9 years) of the pediatric normal ward, the blood pressure was simultaneously determined continuously by means of PTT compared to the intermittent oscillometric long-term measurement. In 9 patients (9.8 +/- 6.8 years) of the pediatric intensive care unit with continuous intra-arterial blood pressure measurement, the blood pressure was measured in parallel by means of PTT.
CRIS-Team WoS Importer:2019-04-02

Continuous therapy response references for BCR::ABL1 monitoring in pediatric chronic myeloid leukemia - Volz, Christian; Zerjatke, Thomas; Gottschalk, Andrea; Semper, Sabine; Suttorp, Meinolf; Glauche, Ingmar; Krumbholz, Manuela; Metzler, Markus (Scientific Reports, 2023)
Response to tyrosine kinase inhibitor (TKI) therapy in patients with chronic myeloid leukemia (CML) is monitored by quantification of BCR::ABL1 transcript levels. Milestones for assessing optimal treatment response have been defined in adult CML patients and are applied to children and adolescents although it is questionable whether transferability to pediatric patients is appropriate regarding genetic and clinical differences. Therefore, we analyzed the molecular response kinetics to TKI therapy in 129 pediatric CML patients and investigated whether response assessment based on continuous references can support an early individual therapy adjustment. We applied a moving quantiles approach to establish a high-resolution response target curve and contrasted the median responses in all patients with the median of the ideal target curve obtained from a subgroup of optimal responders. The high-resolution response target curve of the optimal responder group presents a valuable tool for continuous therapy monitoring of individual pediatric CML patients in addition to the fixed milestones. By further comparing BCR::ABL1 transcript levels with BCR::ABL1 fusion gene copy numbers, it is also possible to model the differential dynamics of BCR::ABL1 expression and cell number under therapy. The developed methodology can be transferred to other biomarkers for continuous therapy monitoring.
CRIS-Team Scopus Importer:2023-11-03

Contrast-Enhanced Multispectral Optoacoustic Tomography for Functional Assessment of the Gastrointestinal Tract - Paulus, Lars-Philip; Bühler, Adrian; Wagner, Alexandra; Raming, Roman; Jüngert, Jörg; Simon, David; Tascilar, Koray; Schnell, Alexander; Rother, Ulrich; Eckstein, Markus; Lang, Werner; Hörning, André; et al. (Advanced Science, 2023)
Real-time imaging and functional assessment of the intestinal tract and its transit pose a significant challenge to conventional clinical diagnostic methods. Multispectral optoacoustic tomography (MSOT), a molecular-sensitive imaging technology, offers the potential to visualize endogenous and exogenous chromophores in deep tissue. Herein, a novel approach using the orally administered clinical-approved fluorescent dye indocyanine green (ICG) for bedside, non-ionizing evaluation of gastrointestinal passage is presented. The authors are able to show the detectability and stability of ICG in phantom experiments. Furthermore, ten healthy subjects underwent MSOT imaging at multiple time points over eight hours after ingestion of a standardized meal with and without ICG. ICG signals can be visualized and quantified in different intestinal segments, while its excretion is confirmed by fluorescent imaging of stool samples. These findings indicate that contrast-enhanced MSOT (CE-MSOT) provides a translatable real-time imaging approach for functional assessment of the gastrointestinal tract.
CRIS-Team Scopus Importer:2023-06-30
Keywords: indocyanine green; intestine; multispectral optoacoustic tomography; optoacoustics; photoacoustics

Contrast-enhanced ultrasound of benign and malignant liver lesions in children - Fang, Cheng; Anupindi, Sudha A.; Back, Susan J.; Franke, Doris; Green, Thomas G.; Harkanyi, Zoltan; Jüngert, Jörg M.; Kwon, Jeannie K.; Paltiel, Harriet J.; Squires, Judy H.; Zefov, Vassil N.; Mccarville, M. Beth (Pediatric Radiology, 2021)
Contrast-enhanced ultrasound (CEUS) is increasingly being used in children. One of the most common referrals for CEUS performance is characterization of indeterminate focal liver lesions and follow-up of known liver lesions. In this setting, CEUS is performed with intravenous administration of ultrasound contrast agents (UCAs). When injected into a vein, UCA microbubbles remain confined within the vascular network until they dissipate. Therefore, visualization of UCA within the tissues and lesions corresponds to true blood flow. CEUS enables continuous, real-time observation of the enhancement pattern of a focal liver lesion, allowing in most cases for a definite diagnosis and obviating the need for further cross-sectional imaging or other interventional procedures. The recent approval of Lumason (Bracco Diagnostics, Monroe Township, NJ) for pediatric liver CEUS applications has spurred the widespread use of CEUS. In this review article we describe the role of CEUS in pediatric liver applications, focusing on the examination technique and interpretation of main imaging findings of the most commonly encountered benign and malignant focal liver lesions. We also compare the diagnostic performance of CEUS with other imaging modalities for accurate characterization of focal liver lesions.
CRIS-Team WoS Importer:2021-06-04

Contrast-enhanced ultrasound of the pediatric brain - Hwang, Misun; Barnewolt, Carol E.; Jüngert, Jörg M.; Prada, Francesco; Sridharan, Anush; Didier, Ryne A. (Pediatric Radiology, 2021)
Brain contrast-enhanced ultrasound (CEUS) is an emerging application that can complement gray-scale US and yield additional insights into cerebral flow dynamics. CEUS uses intravenous injection of ultrasound contrast agents (UCAs) to highlight tissue perfusion and thus more clearly delineate cerebral pathologies including stroke, hypoxic–ischemic injury and focal lesions such as tumors and vascular malformations. It can be applied not only in infants with open fontanelles but also in older children and adults via a transtemporal window or surgically created acoustic window. Advancements in CEUS technology and post-processing methods for quantitative analysis of UCA kinetics further elucidate cerebral microcirculation. In this review article we discuss the CEUS examination protocol for brain imaging in children, current clinical applications and future directions for research and clinical uses of brain CEUS.
CRIS-Team Scopus Importer:2021-03-05
Keywords: Brain; Children; Contrast-enhanced ultrasound; Epilepsy; Hypoxic–ischemic injury; Neurovascular disease; Stroke; Tumor; Ultrasound; Ultrasound contrast agents

Contrast-enhanced ultrasound of the small organs in children - Piskunowicz, Maciej; Back, Susan J.; Darge, Kassa; Humphries, Paul D.; Jüngert, Jörg M.; Ključevšek, Damjana; Lorenz, Norbert; Mentzel, Hans Joachim; Squires, Judy H.; Huang, Dean Y. (Pediatric Radiology, 2021)
In pediatric and adult populations, intravenous contrast-enhanced ultrasound (CEUS) remains off-label for imaging of organs other than the liver and heart. This limited scope inhibits potential benefits of the new modality from a more widespread utilization. Yet, CEUS is potentially useful for imaging small organs such as the thyroid gland, lymph nodes, testes, ovaries and uterus, with all having locations and vasculature favorable for this type of examination. In the adult population, the utility of CEUS has been demonstrated in a growing number of studies for the evaluation of these small organs. The aim of this article is to present a review of pediatric CEUS of the thyroid gland, lymph nodes, testes, ovaries and uterus as well as to draw from the adult literature indications for possible applications in children.
CRIS-Team Scopus Importer:2021-04-23
Keywords: Children; Contrast-enhanced ultrasound; Lymph nodes; Ovary; Testis; Thyroid; Ultrasound; Ultrasound contrast agents; Uterus

Contrast-Enhanced µCT for Visualizing and Evaluating Murine Intestinal Inflammation - Jung, Dennis; Heiß, Rafael; Kramer, Viktoria; Thoma, Oana-Maria; Regensburger, Adrian; Rascher, Wolfgang; Uder, Michael; Neurath, Markus; Knieling, Ferdinand; Waldner, Maximilian (Theranostics, 2018)
Rationale: To develop a simple and fast protocol for the assessment of acute and chronic experimental intestinal inflammation using contrast-enhanced µCT. Methods: For the imaging studies, an acute 2% and 3% dextran sodium sulfate (n = 15, female, 8-12 weeks) and a chronic adoptive transfer colitis model (n = 10, female, 8-9 weeks) were established over 9 days or 6 weeks, respectively. Throughout the experiments, longitudinal measurement of murine intestinal wall thickness and time dependent perfusion was performed on a small animal µCT system (90 kV, 160 μA, FOV: 60 mm, scan time: 17 s, image size: 512x512, layer thickness: 118 µm) between 0.5 and 30 min after intravenous bolus injection of an iodine contrast agent. Weight development, small animal endoscopy, and histological ex vivo analysis were compared to contrast-enhanced µCT imaging findings. Results: Murine intestinal wall thickness was significantly increased in inflamed colons of acute colitis at day 9 in comparison to pre-inflamed state. Perfusion analysis revealed a late contrast enhancement in acute inflamed colons and the renal medulla at day 9 compared to control mice. An increasing intestinal wall thickness was monitored 3, 5 and 6 weeks after on-set of chronic colitis in comparison to controls. A good correlation with endoscopic (r = 0.75, p < 0.0001) and histologic degree of inflammation (r = 0.83, p = 0.04) was found. Conclusion: Contrast-enhanced µCT is a simple and fast method to assess acute intestinal inflammation and to monitor disease progression in experimental models of chronic colitis. According to our findings, one single contrast-enhanced µCT-scan is a valid non-invasive modality to quantify the degree of inflammation in the entire digestive tract in murine inflammatory models.
EVALuna2:35195

Contrast medium application in pediatric high-pitch cardiovascular CT angiography: manual or power injection? - Saake, Marc; Lell, Michael; Rompel, Oliver; Glöckler, Martin; May, Matthias; Eller, Achim; Achenbach, Stephan; Uder, Michael; Wüst, Wolfgang (Journal of Cardiovascular Computed Tomography, 2014)
Dual-source CT offers accurate depiction of cardiac structures in children with congenital heart disease. For cardiac CT, optimal enhancement of the cardiovascular structures is essential. There is considerable controversy about the administration of contrast medium (CM) in infants and small children, with either a power injector or a manual (hand) injection.The aim of this study was to compare image quality with power injection of CM (study group) and manual injection (control group).Thirty-four patients (study group, 6.8 ± 9.6 months and control group, 4.6 ± 8.9 months, nonrandomized) underwent dual-source CT angiography of the chest using a prospective electrocardiography-triggered high-pitch spiral mode (pitch, 3.4; 80 kV). In the study group (17 patients), a power injector was used, and in the control group (17 patients, historical group), manual CM injection had been performed. To assess image quality, both subjective and objective parameters were evaluated independently by 2 experienced radiologists.Subjective overall image quality, signal-to-noise ratio, and contrast-to-noise ratio were significantly higher using power injection compared with manual injection (P < .05). However, depiction of cardiovascular structures did not differ significantly between both groups in all evaluated regions except the superior vena cava and the coronary arteries.In infants and small children with congenital heart disease, both manual and power injector protocols allowed for diagnostic imaging of cardiac and extracardiac structures. However, image quality and vascular attenuation were superior using a power injector.
EVALuna2:11950

Contribution of the ?8 integrin chain to the expression of extracellular matrix components - Volkert, Gudrun; Jahn, Angelika; Dinkel, Christina; Fahlbusch, Fabian; Zuern, Christina; Hilgers, Karl Friedrich; Rascher, Wolfgang; Marek, Ines; Hartner, Andrea (Cell Communication and Adhesion, 2014)
In the kidney, the ?8 integrin chain (itga8) is expressed in mesenchymal cells and is upregulated in fibrotic disease. We hypothesized that itga8 mediates a profibrotic phenotype of renal cells by promoting extracellular matrix and cytokine expression. Genetic itga8 deficiency caused complex changes in matrix expression patterns in mesangial and smooth-muscle cells, with the only concordant effect in both cell types being a reduction of collagen III expression. Silencing of itga8 with siRNA led to a decline of matrix turnover with repression of matrix metalloproteinases and reduction of matrix production. In contrast, de novo expression of itga8 in tubular epithelial cells resulted in reduced collagen synthesis. Overexpression of itga8 in fibroblasts did not change the expression of matrix molecules or regulators of matrix turnover. Thus, the influence of itga8 on the expression of matrix components was not uniform and celltype dependent. Itga8 seems unlikely to exert overall profibrotic effects in renal cells.
EVALuna2:3701

COPHYD (Corona Owed Physical Deficiency): The Impact of Lockdown on Cardiopulmonary Function in Paediatric Cardiology Patients - Stabler, Tim; Weigelt, Annika; Rottermann, Kathrin; Wällisch, Wolfgang; Hübner, Matthias; Dittrich, Sven; Schöffl, Isabelle (Klinische Pädiatrie, 2022)
Introduction Due to the Corona-lockdowns the closure of sports facilities and schools has led to a decline in physical activity (PA) for months. PA is essential for maintaining cardiopulmonary function assessed by peak oxygen uptake. Since peak oxygen uptake represents the best predictor for mortality and morbidity in children with congenital heart disease the impact of lockdowns on this parameter is vital. Methods We evaluated retrospectively cardiopulmonary exercise data from our patient collective from before lockdown with twin-paired data from during lockdown. The twin-pairing was achieved by matching patients with similar heart disease, age, sex, and test method. Cardiopulmonary exercise testing was achieved on either the treadmill or the bicycle. Results We were able to twin-pair 90 cases (26 twins with heart disease and 19 healthy twins). There was a significant decrease of cardiopulmonary function (V?O (2) peak: 35.7 +/- 9.8 vs.30.4 +/- 10.6) in the heart disease cohort along with a significant decrease in peak oxygen pulse (13.3 +/- 4.1 vs. 11.4 +/- 4.5), and peak minute ventilation (V ?E: 83.05 +/- 29.08 vs.71,49 +/- 24.96). The healthy children improved over the timeframe, but this only reached significance for peak minute ventilation (81.72 +/- 25.79 vs.97.94 +/- 31.4). Conclusion We observed a significant decline of peak oxygen uptake during lockdown in the group of congenital heart disease (CHD) patients. This involved a loss of cardiac function as well as pulmonary function. This could be explained by limited access to sports facilities and restriction of regular daily movement due to school closure and overprotection. Healthy children improved their pulmonary function. This might be an indication of an improvement of exercise during confinement.
CRIS-Team WoS Importer:2022-10-14

Copy Number Variation Analysis Facilitates Identification of Genetic Causation in Patients with Congenital Anomalies of the Kidney and Urinary Tract - Wu, Chen Han Wilfred; Lim, Tze Y.; Wang, Chunyan; Seltzsam, Steve; Zheng, Bixia; Schierbaum, Luca; Schneider, Sophia; Mann, Nina; Connaughton, Dervla M.; Nakayama, Makiko; van der Ven, Amelie T.; Dai, Rufeng; et al. (European Urology Open Science, 2022)
Background: Congenital anomalies of the kidneys and urinary tract (CAKUT) are the most common cause of chronic kidney disease among children and adults younger than 30 yr. In our previous study, whole-exome sequencing (WES) identified a known monogenic cause of isolated or syndromic CAKUT in 13% of families with CAKUT. However, WES has limitations and detection of copy number variations (CNV) is technically challenging, and CNVs causative of CAKUT have previously been detected in up to 16% of cases. Objective: To detect CNVs causing CAKUT in this WES cohort and increase the diagnostic yield. Design, setting, and participants: We performed a genome-wide single nucleotide polymorphism (SNP)-based CNV analysis on the same CAKUT cohort for whom WES was previously conducted. Outcome measurements and statistical analysis: We evaluated and classified the CNVs using previously published predefined criteria. Results and limitations: In a cohort of 170 CAKUT families, we detected a pathogenic CNV known to cause CAKUT in nine families (5.29%, 9/170). There were no competing variants on genome-wide CNV analysis or WES analysis. In addition, we identified novel likely pathogenic CNVs that may cause a CAKUT phenotype in three of the 170 families (1.76%). Conclusions: CNV analysis in this cohort of 170 CAKUT families previously examined via WES increased the rate of diagnosis of genetic causes of CAKUT from 13% on WES to 18% on WES + CNV analysis combined. We also identified three candidate loci that may potentially cause CAKUT. Patient summary: We conducted a genetics study on families with congenital anomalies of the kidney and urinary tract (CAKUT). We identified gene mutations that can explain CAKUT symptoms in 5.29% of the families, which increased the percentage of genetic causes of CAKUT to 18% from a previous study, so roughly one in five of our patients with CAKUT had a genetic cause. These analyses can help patients with CAKUT and their families in identifying a possible genetic cause.
CRIS-Team Scopus Importer:2022-09-09
Keywords: Congenital anomalies of the kidney and urinary tract; Copy number variation; Monogenic disease causation; Renal developmental; Vesicoureteral reflux; Whole-exome sequencing

Correction of Vertebral Bone Development in Ectodysplasin A1-Deficient Mice by Prenatal Treatment With a Replacement Protein - Kossel, Clara-Sophie; Wahlbuhl-Becker, Mandy; Schuepbach-Mallepell, Sonia; Park, Jung; Kowalczyk-Quintas, Christine; Seeling, Michaela; von der Mark, Klaus; Schneider, Pascal; Schneider, Holm (Frontiers in Genetics, 2021)
X-linked hypohidrotic ectodermal dysplasia with the cardinal symptoms hypodontia, hypotrichosis and hypohidrosis is caused by a genetic deficiency of ectodysplasin A1 (EDA1). Prenatal EDA1 replacement can rescue the development of skin appendages and teeth. Tabby mice, a natural animal model of EDA1 deficiency, additionally feature a striking kink of the tail, the cause of which has remained unclear. We studied the origin of this phenomenon and its response to prenatal therapy. Alterations in the distal spine could be noticed soon after birth, and kinks were present in all Tabby mice by the age of 4 months. Although their vertebral bones frequently had a disorganized epiphyseal zone possibly predisposing to fractures, cortical bone density was only reduced in vertebrae of older Tabby mice and even increased in their tibiae. Different availability of osteoclasts in the spine, which may affect bone density, was ruled out by osteoclast staining. The absence of hair follicles, a well-known niche of epidermal stem cells, and much lower bromodeoxyuridine uptake in the tail skin of 9-day-old Tabby mice rather suggest the kink being due to a skin proliferation defect that prevents the skin from growing as fast as the skeleton, so that caudal vertebrae may be squeezed and bent by a lack of skin. Early postnatal treatment with EDA1 leading to delayed hair follicle formation attenuated the kink, but did not prevent it. Tabby mice born after prenatal administration of EDA1, however, showed normal tail skin proliferation, no signs of kinking and, interestingly, a normalized vertebral bone density. Thus, our data prove the causal relationship between EDA1 deficiency and kinky tails and indicate that hair follicles are required for murine tail skin to grow fast enough. Disturbed bone development appears to be partially pre-determined in utero and can be counteracted by timely EDA1 replacement, pointing to a role of EDA1 also in osteogenesis.
CRIS-Team Scopus Importer:2021-09-10
Keywords: bone; development; ectodermal dysplasia; ectodysplasin A1; fetal therapy; NF-κB

Correction to: Assessment of treatment responses in children and adolescents with Ewing sarcoma with metabolic tumor parameters derived from 18F-FDG-PET/CT and circulating tumor DNA (European Journal of Nuclear Medicine and Molecular Imaging, (2019), 10.1007/s00259-019-04649-1) - Schmidkonz, Christian; Krumbholz, Manuela; Atzinger, Armin; Cordes, Michael; Götz, Theresa; Prante, Olaf; Ritt, Philipp; Schaefer, Christiane; Agaimy, Abbas; Hartmann, Wolfgang; Roessig, Claudia; Froehlich, Birgit; et al. (European Journal of Nuclear Medicine and Molecular Imaging, 2020)
The original version on this paper contained an error. The author names, though correctly appeared in the PDF version, were incorrectly displayed in indexing sites. This error occurred because of the incorrect tagging of their names in themetadata of this article. The purpose of this Erratum is the correction of metadata. Therefore, indexing sites should now reflect their names as Schmidkonz C, Krumbholz M, Atzinger A, Cordes M, Goetz TI, Prante O, Ritt P, Schaefer C, Agaimy A, Hartmann W, Rössig C, Fröhlich B, Bäuerle T, Dirksen U, Kuwert T, Metzler M. The original article has been corrected.
CRIS-Team Scopus Importer:2020-02-25

Correction to: Rare variants in KDR, encoding VEGF Receptor 2, are associated with tetralogy of Fallot (Genetics in Medicine, (2021), 10.1038/s41436-021-01212-y) - Skoric-Milosavljevic, Doris; Lahrouchi, Najim; Bosada, Fernanda M.; Dombrowsky, Gregor; Williams, Simon G.; Lesurf, Robert; Tjong, Fleur V. Y.; Walsh, Roddy; El Bouchikhi, Ihssane; Breckpot, Jeroen; Audain, Enrique; Ilgun, Aho; et al. (Genetics in Medicine, 2021)
Due to a processing error the author’s Doris Škorić-Milosavljević, Najim Lahrouchi, Alex V. Postma, Connie R. Bezzina were assigned to affiliation 38. However, affiliation 38 does not exist. In addition, the affiliations of Najim Lahrouchi, Elisabeth M. Lodder, and Connie R. Bezzina should be number 1 instead of number 2. The correct affiliation is Department of Clinical and Experimental Cardiology, Amsterdam University Medical Center, Amsterdam, The Netherlands. The original article has been corrected.
CRIS-Team Scopus Importer:2021-10-01

Correction to: Short-term safety results from compassionate use of risdiplam in patients with spinal muscular atrophy in Germany (Orphanet Journal of Rare Diseases, (2022), 17, 1, (276), 10.1186/s13023-022-02420-8) - Hahn, Andreas; Günther, René; Ludolph, Albert; Schwartz, Oliver; Trollmann, Regina; Weydt, Patrick; Weiler, Markus; Neuland, Kathrin; Schwaderer, Martin Sebastian; Hagenacker, Tim (Orphanet Journal of Rare Diseases, 2022)
Following publication of the original article [1], we have been notified that there is a typographical error in the Fig. 1 text. It should be as per below: Figure 1: “111 patients received ≥ 1 risdiplam dose.
CRIS-Team Scopus Importer:2022-11-04

Correlations Between Interleukin-11 Expression and Hypertensive Kidney Injury in a Rat Model of Renovascular Hypertension - Menendez-Castro, Carlos; Cordasic, Nada; Dambietz, Thomas; Veelken, Roland; Amann, Kerstin Ute; Hartner, Andrea; Hilgers, Karl Friedrich (American Journal of Hypertension, 2020)
BACKGROUND: Interleukin-11 (IL-11) is a pleiotropic cytokine of the interleukin-6 family. Recent studies revealed its crucial role in the development of cardiovascular fibrosis. In this study we examined IL-11 expression levels in the heart and the kidney exposed to high blood pressure in renovascular hypertensive rats and their correlations to fibrotic markers and kidney injury. METHODS: Two-kidney, one-clip renovascular hypertension (2K1C) was induced in rats. IL-11 expression was measured by real-time polymerase chain reaction in the left ventricle and the right kidney. The correlation of cardiac IL-11 expression with biomarkers of renal fibrosis was assessed. We further investigated IL-11 expression in 2K1C rats grouped into rats with malignant vs. nonmalignant hypertension (distinguishing criteria: weight loss, number of fibrinoid necrosis, and onion skin lesions). RESULTS: Thirty-five days after clipping, mean arterial pressure was significantly increased in 2K1C. Renal IL-11 expression was elevated in 2K1C. In the heart there was only a trend toward higher IL-11 expression in 2K1C. IL-11 in the kidney in 2K1C correlated with the expression of transforming growth factor (TGF)-β1/2, collagens, fibronectin, osteopontin, as well as tissue inhibitors of metalloprotease 1/2. There were also correlations of IL-11 with tissue collagen expansion, number of activated fibroblasts and serum creatinine, but no correlation with mean arterial pressure. Renal expression of IL-11 was highest in rats with malignant hypertension. CONCLUSIONS: Renal IL-11 expression of renovascular hypertensive rats is markedly increased and correlates with profibrotic markers and loss of function and might therefore serve as a biomarker for the severity of hypertensive nephrosclerosis.
CRIS-Team Scopus Importer:2020-04-14
Keywords: blood pressure; hypertension; interleukin-11 (IL-11); malignant hypertension; renal fibrosis; two-kidney one-clip renovascular hypertension (2K1C)

Corrigendum: Patient-reported long-term outcome following allogeneic hematopoietic stem cell transplantation in pediatric chronic myeloid leukemia. - Schleicher, Oliver; Horndasch, Annkathrin; Krumbholz, Manuela; Sembill, Stephanie; Bremensdorfer, Claudia; Grabow, Desiree; Erdmann, Friederike; Karow, Axel; Metzler, Markus; Suttorp, Meinolf (Frontiers in Oncology, 2022)
[This corrects the article DOI: 10.3389/fonc.2022.963223.].
EVALuna2:517750

Corrigendum to: “Resistance to antibacterial therapy in pediatric febrile urinary tract infectionsda single-center analysis” [J Pediatr Urol 16 (2020) 71–79] (Journal of Pediatric Urology (2020) 16(1) (71–79), (S1477513119303389), (10.1016/j.jpurol.2019.10.018)) - Raupach, Thomas; Held, Jürgen; Prokosch, Hans-Ulrich; Rascher, Wolfgang; Zierk, Jakob (Journal of Pediatric Urology, 2022)
In order to fulfil the requirements of the doctoral office of the Friedrich-Alexander-University Erlangan-Nuremberg (FAU), the following updates have been made to the abovementioned article: Affiliation ‘a’ now reads as: Department of Pediatrics and Adolescent Medicine, Friedrich-Alexander-University Erlangen-Nuremberg (FAU), Erlangen, Germany. The following has been added to the Acknowledgements: The present work was performed in fulfilment of the requirements for obtaining the degree “Dr. med. (Doctor medicinae) at the Friedrich-Alexander University Erlangen-Nuremberg (FAU)”.
CRIS-Team Scopus Importer:2024-12-16

Course of renal allograft function after diagnosis and treatment of post-transplant lymphoproliferative disorders in pediatric kidney transplant recipients - Zierhut, Henriette; Kanzelmeyer, Nele; Buescher, Anja; Hoecker, Britta; Mauz-Korholz, Christine; Tonshoff, Burkhard; Metzler, Markus; Pohl, Martin; Pape, Lars; Maecker-Kolhoff, Britta (Pediatric Transplantation, 2021)
Background Post-transplant lymphoproliferative disease (PTLD) is a life-threatening complication in renal transplant recipients. Immunomodulatory and chemotherapeutic treatment potentially affect allograft function. The aim of this study was to evaluate graft function of pediatric kidney transplant recipients following diagnosis and standardized treatment of PTLD.
CRIS-Team WoS Importer:2021-05-28

COVID-19 and increased prevalence of female precocious puberty in Germany - Baehr, Sonja; Schnabel, Dirk; Wölfle, Joachim; Schreiner, Felix; Gohlke, Bettina (HORMONE RESEARCH IN PAEDIATRICS, 2022)
CRIS-Team WoS Importer:2022-10-07

COVID-19 infection in patients with history of pediatric heart transplant in Germany, Austria, and Switzerland - Ulrich, Sarah; Balmer, Christian; Becker, Kolja; Bruhs, Josefin; Danne, Friederike; Debus, Volker; Dewein, Leonie; Di-Bernardo, Stefano; Doll, Ulrike; Fleck, Thilo; Tirilomis, Theodor; Glöckler, Martin; et al. (Clinical Transplantation, 2024)
COVID-19 is a heterogenous infection—asymptomatic to fatal. While the course of pediatric COVID-19 infections is usually mild or even asymptomatic, individuals after adult heart transplantation are at high risk of a severe infection. We conducted a retrospective, multicenter survey of 16 pediatric heart transplant centers in Germany, Austria and Switzerland to evaluate the risk of a severe COVID-19 infection after pediatric heart transplantation between 02/2020 and 06/2021. Twenty-six subjects (11 male) with a median age of 9.77 years at time of transplantation and a median of 4.65 years after transplantation suffered from COVID-19 infection. The median age at time of COVID-10 infection was 17.20 years. Fourteen subjects had an asymptomatic COVID-19 infection. The most frequent symptoms were myalgia/fatigue (n = 6), cough (n = 5), rhinitis (n = 5), and loss of taste (n = 5). Only one subject showed dyspnea. Eleven individuals needed therapy in an outpatient setting, four subjects were hospitalized. One person needed oxygen supply, none of the subjects needed non-invasive or invasive mechanical ventilation. No specific signs for graft dysfunction were found by non-invasive testing. In pediatric heart transplant subjects, COVID-19 infection was mostly asymptomatic or mild. There were no SARS-CoV-2 associated myocardial dysfunction in heart transplant individuals.
CRIS-Team Scopus Importer:2024-03-15
Keywords: asymptomatic course; COVID-19 infection; pediatric heart transplantation; SARS-CoV-2 associated myocardial dysfunction

Creating a Medication Therapy Observational Research Database from an Electronic Medical Record: Challenges and Data Curation - Rödle, Wolfgang; Prokosch, Hans-Ulrich; Neumann, Eva; Toni, Irmgard; Haering-Zahn, Julia; Neubert, Antje; Eberl, Sonja (Applied Clinical Informatics, 2024)
Background: Observational research has shown its potential to complement experimental research and clinical trials by secondary use of treatment data from hospital care processes. It can also be applied to better understand pediatric drug utilization for establishing safer drug therapy. Clinical documentation processes often limit data quality in pediatric medical records requiring data curation steps, which are mostly underestimated. Objectives: The objectives of this study were to transform and curate data from a departmental electronic medical record into an observational research database. We particularly aim at identifying data quality problems, illustrating reasons for such problems and describing the systematic data curation process established to create high-quality data for observational research. Methods: Data were extracted from an electronic medical record used by four wards of a German university children's hospital from April 2012 to June 2020. A four-step data preparation, mapping, and curation process was established. Data quality of the generated dataset was firstly assessed following an established 3 × 3 Data Quality Assessment guideline and secondly by comparing a sample subset of the database with an existing gold standard. Results: The generated dataset consists of 770,158 medication dispensations associated with 89,955 different drug exposures from 21,285 clinical encounters. A total of 6,840 different narrative drug therapy descriptions were mapped to 1,139 standard terms for drug exposures. Regarding the quality criterion correctness, the database was consistent and had overall a high agreement with our gold standard. Conclusion: Despite large amounts of freetext descriptions and contextual knowledge implicitly included in the electronic medical record, we were able to identify relevant data quality issues and to establish a semi-automated data curation process leading to a high-quality observational research database. Because of inconsistent dosage information in the original documentation this database is limited to a drug utilization database without detailed dosage information.
CRIS-Team Scopus Importer:2024-02-23
Keywords: data curation; Data Quality Assessment; electronic medical records; medication data; pediatrics

Criteria for good prescribing practice in children - Neubert, Antje; Wimmer, Stefan (Therapeutische Umschau. Revue therapeutique, 2014)
Paediatric prescribing is complex. A whole range of aspects needs to be considered to achieve an efficacious and safe drug therapy for children. Legal requirements for prescribing are clearly insufficient for this purpose. Children are immature individuals under constant growth and development. Consequently, based on age and cognitive abilities of the child individual drugs and dosing regimens have to be chosen. Frequent off-label use and a lack of age-appropriate formulation worsen the situation. Additionally, not all dosage forms are similarly adequate in different age groups. Taste significantly influences patient adherence. Dose calculations based on body weight are prone to errors, putting a point on the wrong place or mixing up measuring units easily result in ten-fold dosing errors. Computer-based tools to enhance prescribing are promising but, however, not yet widely implemented in paediatrics because of missing evidence-based data sources and the hugely complex process. Communication between clinicians and pharmacists as well as with the patient remains very important.
EVALuna2:18902

Critical incidents, nocturnal supervision, and caregiver knowledge on SUDEP in patients with Dravet syndrome: A prospective multicenter study in Germany - Maltseva, Margarita; Rosenow, Felix; Schubert-Bast, Susanne; Flege, Silke; Wolff, Markus; von Spiczak, Sarah; Trollmann, Regina; Syrbe, Steffen; Ruf, Susanne; Polster, Tilman; Neubauer, Bernd A.; Mayer, Thomas; et al. (Epilepsia, 2023)
Objective: The aim was to investigate the monitoring, interventions, and occurrence of critical, potentially life-threatening incidents in patients with Dravet syndrome (DS) and caregivers’ knowledge about sudden unexpected death in epilepsy (SUDEP). Methods: This multicenter, cross-sectional study of patients with DS and their caregivers in Germany consisted of a questionnaire and prospective diary querying the disease characteristics and demographic data of patients and caregivers. Results: Our analysis included 108 questionnaires and 82 diaries. Patients with DS were 49.1% male (n = 53), with a mean age of 13.5 (SD ± 10.0 years) and primary caregivers were 92.6% (n = 100) female, with a mean age of 44.7 (SD ± 10.6 years). Monitoring devices were used regularly by 75.9% (n = 82) of caregivers, and most monitored daily/nightly. Frequently used devices were pulse oximeters (64.6%), baby monitors (64.6%), thermometers (24.1%), and Epi-Care (26.8%). Younger caregiver and patient age and history of status epilepticus were associated with increased use of monitoring, and 81% of monitor users reported having avoided a critical incident with nocturnal monitoring. The need for resuscitation due to cardiac or respiratory arrest was reported by 22 caregivers (20.4%), and most cases (72.7%) were associated with a seizure. Caregivers reported frequently performing interventions at night, including oropharyngeal suction, oxygenation, personal hygiene, and change of body position. Most caregivers were well informed about SUDEP (n = 102; 94%) and monitored for a lateral or supine body position; however, only 39.8% reported receiving resuscitation training, whereas 52.8% (n = 57) knew what to do in case the child's breathing or heart activity failed. Significance: Critical incidents and the need for resuscitation are reported frequently by caregivers and may be related to high mortality and SUDEP rates in DS. Resuscitation training is welcomed by caregivers and should be continuously provided. Oxygen monitoring devices are frequently used and considered useful by caregivers.
CRIS-Team Scopus Importer:2023-11-24
Keywords: encephalopathy; epilepsy; near-SUDEP; seizure

CtDNA release mechanisms in a therapeutic Ewing Sarcoma mouse model - Eiblwieser, Johanna; Krumbholz, Manuela; Semper, S.; Frey, Benjamin; Nagel, L.; Bäuerle, Tobias; Metzler, Markus (KLINISCHE PADIATRIE, 2022)
CRIS-Team WoS Importer:2022-07-08

Cullin 7 and Fbxw 8 expression in trophoblastic cells is regulated via oxygen tension: Implications for intrauterine growth restriction - Fahlbusch, Fabian; Dawood, Yousif Louay; Hartner, Andrea; Menendez-Castro, Carlos; Nögel, Stephanie; Tzschoppe, Anja; Schneider, Holm; Strissel, Pamela; Beckmann, Matthias; Schleussner, Ekkehard; Rübner, Matthias; Dörr, Helmuth-Günther; et al. (Journal of Maternal-Fetal & Neonatal Medicine, 2012)
Objective: The F-box protein Fbxw8 is a cofactor of Cullin 7 (Cul7), which regulates protein transfer to the proteasome and cell growth. Cul7 or Fbxw8 deficiency is associated with intrauterine growth restriction (IUGR) due to abnormal placental development leading to poor oxygen supply to the fetus. We studied the role of hypoxia for Fbxw8 and Cul7 expression in trophoblastic cells. Methods: Immunomagnetic bead-separated extravillous trophoblast (EVT) and villous trophoblast (VT) and trophoblast cell lines were incubated with 1 or 8% O2. Fbxw8 and Cul7 expression was determined in IUGR versus matched control placentas. Results: Fbxw8 was expressed uniformly in trophoblasts, whereas Cul7 expression was most prominent in trophoblast cell lines. Hypoxia reduced expression of Cul7 and Fbxw8 in all trophoblastic cells, except for villous trophoblasts. In vivo, Cul7 and Fbxw8 were detected in syncytiotrophoblast cells, VT, and EVT cells. Although no significant changes in expression levels of Fbxw8 or Cul7 were noted in IUGR compared with control placentas, Fbxw8 expression correlated negatively with gestational age in the control, but not in the IUGR group. Conclusion: Fbxw8 and Cul7 expression reveals a complex regulation in trophoblastic cells. Our findings suggest that dysregulation of Cul7 and Fbxw8 expression might affect trophoblast turnover in IUGR. © 2012 Informa UK, Ltd.
CRIS-Team Scopus Importer:2020-07-01
Keywords: Cul7; Fbxw8; IUGR; Oxygen; Placenta; Trophoblast

Current clinical practice of prenatal dexamethasone treatment in at risk pregnancies for classic 21-hydroxylase deficiency in Europe - Nowotny, Hanna F.; Neumann, Uta; Tardy-Guidollet, Veronique; Ahmed, S. Faisal; Baronio, Federico; Battelino, Tadej; Bertherat, Jerome; Blankenstein, Oliver; Bonomi, Marco; Bouvattier, Claire; De La Perriere, Aude Brac; Brucker, Sara; et al. (HORMONE RESEARCH IN PAEDIATRICS, 2021)
CRIS-Team WoS Importer:2021-10-08

Current Role of Monoclonal Antibody Therapy in Pediatric IBD: A Special Focus on Therapeutic Drug Monitoring and Treat-to-Target Strategies - Claßen, Merle; Hörning, André (Children, 2023)
In the last two decades, biologicals have become essential in treating children and adolescents with inflammatory bowel disease. TNF-α inhibitors (infliximab, adalimumab and golimumab) are preferentially used. Recent studies suggest that early application of TNF-α inhibitors is beneficial to inducing disease remission and preventing complications such as development of penetrating ulcers and fistulas. However, treatment failure occurs in about one third of pediatric patients. Particularly, children and adolescents differ in drug clearance, emphasizing the importance of pharmacokinetic drug monitoring in the pediatric setting. Here, current data on the choice and effectiveness of biologicals and therapeutic drug monitoring strategies are reviewed.
CRIS-Team Scopus Importer:2023-05-05
Keywords: biologics; Crohn’s disease; treatment optimization; trough levels; ulcerative colitis

CXCR4 blockade reduces the severity of murine heart allograft rejection by plasmacytoid dendritic cell-mediated immune regulation - Fu, Jian; Lehmann, Christian; Wang, Xinning; Wahlbuhl, Mandy; Allabauer, Ida; Wilde, Benjamin; Amon, Lukas; Dolff, Sebastian; Cesnjevar, Robert; Kribben, Andreas; Wölfle, Joachim; Rascher, Wolfgang; et al. (Scientific Reports, 2021)
Allograft-specific regulatory T cells (Treg cells) are crucial for long-term graft acceptance after transplantation. Although adoptive Treg cell transfer has been proposed, major challenges include graft-specificity and stability. Thus, there is an unmet need for the direct induction of graft-specific Treg cells. We hypothesized a synergism of the immunotolerogenic effects of rapamycin (mTOR inhibition) and plerixafor (CXCR4 antagonist) for Treg cell induction. Thus, we performed fully-mismatched heart transplantations and found combination treatment to result in prolonged allograft survival. Moreover, fibrosis and myocyte lesions were reduced. Although less CD3+ T cell infiltrated, higher Treg cell numbers were observed. Noteworthy, this was accompanied by a plerixafor-dependent plasmacytoid dendritic cells-(pDCs)-mobilization. Furthermore, in vivo pDC-depletion abrogated the plerixafor-mediated Treg cell number increase and reduced allograft survival. Our pharmacological approach allowed to increase Treg cell numbers due to pDC-mediated immune regulation. Therefore pDCs can be an attractive immunotherapeutic target in addition to plerixafor treatment.
CRIS-Team Scopus Importer:2021-12-24

CXCR4-SDF1 alpha Blockade Reduces the Severity of Murine Heart Allograft Rejection - Fu, J.; Wahlbuhl, Mandy; Wang, X.; Wilde, B.; Jing, L.; Kribben, A.; Hoyer, P.; Lehmann, C. H. K.; Dudziak, Diana; Witzke, O.; Hoerning, A. (2017)
EVALuna2:34369

Das nicht klassische adrenogenitale Syndrom mit 21-Hydroxylase-Defekt bei Kindern und Jugendlichen - Dörr, Helmuth-Günther; Schulze, Nadja (Pädiatrische Praxis, 2020)
Non-classical AGS with 21-hydroxylase defect is a common monogenetic disorder that is often not diagnosed or diagnosed too late. The leading clinical symptom in girls is the premature pubarche before the 8th birthday. For diagnostic purposes, 17-OHP should be measured in serum in the morning for children in the first step and in the follicular phase for menstruating girls. The gold standard in diagnostics is the ACTH test, whereby cortisol should also be determined in the serum in addition to 17-OHP. The laboratory chemical diagnosis should in any case be confirmed by molecular genetic analysis. Drug therapy in children with hydrocortisone is carried out in a low dose if the clinical symptoms are progressive and, above all, there is a poor prognosis of the final size due to the acceleration of bone age. If a therapy with glucocorticoids is carried out, then an emergency ID card should also be issued.
CRIS-Team Scopus Importer:2021-04-19
Keywords: 17-OHP; ACTH test; Cortisol; CYP21A2; Premature pubarche

Das nicht klassische Adrenogenitale Syndrom mit 21-Hydroxylase-Defekt bei Kindern und Jugendlichen - Dörr, Helmuth-Günther; Schulze, Nadja (gynäkologische praxis, 2021)
Non-classical AGS with 21-hydroxylase defect is a common monogenetic disorder that is often not diagnosed or diagnosed too late. The leading clinical symptom in girls is the premature pubarche before the 8th birthday. For diagnostic purposes, 17-OHP should be measured in serum in the morning for children in the first step and in the follicular phase for menstruating girls. The gold standard in diagnostics is the ACTH test, whereby cortisol should also be determined in the serum in addition to 17-OHP. The laboratory chemical diagnosis should in any case be confirmed by molecular genetic analysis. Drug therapy in children with hydrocortisone is carried out in a low dose if the clinical symptoms are progressive and, above all, there is a poor prognosis of the final size due to the acceleration of bone age. If a therapy with glucocorticoids is carried out, then an emergency ID card should also be issued.
CRIS-Team Scopus Importer:2024-12-16
Keywords: 17-OHP; ACTH test; cortisol; CYP21A2; premature pubarche

Data mining of pediatric reference intervals - Zierk, Jakob; Metzler, Markus; Rauh, Manfred (Journal of Laboratory Medicine, 2021)
Laboratory tests are essential to assess the health status and to guide patient care in individuals of all ages. The interpretation of quantitative test results requires availability of appropriate reference intervals, and reference intervals in children have to account for the extensive physiological dynamics with age in many biomarkers. Creation of reference intervals using conventional approaches requires the sampling of healthy individuals, which is opposed by ethical and practical considerations in children, due to the need for a large number of blood samples from healthy children of all ages, including neonates and young infants. This limits the availability and quality of pediatric reference intervals, and ultimately negatively impacts pediatric clinical decision-making. Data mining approaches use laboratory test results and clinical information from hospital information systems to create reference intervals. The extensive number of available test results from laboratory information systems and advanced statistical methods enable the creation of pediatric reference intervals with an unprecedented age-related accuracy for children of all ages. Ongoing developments regarding the availability and standardization of electronic medical records and of indirect statistical methods will further improve the benefit of data mining for pediatric reference intervals.
CRIS-Team Scopus Importer:2021-10-29
Keywords: data mining; indirect methods; pediatric reference intervals

Data mining of reference intervals for coagulation screening tests in adult patients - Zierk, Jakob; Ganslandt, Thomas; Rauh, Manfred; Metzler, Markus; Strasser, Erwin (Clinica Chimica Acta, 2019)
Background: Appropriate reference intervals are essential when evaluating laboratory test results. However, establishment of reference intervals is challenging, especially for coagulation screening tests, and uncertainty exists regarding age- and sex-dependency of test results. Data mining of laboratory information systems is an emerging approach to reference interval determination, and we evaluated its applicability to coagulation tests. Methods: We analyzed measurements of activated partial thromboplastin time (aPTT), prothrombin time (PT), international normalized ratio (INR), thrombin time (TT), and fibrinogen performed during clinical care in the University Hospital Erlangen, Germany (1,778,738 samples from 116,754 adult patients, 45,577-509,859 samples per analyte). We identified the proportion of samples from healthy individuals using an established statistical approach (Reference Limit Estimator), in which the distribution of physiological test results is approximated using a parametrical function, and used for the calculation of reference intervals. Results: We established age- and sex specific reference intervals for aPTT, PT, INR, TT, and fibrinogen, and created batch- and reagent-specific aPTT-reference intervals. Additionally, we evaluated the sensitivity of the established aPTT reference intervals for the detection of factor VIII, IX, XI, XII deficiencies. Conclusion: Data mining of laboratory test results allows the creation of age- and sex-reference intervals for coagulation tests that are specific to the examined population, analytical framework, and reagent. This approach can complement conventional methods when establishing reference intervals and improve clinical decision-making based on coagulation tests. The reference intervals established in this study show only minor variation with sex and age, supporting the practice of providing a common reference interval for adult women and men.
CRIS-Team Scopus Importer:2019-09-24
Keywords: Coagulation screening tests; Data mining; Reference intervals

Dead space washout by intentional leakage flow during conventional ventilation of premature infants-an experimental study - Schoeber, Martin; Bohnhorst, Bettina; Annon-Eberharter, Natalee; Wald, Martin (Pediatric Pulmonology, 2022)
Objective Invasive mechanical ventilation poses a strong risk factor for the development of chronic lung disease in preterm infants. A reduction of the dead space as part of the total breathing volume would reduce the ventilation effort and thereby lower the risk of ventilator-induced lung injuries. In this experimental study, we compared the efficacy of mechanical dead space washout via uncontrolled and controlled leakage flow in their ability to eliminate CO2 during conventional ventilation in preterm infants. Methods Three frequently used neonatal ventilators, operating under standard conventional ventilating parameters, were individually connected to a test lung. To maintain a constant physiological end-expiratory pCO(2) level during ventilation, the test lung was continuously flooded with CO2. A side port in the area of the connector between the endotracheal tube and the flow sensor allowed breathing gas to escape passively or in a second experimental setup, regulated by a pump. Measurements of end-expiratory pCO(2) were taken in both experiments and compared to end-expiratory pCO(2) levels of ventilation without active dead space leakage. Results Following dead space washout, a significant reduction of end-expiratory pCO(2) was attained. Under conditions of uncontrolled leakage, the mean decrease was 14.1% while controlled leakage saw a mean reduction of 16.1%. Conclusion Washout of dead space by way of leakage flow is an effective method to reduce end-expiratory pCO(2). Both controlled and uncontrolled leakage provide comparable results, but precise regulation of leakage allows for a more stable ventilation by preventing uncontrolled loss of tidal volume during inspiration.
CRIS-Team WoS Importer:2022-07-01
Keywords: dead space washout; leakage flow; mechanical ventilation; preterm infant

Decreased IL-10(+) regulatory B cells (Bregs) in lupus nephritis patients - Heinemann, K.; Wilde, B.; Hoerning, A.; Tebbe, B.; Kribben, A.; Witzke, O.; Dolff, S. (Scandinavian Journal of Rheumatology, 2016)
OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by B cell-dependent autoantibody production. Recently, a new B-cell subset was discovered that has a regulatory capacity. The aim of this study was to analyse regulatory B cells (Bregs) in SLE patients. METHOD: Peripheral mononuclear blood cells (PBMCs) of 34 SLE patients fulfilling the American College of Rheumatology (ACR) criteria for SLE and 21 healthy controls (HC) were included. PBMCs were stained for CD19, CD24, and CD38 and analysed by flow cytometry. In vitro stimulated PBMCs with CpG and restimulated with phorbol 12-myristate 13-acetate (PMA) and ionomycin were investigated for IL-10(+) Bregs . RESULTS: The percentages of circulating CD19(+)CD24(hi)CD38(hi) cells in HC were not different those in from SLE patients. The percentages of IL-10(+) Bregs were significantly decreased in SLE patients, in particular those with lupus nephritis (LN), compared to HC. The proportion was independent of disease activity. CONCLUSIONS: This is the first study to demonstrate a decrease in IL-10-producing B cells in LN patients compared to HC, reflecting an impaired regulatory function.
EVALuna2:33929

Deficiency of ECHS1 causes mitochondrial encephalopathy with cardiac involvement - Haack, Tobias B.; Jackson, Christopher B.; Murayama, Kei; Kremer, Laura S.; Schaller, Andre; Kotzaeridou, Urania; De Vries, Maaike C.; Schottmann, Gudrun; Santra, Saikat; Buechner, Boriana; Wieland, Thomas; Graf, Elisabeth; et al. (Annals of Clinical and Translational Neurology, 2015)
Short-chain enoyl-CoA hydratase (ECHS1) is a multifunctional mitochondrial matrix enzyme that is involved in the oxidation of fatty acids and essential amino acids such as valine. Here, we describe the broad phenotypic spectrum and pathobiochemistry of individuals with autosomal-recessive ECHS1 deficiency.Using exome sequencing, we identified ten unrelated individuals carrying compound heterozygous or homozygous mutations in ECHS1. Functional investigations in patient-derived fibroblast cell lines included immunoblotting, enzyme activity measurement, and a palmitate loading assay.Patients showed a heterogeneous phenotype with disease onset in the first year of life and course ranging from neonatal death to survival into adulthood. The most prominent clinical features were encephalopathy (10/10), deafness (9/9), epilepsy (6/9), optic atrophy (6/10), and cardiomyopathy (4/10). Serum lactate was elevated and brain magnetic resonance imaging showed white matter changes or a Leigh-like pattern resembling disorders of mitochondrial energy metabolism. Analysis of patients' fibroblast cell lines (6/10) provided further evidence for the pathogenicity of the respective mutations by showing reduced ECHS1 protein levels and reduced 2-enoyl-CoA hydratase activity. While serum acylcarnitine profiles were largely normal, in vitro palmitate loading of patient fibroblasts revealed increased butyrylcarnitine, unmasking the functional defect in mitochondrial ?-oxidation of short-chain fatty acids. Urinary excretion of 2-methyl-2,3-dihydroxybutyrate - a potential derivative of acryloyl-CoA in the valine catabolic pathway - was significantly increased, indicating impaired valine oxidation.In conclusion, we define the phenotypic spectrum of a new syndrome caused by ECHS1 deficiency. We speculate that both the ?-oxidation defect and the block in l-valine metabolism, with accumulation of toxic methacrylyl-CoA and acryloyl-CoA, contribute to the disorder that may be amenable to metabolic treatment approaches.
EVALuna2:18926

Deficiency of Fhl2 leads to delayed neuronal cell migration and premature astrocyte differentiation - Kim, Soung Yung; Ludwig, Stephan; Schneider, Holm; Wixler, Viktor; Park, Jung; Völkl, Simon (Journal of Cell Science, 2019)
The four and a half LIM domains protein 2 (Fhl2) is an adaptor protein capable of mediating protein-protein interactions. Here, we report for the first time phenotypic changes in the brain of Fhl2-deficient mice. We showed that Fhl2 is expressed in neural stem cells, precursors and mature cells of neuronal lineage. Moreover, Fhl2 deficiency leads to delayed neuroblast migration in vivo, premature astroglial differentiation of neural stem cells (NSCs) in vitro, and a gliosis-like accumulation of glial fibrillary acidic protein (GFAP)-positive astrocytes in vivo that substantially increases with age. Collectively, Fhl2-deficiency in the brain interrupts the maintenance and the balanced differentiation of adult NSCs, resulting in preferentially glial differentiation and early exhaustion of the NSC pool required for adult neurogenesis.
CRIS-Team WoS Importer:2019-04-12

Definition, diagnosis and clinical management of non-obstructive kidney dysplasia: a consensus statement by the ERKNet Working Group on Kidney Malformations - Kohl, Stefan; Avni, Fred E.; Boor, Peter; Capone, Valentina; Clapp, William L.; De Palma, Diego; Harris, Tess; Heidet, Laurence; Hilger, Alina Christine; Liapis, Helen; Lilien, Marc; Manzoni, Gianantonio; et al. (Nephrology Dialysis Transplantation, 2022)
Kidney dysplasia is one of the most frequent causes of chronic kidney failure in children. While dysplasia is a histological diagnosis, the term 'kidney dysplasia' is frequently used in daily clinical life without histopathological confirmation. Clinical parameters of kidney dysplasia have not been clearly defined, leading to imprecise communication amongst healthcare professionals and patients. This lack of consensus hampers precise disease understanding and the development of specific therapies. Based on a structured literature search, we here suggest a common basis for clinical, imaging, genetic, pathological and basic science aspects of non-obstructive kidney dysplasia associated with functional kidney impairment. We propose to accept hallmark sonographic findings as surrogate parameters defining a clinical diagnosis of dysplastic kidneys. We suggest differentiated clinical follow-up plans for children with kidney dysplasia and summarize established monogenic causes for non-obstructive kidney dysplasia. Finally, we point out and discuss research gaps in the field.
CRIS-Team WoS Importer:2022-09-16

Definition, epidemiology, pathophysiology, and essential criteria for diagnosis of pediatric chronic myeloid leukemia - Suttorp, Meinolf; Sembill, Stephanie; Deutsch, Hélène; Metzler, Markus; Millot, Frederic (Cancers, 2021)
Depending on the analytical tool applied, the hallmarks of chronic myeloid leukemia (CML) are the Philadelphia Chromosome and the resulting mRNA fusion transcript BCR-ABL1. With an incidence of 1 per 1 million of children this malignancy is very rare in the first 20 years of life. This article aims to; (i) define the disease based on the WHO nomenclature, the appropriate ICD 11 code and to unify the terminology, (ii) delineate features of epidemiology, etiology, and pathophysiology that are shared, but also differing between adult and pediatric patients with CML, iii) give a short summary on the diseases to be considered as a differential diagnosis of pediatric CML, (iv) to describe the morphological, histopathological and immunophenotypical findings of CML in pediatric patients, (v) illustrate rare but classical complications resulting from rheological problems observed at diagnosis, (vi) list essential and desirable diagnostic criteria, which hopefully in the future will help to unify the attempts when approaching this rare pediatric malignancy.
CRIS-Team Scopus Importer:2021-02-26
Keywords: Diagnostic essential criteria; Epidemiology; Pathophysiology; Pediatric CML

Delineation of the clinical phenotype caused by de novo CLTC variants - Sa, M. J. Nabais; Venselaar, H.; Wiel, L.; Trimouille, A.; Lasseaux, E.; Naudion, S.; Lacombe, D.; Piton, A.; Vincent-Delorme, C.; Zweier, Christiane; Wiesmann da Silva Reis, André; Trollmann, Regina; et al. (EUROPEAN JOURNAL OF HUMAN GENETICS, 2019)
CRIS-Team WoS Importer:2019-10-25

De novo CLTC variants are associated with a variable phenotype from mild to severe intellectual disability, microcephaly, hypoplasia of the corpus callosum, and epilepsy - Nabais Sá, Maria J.; Venselaar, Hanka; Wiel, Laurens; Trimouille, Aurélien; Lasseaux, Eulalie; Naudion, Sophie; Lacombe, Didier; Piton, Amélie; Vincent-Delorme, Catherine; Zweier, Christiane; Reis, André; Trollmann, Regina; et al. (Genetics in Medicine, 2019)
Purpose: To delineate the genotype–phenotype correlation in individuals with likely pathogenic variants in the CLTC gene. Methods: We describe 13 individuals with de novo CLTC variants. Causality of variants was determined by using the tolerance landscape of CLTC and computer-assisted molecular modeling where applicable. Phenotypic abnormalities observed in the individuals identified with missense and in-frame variants were compared with those with nonsense or frameshift variants in CLTC. Results: All de novo variants were judged to be causal. Combining our data with that of 14 previously reported affected individuals (n = 27), all had intellectual disability (ID), ranging from mild to moderate/severe, with or without additional neurologic, behavioral, craniofacial, ophthalmologic, and gastrointestinal features. Microcephaly, hypoplasia of the corpus callosum, and epilepsy were more frequently observed in individuals with missense and in-frame variants than in those with nonsense and frameshift variants. However, this difference was not significant. Conclusions: The wide phenotypic variability associated with likely pathogenic CLTC variants seems to be associated with allelic heterogeneity. The detailed clinical characterization of a larger cohort of individuals with pathogenic CLTC variants is warranted to support the hypothesis that missense and in-frame variants exert a dominant-negative effect, whereas the nonsense and frameshift variants would result in haploinsufficiency.
CRIS-Team Scopus Importer:2019-12-10
Keywords: CLTC; intellectual disability; neurodevelopmental disorder

Descriptive analysis of adverse drug reaction reports in children and adolescents from Germany: frequently reported reactions and suspected drugs - Dubrall, Diana; Leitzen, Sarah; Toni, Irmgard; Stingl, Julia; Schulz, M.; Schmid, Matthias; Neubert, Antje; Sachs, Bernhardt (BMC pharmacology & toxicology, 2021)
Background: Adverse drug reactions (ADRs) in the pediatric population may differ in types and frequencies compared to other populations. Respective studies analyzing ADR reports referring to children have already been performed for certain countries. However, differences in drug prescriptions, among others, complicate the transferability of the results from other countries to Germany or were rarely considered. Hence, the first aim of our study was to analyze the drugs and ADRs reported most frequently in ADR reports from Germany referring to children contained in the European ADR database (EudraVigilance). The second aim was to set the number of ADR reports in relation to the number of drug prescriptions. These were provided by the Research Institute for Ambulatory Health Care in Germany. Methods: For patients aged 0–17 years 20,854 spontaneous ADR reports were received between 01/01/2000–28/2/2019. The drugs and ADRs reported most frequently were identified. Stratified analyses with regard to age, sex and drugs used “off-label” were performed. Reporting rates (number of ADR reports/number of drug prescriptions) were calculated. Results: Methylphenidate (5.5%), ibuprofen (2.3%), and palivizumab (2.0%) were most frequently reported as suspected. If related to the number of drug prescriptions, the ranking changed (palivizumab, methylphenidate, ibuprofen). Irrespective of the applied drugs, vomiting (5.4%), urticaria (4.6%) and dyspnea (4.2%) were the ADRs reported most frequently. For children aged 0–1 year, drugs for the treatment of nervous system disorders and foetal exposure during pregnancy were most commonly reported. In contrast, methylphenidate ranked first in children older than 6 years and referred 3.5 times more often to males compared to females. If age- and sex-specific exposure was considered, more ADR reports for methylphenidate referred to children 4–6 years and females 13–17 years. Drugs for the treatment of nervous system disorders ranked first among “off-label” ADR reports. Conclusions: Our analysis underlines the importance of putting the number of ADR reports of a drug in context with its prescriptions. Additionally, differences in age- and sex-stratified analysis were observed which may be associated with age- and sex-specific diseases and, thus, drug exposure. The drugs most frequently included in “off-label” ADR reports differed from those most often used according to literature.
CRIS-Team Scopus Importer:2021-10-22
Keywords: Adolescent; Adverse drug reaction database analysis; Adverse drug reaction reports; Adverse drug reactions; Children; Off-label use; Side effects

Detection of collagens by multispectral optoacoustic tomography as an imaging biomarker for Duchenne muscular dystrophy - Regensburger, Adrian; Fonteyne, Lina M.; Jüngert, Jörg; Wagner, Anna; Gerhalter, Teresa; Nagel, Armin Michael; Heiß, Rafael; Flenkenthaler, Florian; Qurashi, Matthias; Neurath, Markus; Klymiuk, Nikolai; Kemter, Elisabeth; et al. (Nature Medicine, 2019)
Biomarkers for monitoring of disease progression and response to therapy are lacking for muscle diseases such as Duchenne muscular dystrophy. Noninvasive in vivo molecular imaging with multispectral optoacoustic tomography (MSOT) uses pulsed laser light to induce acoustic pressure waves, enabling the visualization of endogenous chromophores. Here we describe an application of MSOT, in which illumination in the near- and extended near-infrared ranges from 680–1,100 nm enables the visualization and quantification of collagen content. We first demonstrated the feasibility of this approach to noninvasive quantification of tissue fibrosis in longitudinal studies in a large-animal Duchenne muscular dystrophy model in pigs, and then applied this approach to pediatric patients. MSOT-derived collagen content measurements in skeletal muscle were highly correlated to the functional status of the patients and provided additional information on molecular features as compared to magnetic resonance imaging. This study highlights the potential of MSOT imaging as a noninvasive, age-independent biomarker for the implementation and monitoring of newly developed therapies in muscular diseases.
CRIS-Team Scopus Importer:2019-12-17

Detection of expressional changes induced by intrauterine growth restriction in the developing rat mammary gland via exploratory pathways analysis - Beinder, Lea; Fährmann, Nina; Wachtveitl, Rainer; Winterfeld, Ilona; Hartner, Andrea; Menendez-Castro, Carlos; Rauh, Manfred; Ruebner, Matthias; Hübner, Hanna; Nögel, Stephanie; Dörr, Helmuth-Günther; Rascher, Wolfgang; et al. (PLoS ONE, 2014)
Intrauterine growth restriction (IUGR) is thought to lead to fetal programming that in turn contributes to developmental changes of many organs postnatally. There is evidence that IUGR is a risk factor for the development of metabolic and cardiovascular disease later in life. A higher incidence of breast cancer was also observed after IUGR. This could be due to changes in mammary gland developmental pathways. We sought to characterise IUGR-induced alterations of the complex pathways of mammary development at the level of the transcriptome in a rat model of IUGR, using pathways analysis bioinformatics.We analysed the mammary glands of Wistar rats with IUGR induced by maternal low protein (LP) diet at the beginning (d21) and the end (d28) of pubertal ductal morphogenesis. Mammary glands of the LP group were smaller in size at d28, however did not show morphologic changes. We identified multiple differentially expressed genes in the mammary gland using Agilent SurePrint arrays at d21 and d28. In silico analysis was carried out using Ingenuity Pathways Analysis. In mammary gland tissue of LP rats at d21 of life a prominent upregulation of WT1 and CDKN1A (p21) expression was observed. Differentially regulated genes were associated with the extracellular regulated kinase (ERK)-1/-2 pathway. Western Blot analysis showed reduced levels of phosphorylated ERK-1/-2 in the mammary glands of the LP group at d21. To identify possible changes in circulating steroid levels, serum LC-Tandem mass-spectrometry was performed. LP rats showed higher serum progesterone levels and an increased corticosterone/dehydrocorticosterone-ratio at d28.Our data obtained from gene array analysis support the hypothesis that IUGR influences pubertal development of the rat mammary gland. We identified prominent differential regulation of genes and pathways for factors regulating cell cycle and growth. Moreover, we detected new pathways which appear to be programmed by IUGR.
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Detection of signature double-negative T cells is a predictive marker to identify autoimmune lymphoproliferative syndrome associated with FAS loss of function - Eisenhauer, Nina; Miano, Maurizio; Naumann-Bartsch, Nora; Leyh, Jörg; Dell'Orso, Gianluca; Aigner, Michael; Fecker, Gisela; Hinze, Claas; Wittkowski, Helmut; Bruns, Heiko; Zierk, Jakob; Metzler, Markus; et al. (American Journal of Hematology, 2024)
CRIS-Team Scopus Importer:2024-03-29

Detection of Signature Double-Negative T Cells Is a Reliable Marker for ALPS Associated with FAS Mutation - Eisenhauer, Nina; Miano, Maurizio; Naumann-Bartsch, Nora; Leyh, Jörg; Terranova, Paola; Hinze, Claas; Aigner, Michael; Wittkowski, Helmut; Bruns, Heiko; Ehl, Stephan; Metzler, Markus; Arkwright, Peter; et al. (BLOOD, 2022)
CRIS-Team WoS Importer:2023-03-17

Detection of wound healing disorders after major amputations by measurements of the microcirculation: A prospective single-center study - Zetzmann, Katharina; Papatheodorou, Nikolaos; Rühl, Eva; Yagshyyev, Shatlyk; Haney, Briain; Moosmann, Oxana; Li, Yi; Meyer, Alexander; Knieling, Ferdinand; Behrendt, Christian Alexander; Lang, Werner; Rother, Ulrich (SAGE Open Medicine, 2024)
Introduction: Although major amputations can often be avoided due to evolving methods of endovascular and surgical revascularizations techniques, in patients with chronic limb-threatening ischemia, it is still necessary in some cases. Aim of this study was the detection of wound healing disorders through intraoperative microcirculation measurements in major limb amputations. Materials and methods: In this single-center clinical study, patients with an indication for major amputation were enrolled prospectively. Cause of amputation, patients’ comorbidities including cardiovascular risk profile were assessed. Macrocirculation, as well as microcirculation were assessed. Microcirculation measurements were performed by fluorescence angiography with the administration of indocyanine green. A preoperative measurement was obtained at the amputation level, followed by three additional measurements of the amputation stump postoperatively. Wound healing was monitored and correlated with the microcirculatory findings, based on the perfusion parameters ingress and ingress rate, calculated in the indocyanine green fluorescence video sequences of the amputation stumps. Results: Forty-five patients were enrolled, including 19 (42%) below-the-knee amputations and 26 (58%) above-the-knee amputations. When considering the need for revision, a change in the microperfusion parameters was observed postoperatively. The mean value for ingress was significantly lower directly postoperatively in stumps requiring revisions (5 ± 0 A.U. versus 40.5 ± 42.5 A.U., p < 0.001). The mean value of ingress rate behaved similarly (0.15 ± 0.07 A.U./s versus 2.8 ± 5.0 A.U./s, p = 0.005). The evaluation of indocyanine green measurements when wound healing disorders occurred also showed nonsignificant differences in the mean values. Conclusion: Fluorescence angiography after major lower limb amputations appears to be an option of depicting microperfusion. Especially, the early postoperative detection of reduced perfusion can indicate a subsequent need for revision. Therefore, this method could possibly serve as a tool for intraoperative quality control after major limb amputation.
CRIS-Team Scopus Importer:2024-08-02
Keywords: fluorescence angiography; indocyanine green; Major limb amputation; microperfusion; wound healing

Detyrosinated tubulin is decreased in fetal vessels of preeclampsia placentas - Huebner, H.; Knoerr, B.; Betzler, A.; Kehl, Sven; Baier, F.; Wachter, David Lukas; Strick, Reiner; Beckmann, Matthias; Fahlbusch, F. B.; Rübner, Matthias; Hartner, Andrea (Placenta, 2018)
INTRODUCTION: Preeclampsia is a hypertensive, gestational disease, which is still the leading cause of pregnancy related morbidity and mortality. The impairment of placental angiogenesis and vascularization is discussed to be of etiopathologic relevance. Deytrosination and tyrosination of α-tubulin is important for the stability and dynamics of microtubules. An increase of α-tubulin detyrosination leads to microtubule stabilization, which is an essential prerequisite for physiologic vascular tube morphogenesis during angiogenesis. So far, little is known about the specific localization of detyrosinated (detyr) and tyrosinated (tyr) tubulin in the placenta and its relevance for preeclampsia. METHODS: Placental expression of detyr- and tyr-tubulin was analyzed by immunohistochemistry, immunofluorescence and western blot. For western blot quantification we used biopsies from healthy placentas (n = 21) and placentas from pregnancies complicated with small for gestational age (n = 5), preeclampsia (n = 5) or both (n = 5). RESULTS: Specific placental localization of detyr-tubulin was detected in the fetal endothelial cells of the placenta. Villous and extravillous trophoblasts as well as villous stroma cells were tyr-tubulin positive. Detyr-tubulin protein expression was significantly decreased in placentas complicated by preeclampsia. CONCLUSIONS: In summary, we report an accumulation of detyr-tubulin in villous vessels of the placenta and a significantly reduced level of detyr-tubulin in placental biopsies of preeclampsia cases. The reduction of placental detyr-tubulin in preeclampsia could suggest a deficit in villous vascular plasticity and might be associated with the impaired arborization of the disease.
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Development and Adjustment of an Algorithm for Identifying Drug-Related Hospital Admissions in Pediatrics - Schulze, Christopher; Toni, Irmgard; Moritz, Katrin; Eberl, Sonja; Rascher, Wolfgang; Neubert, Antje (Journal of Patient Safety, 2022)
Objective Adverse drug events (ADEs) in the outpatient pediatric pharmacotherapy can be serious and lead to inpatient admissions. Recent research only focused on ADE identification during hospitalization. The aim of the present study was to develop an algorithm to identify drug-related hospital admissions in pediatrics. Methods A systematic literature research was performed, and a pediatric trigger tool for identifying drug-related inpatient admissions was built. The initial version was tested in a sample of 292 patients admitted to a German university children's hospital. Subsequently, the tool was further improved by combining different modules as a novel approach. Results The obtained algorithm with 39 triggers in 5 modules identified drug-related inpatient admissions at a sensitivity of 95.5% (95% confidence interval [CI], 89.3%-100%) and a specificity of 16.5% (95% CI, 11.9%-21.2%), respectively. After modifications including trigger activation requiring a combination of different modules, specificity increased to 56.9% (95% CI, 50.7%-63.0%). Identifying 36 of 44 ADEs leading to admission, sensitivity remained high (81.8% [95% CI, 70.4%-93.2%]). The overall positive predictive value was 25.2% (95% CI, 18.1%-32.3%). Conclusions The algorithm is the first trigger tool to identify ambulant acquired ADEs leading to hospital admission in pediatrics. However, the underlying patient sample is small. Using a larger population for refinement will allow further specifications and reduction in the total amount of triggers and thus signals.
CRIS-Team WoS Importer:2022-08-26

Development and Evaluation of a Web-Based Paediatric Drug Information System for Germany - Zahn, Julia; Wimmer, Stefan; Rödle, Wolfgang; Toni, Irmgard; Sedlmayr, Brita; Prokosch, Hans-Ulrich; Rascher, Wolfgang; Neubert, Antje (Pharmacy, 2021)
Background: Off-label use is frequent in paediatrics but that does not necessarily mean that the risk-benefit ratio is negative. Nevertheless, evidence-based data is essential for safe drug therapy. In Germany, there is no publicly available compendium providing transparent, evidence-based information for paediatric pharmacotherapy to date. This work describes the development of a web-based paediatric drug information system (PDIS) for Germany and its evaluation by health care professionals (HCP). Methods: Since 2012, a PDIS is being developed by the authors and is supported by the Federal Ministry of Health since 2016. Dosing recommendations were established based on systematic literature reviews and subsequent evaluation by clinical experts. The prototype was evaluated by HCP. Based on the results, the further development was concluded. Results: 92% of HCP believed that the PDIS could improve the quality of prescribing, as currently available information is deficient. Besides the license and formulations, dosing recommendations were the most relevant modules. A dosage calculator was the most wanted improvement. To facilitate sustainability of future development, a collaboration with the Dutch Kinderformularium was established. As of 2021, the database will be available to German HCP. Conclusion: The fundamentals for a German PDIS were established, and vital steps were taken towards successful continuation.
CRIS-Team WoS Importer:2021-04-16

Development and Usability Analysis of a Multimedia eConsent Solution - Schneiderheinze, Hauke; Prokosch, Hans-Ulrich; Apel, Hendrik; Bellut, Laura; Wullich, Bernd; Trollmann, Regina; Schüttler, Christina (German Medical Data Sciences: Shaping Change – Creative Solutions for Innovative Medicine, 2019)
BACKGROUND: More and more medical data is being stored digitally in routine care. The secondary use of patient data is only possible to a limited extent for data protection reasons. In order to enable a long-term and far-reaching use of secondary data, a possible approach is to obtain "broad consent" from patients, e.g. on research projects whose purpose is still unknown at the time of consent. OBJECTIVE: To develop and evaluate an interactive eConsent prototype that presents the extensive contents of the "broad consent" in multimedia form for the purpose of a successful and resource-efficient information and consent process. METHODS: The eConsent prototype was designed on basis of a literature review and in accordance with the goals of the German medical informatics initiative. User tests and subsequent questionnaire surveys using the System Usability Scale (SUS) were carried out with patients from a university hospital to assess the prototype's usability. The study was conducted in a quasi-experimental, one-group posttest-only design. RESULTS: The created interactive prototype can present the contents acoustically and visually and offers the possibility to retrieve additional information. With a SUS score of 84,1/100 the results indicate a very good usability of the prototype. CONCLUSION: The next steps will include further refinements of the prototype based on the feedback received and a subsequent study with a broader user group aimed at introducing an eConsent tool as part of a patient portal.
CRIS-Team Scopus Importer:2019-09-24
Keywords: Informed consent; multimedia; patient participation; patient portals

Development of a rapid and specific MALDI-TOF mass spectrometric assay for SARS-CoV-2 detection - Kollhoff, Lydia; Kipping, Marc; Rauh, Manfred; Ceglarek, Uta; Barka, Günes; Barka, Frederik; Sinz, Andrea (Clinical Proteomics, 2023)
<?qj left?>Abstract: We have developed a rapid and highly specific assay for detecting and monitoring SARS-CoV-2 infections by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS). As MALDI-TOF mass spectrometers are available in a clinical setting, our assay has the potential to serve as alternative to the commonly used reverse transcriptase quantitative polymerase chain reaction (RT-qPCR). Sample preparation prior to MALDI-TOF-MS involves the tryptic digestion of SARS-CoV-2 proteins, followed by an enrichment of virus-specific peptides from SARS-CoV-2 nucleoprotein via magnetic antibody beads. Our MALDI-TOF-MS method allows the detection of SARS-CoV-2 nucleoprotein in sample collection medium as low as 8 amol/µl. MALDI-TOF mass spectra are obtained in just a few seconds, which makes our MS-based assay suitable for a high-throughput screening of SARS-CoV-2 in healthcare facilities in addition to PCR. Due to the specific detection of virus peptides, different SARS-CoV-2 variants are readily distinguished from each other. Specifically, we show that our MALDI-TOF-MS assay discriminates SARS-CoV-2 strain B.1.617.2 “delta variant” from all other variants in patients’ samples, making our method highly valuable to monitor the emergence of new virus variants. Graphical Abstract: [Figure not available: see fulltext.]
CRIS-Team Scopus Importer:2023-07-21
Keywords: COVID-19; MALDI; Mass spectrometry; SARS-COV-2

Dexamethasone alleviates tumor-associated brain damage and angiogenesis - Fan, Zheng; Sehm, Tina; Rauh, Manfred; Buchfelder, Michael; Eyupoglu, Ilker Y.; Savaskan, Nicolai E. (PLoS ONE, 2014)
Children and adults with the most aggressive form of brain cancer, malignant gliomas or glioblastoma, often develop cerebral edema as a life-threatening complication. This complication is routinely treated with dexamethasone (DEXA), a steroidal anti-inflammatory drug with pleiotropic action profile. Here we show that dexamethasone reduces murine and rodent glioma tumor growth in a concentration-dependent manner. Low concentrations of DEXA are already capable of inhibiting glioma cell proliferation and at higher levels induce cell death. Further, the expression of the glutamate antiporter xCT (system Xc-; SLC7a11) and VEGFA is up-regulated after DEXA treatment indicating early cellular stress responses. However, in human gliomas DEXA exerts differential cytotoxic effects, with some human glioma cells (U251, T98G) resistant to DEXA, a finding corroborated by clinical data of dexamethasone non-responders. Moreover, DEXA-resistant gliomas did not show any xCT alterations, indicating that these gene expressions are associated with DEXA-induced cellular stress. Hence, siRNA-mediated xCT knockdown in glioma cells increased the susceptibility to DEXA. Interestingly, cell viability of primary human astrocytes and primary rodent neurons is not affected by DEXA. We further tested the pharmacological effects of DEXA on brain tissue and showed that DEXA reduces tumor-induced disturbances of the microenvironment such as neuronal cell death and tumor-induced angiogenesis. In conclusion, we demonstrate that DEXA inhibits glioma cell growth in a concentration and species-dependent manner. Further, DEXA executes neuroprotective effects in brains and reduces tumor-induced angiogenesis. Thus, our investigations reveal that DEXA acts pleiotropically and impacts tumor growth, tumor vasculature and tumor-associated brain damage.
EVALuna2:18894

Diagnosis and treatment of Guillain-Barré Syndrome in childhood and adolescence: An evidence- and consensus-based guideline - Korinthenberg, R.; Trollmann, Regina; Felderhoff-Müser, U.; Bernert, G.; Hackenberg, A.; Hufnagel, M.; Pohl, M.; Hahn, G.; Mentzel, H. J.; Sommer, C.; Lambeck, J.; Mecher, F.; et al. (European Journal of Paediatric Neurology, 2020)
This evidence- and consensus-based practical guideline for the diagnosis and treatment of Guillain-Barré Syndrome (GBS) in childhood and adolescence has been developed by a group of delegates from relevant specialist societies and organisations; it is the result of an initiative by the German-Speaking Society of Neuropediatrics (GNP), and is supported by the Association of Scientific Medical Societies (AWMF, Arbeitsgemeinschaft der Wissenschaftlichen Medizinischen Fachgesellschaften). A systematic analysis of the literature revealed that only a few adequately-controlled studies exist for this particular age group, while none carries a low risk of bias. For this reason, the diagnostic and therapeutic recommendations largely rely on findings in adult patients with GBS, for which there are a higher number of suitable studies available. Consensus was established using a written, multi-step Delphi process. A high level of consensus could be reached for the crucial steps in diagnosis and treatment. We recommend basing the diagnostic approach on the clinical criteria of GBS and deriving support from CSF and electrophysiological findings. Repetition of invasive procedures that yield ambiguous results is only recommended if the diagnosis cannot be ascertained from the other criteria. For severe or persistently-progressive GBS treatment with intravenous immunoglobulin (IVIG) is recommended, whereas in cases of IVIG intolerance or inefficacy we recommended treatment with plasmapheresis. Corticosteroids are ineffective for GBS but can be considered when acute onset chronic inflammatory demyelinating polyneuropathy (A-CIDP) is suspected due to a prolonged disease course. The full German version of the Guideline is available on the AWMF website (https://www.awmf.org/leitlinien/detail/ll/022-008.html).
CRIS-Team Scopus Importer:2020-01-21
Keywords: Children; Diagnosis; Guillain-barré syndrome; Intravenous immunoglobulin; Plasmapheresis/plasma exchange; Supportive care

Diagnosis of Complex Pulley Ruptures Using Ultrasound in Cadaver Models - Schoffl, Isabelle; Hugel, Arnika; Schoffl, Volker; Rascher, Wolfgang; Jungert, Jorg (Ultrasound in Medicine and Biology, 2017)
Pulley ruptures are common in climbing athletes. The purposes of this study were to determine the specific positioning of each pulley with regards to the joint, and to evaluate the ultrasound diagnostics of various pulley rupture combinations. For this, 34 cadaver fingers were analyzed via ultrasound, the results of which were compared to anatomic measurements. Different pulley ruptures were then simulated and evaluated using ultrasound in standardized dynamic forced flexion. Visualization of the A2 and A4 pulleys was achieved 100% of the time, while the A3 pulley was visible in 74% of cases. Similarly, injuries to the A2 and A4 pulleys were readily observable, while A3 pulley injuries were more challenging to identify (sensitivity of 0.2 for singular A3 pulley, 0.5 for A2/A4 pulley and 0.33 for A3/A4 pulley ruptures). Receiver operating characteristic analysis was used to evaluate the optimal tendon-bone distance for pulley rupture diagnosis, a threshold which was determined to be 1.9 mm for A2 pulley ruptures and 1.85 for A4 pulley ruptures. This study was the first to carry out a cadaver ultrasound examination of a wide variety of pulley ruptures. Ultrasound is a highly accurate tool for visualizing the A2 and A4 pulleys in a cadaver model. This method of pathology diagnosis was determined to be suitable for injuries to the A2 and A4 pulleys, but inadequate for A3 pulley injuries.
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Diagnosis of X-Linked Hypohidrotic Ectodermal Dysplasia by Meibography and Infrared Thermography of the Eye - Kärcher, Thomas; Dietz, Jasna; Jacobi, Christina; Berz, Reinhold; Schneider, Holm (Current Eye Research, 2015)
X-linked hypohidrotic ectodermal dysplasia (XLHED) is the most common form of ectodermal dysplasia. Clinical characteristics include meibomian gland disorder and the resulting hyperevaporative dry eye. In this study, we evaluated meibography and ocular infrared thermography as novel methods to diagnose XLHED.Eight infants, 12 boys and 14 male adults with XLHED and 12 healthy control subjects were subjected to a panel of tests including the ocular surface disease index (OSDI), meibography and infrared thermography, non-invasive measurement of tear film break-up time (NIBUT) and osmolarity, Schirmer's test, lissamine green staining and fluorescein staining. Sensitivity and specificity were determined for single tests and selected test combinations.Meibography had 100% sensitivity and specificity for identifying XLHED. Infrared thermography, a completely non-invasive procedure, revealed a typical pattern for male subjects with XLHED. It was, however, less sensitive (86% for adults and 67% for children) than meibography or a combination of established routine tests. In adults, OSDI and NIBUT were the best single routine tests (sensitivity of 86% and 71%, respectively), whereas increased tear osmolarity appeared as a rather unspecific ophthalmic symptom. In children, NIBUT was the most convincing routine test (sensitivity of 91%).Meibography is the most reliable ophthalmic examination to establish a clinical diagnosis in individuals with suspected hypohidrotic ectodermal dysplasia, even before genetic test results are available. Tear film tests and ocular surface staining are less sensitive in children, but very helpful for estimating the severity of ocular surface disease in individuals with known XLHED.
EVALuna2:18886

Diagnosis, Therapy and Follow-up of Cervical Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry No. 032/033OL, May 2021) – Part 1 with Recommendations on Epidemiology, Screening, Diagnostics and Therapy - Beckmann, Matthias; Stübs, Frederik; Koch, Martin; Mallmann, Peter; Dannecker, Christian; Dietl, Anna; Sevnina, Anna; Mergel, Franziska; Lotz, Laura; Hack, Carolin; Ehret, Anne; Gantert, Daniel; et al. (Geburtshilfe und Frauenheilkunde, 2022)
Aim This update of the interdisciplinary S3 guideline on the Diagnosis, Therapy and Follow-up of Cervical Cancer (AWMF Registry No. 032/033OL) was published in March 2021. This updated guideline was funded by German Cancer Aid (Deutsche Krebshilfe) as part of the German Guideline Program in Oncology. The guideline was coordinated by the German Society of Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG) and the Working Group on Gynecological Oncology (Arbeitsgemeinschaft Gynäkologische Onkologie, AGO) of the German Cancer Society (Deutsche Krebsgesellschaft, DKG). Method The process of updating the S3 guideline dating from 2014 was based on an appraisal of the available evidence using the criteria of evidence-based medicine, adaptations of existing evidence-based national and international guidelines or - if evidence was lacking - on a consensus of the specialists involved in compiling the update. After an initial review of the current literature was carried out according to a prescribed algorithm, several areas were identified which, in contrast to the predecessor version from September 2014, required new recommendations or statements which took account of more recently published literature and the appraisal of the new evidence. Recommendations The short version of this guideline consists of recommendations and statements on the epidemiology, screening, diagnostic workup and therapy of patients with cervical cancer. The most important new aspects included in this updated guideline include the newly published FIGO classification of 2018, the radical open surgery approach for cervical cancers up to FIGO stage IB1, and use of the sentinel lymph node technique for tumors ≤ 2 cm. Other changes include the use of PET-CT, new options in radiotherapy (e.g., intensity-modulated radiotherapy, image-guided adaptive brachytherapy), and drug therapies to treat recurrence or metastasis.
CRIS-Team Scopus Importer:2022-03-04
Keywords: cervical cancer; cervical intraepithelial neoplasia; follow-up; guideline; therapy

Diagnosis, Therapy and Follow-up of Cervical Cancer. Guideline of the DGGG, DKG and DKH (S3-Level, AWMF Registry No. 032/033OL, May 2021) – Part 2 with Recommendations on Psycho-oncology, Rehabilitation, Follow-up, Recurrence, Palliative Therapy and Healthcare Facilities - Fehm, Tanja; Stübs, Frederik; Koch, Martin; Mallmann, Peter; Dannecker, Christian; Dietl, Anna; Sevnina, Anna; Mergel, Franziska; Lotz, Laura; Hack, Carolin; Ehret, Anne; Gantert, Daniel; et al. (Geburtshilfe und Frauenheilkunde, 2022)
Aim This is an update of the interdisciplinary S3-guideline on the Diagnosis, Therapy and Follow-up of Cervical Cancer (AWMF Registry No. 032/033OL), published in March 2021. The work on the updated guideline was funded by German Cancer Aid (Deutsche Krebshilfe) as part of the German Guideline Program in Oncology. The guideline was coordinated by the German Society of Gynecology and Obstetrics (Deutsche Gesellschaft für Gynäkologie und Geburtshilfe, DGGG) and the Working Group on Gynecological Oncology (Arbeitsgemeinschaft Gynäkologische Onkologie, AGO) of the German Cancer Society (Deutsche Krebsgesellschaft, DKG). Method The process used to update the 2014 S3-guideline was based on an appraisal of the available evidence using the criteria of evidence-based medicine, adaptations of existing evidence-based national and international guidelines or - if evidence was lacking - on the consensus of the specialists involved in compiling the update. After an initial review of the current literature was carried out according to a prescribed algorithm, several areas were identified which, in contrast to the predecessor version from September 2014, required new recommendations or statements which would take account of more recently published literature and the recent appraisal of new evidence. Recommendations The short version of this guideline consists of recommendations and statements on palliative therapy and follow-up of patients with cervical cancer. The most important aspects included in this updated guideline are the new FIGO classification published in 2018, the radical open surgery approach used to treat cervical cancer up to FIGO stage IB1, and the use of the sentinel lymph node technique for tumors ≤ 2 cm. Other changes include the use of PET-CT, new options in radiotherapy (e.g., intensity-modulated radiotherapy, image-guided adaptive brachytherapy), and drug therapies to treat recurrence or metastasis.
CRIS-Team Scopus Importer:2022-02-25
Keywords: cervical cancer; cervical intraepithelial neoplasia; follow-up; guideline; therapy

Diagnostic Challenges Using a 2-Tier Strategy for Methylmalonic Acidurias: Data from 1.2 Million Dried Blood Spots - Weiss, Katharina J.; Röschinger, Wulf; Blessing, Holger; Lotz-Havla, Amelie S.; Schiergens, Katharina A.; Maier, Esther M. (Annals of Nutrition and Metabolism, 2020)
Background: The detection of methylmalonic acid (MMA) by second-tier analysis has been shown to reduce the number of false positives in newborn screening (NBS) for genetically determined methylmalonic acidurias (MMAuria). In addition to genetic conditions, MMA is an indicator of vitamin B12 status, thus applicable to detect maternal vitamin B12 deficiency in the newborns screened. Methods: Biochemical and clinical follow-up data of a 7.5-year pilot study with 1.2 million newborns screened were reviewed. Results: Among 1,195,850 NBS samples, 3,595 (0.3%) fulfilled criteria for second-tier analysis of MMA. In 37 (0.003%; 1/32,000) samples, elevated concentrations of MMA were detected, resulting in diagnostic workup at a metabolic center in 21 newborns. In 6 infants (1/199,000), genetic conditions were established, 1 infant with cobalamin C deficiency (CblC) showed only a moderate elevation of MMA. The remaining 15 newborns (1/79,000) displayed significantly lower concentrations of MMA and were evaluated for maternal vitamin B12 deficiency. In 9 mothers, vitamin B12 deficiency was verified, and 6 showed no indication for vitamin B12 deficiency. Treatment with vitamin B12 normalized biochemical parameters in all 15 infants. Conclusions: Applying a 2-tier strategy measuring MMA in NBS identified genetic conditions of MMAuria. It was possible to separate severe, early-onset phenotypes from maternal vitamin B12 deficiency. However, the detection of CblC deficiency with mildly elevated MMA interferes with impaired vitamin B12 status of unknown relevance and thus burdens possibly healthy newborns. Regarding maternal vitamin B12 deficiency, testing and supplementing mothers-to-be is preferable. This might decrease straining follow-up of newborns and improve quality and overall perception of NBS.
CRIS-Team Scopus Importer:2020-10-16

Diagnostic evaluation of paediatric autoimmune lymphoproliferative immunodeficiencies (ALPID): a prospective cohort study - Hägele, Pauline; Staus, Paulina; Scheible, Raphael; Uhlmann, Annette; Heeg, Maximilian; Klemann, Christian; Maccari, Maria Elena; Ritterbusch, Henrike; Armstrong, Martin; Cutcutache, Ioana; Elliott, Katherine S.; von Bernuth, Horst; et al. (Lancet Haematology, 2024)
BACKGROUND: Lymphoproliferation and autoimmune cytopenias characterise autoimmune lymphoproliferative syndrome. Other conditions sharing these manifestations have been termed autoimmune lymphoproliferative syndrome-like diseases, although they are frequently more severe. The aim of this study was to define the genetic, clinical, and immunological features of these disorders to improve their diagnostic classification. METHODS: In this prospective cohort study, patients were referred to the Center for Chronic Immunodeficiency in Freiburg, Germany, between Jan 1, 2008 and March 5, 2022. We enrolled patients younger than 18 years with lymphoproliferation and autoimmune cytopenia, lymphoproliferation and at least one additional sign of an inborn error of immunity (SoIEI), bilineage autoimmune cytopenia, or autoimmune cytopenia and at least one additional SoIEI. Autoimmune lymphoproliferative syndrome biomarkers were determined in all patients. Sanger sequencing followed by in-depth genetic studies were recommended for patients with biomarkers indicative of autoimmune lymphoproliferative syndrome, while IEI panels, exome sequencing, or genome sequencing were recommended for patients without such biomarkers. Genetic analyses were done as decided by the treating physician. The study was registered on the German Clinical Trials Register, DRKS00011383, and is ongoing. FINDINGS: We recruited 431 children referred for autoimmune lymphoproliferative syndrome evaluation, of whom 236 (55%) were included on the basis of lymphoproliferation and autoimmune cytopenia, 148 (34%) on the basis of lymphoproliferation and another SoIEI, 33 (8%) on the basis of autoimmune bicytopenia, and 14 (3%) on the basis of autoimmune cytopenia and another SoIEI. Median age at diagnostic evaluation was 9·8 years (IQR 5·5-13·8), and the cohort comprised 279 (65%) boys and 152 (35%) girls. After biomarker and genetic assessments, autoimmune lymphoproliferative syndrome was diagnosed in 71 (16%) patients. Among the remaining 360 patients, 54 (15%) had mostly autosomal-dominant autoimmune lymphoproliferative immunodeficiencies (AD-ALPID), most commonly affecting JAK-STAT (26 patients), CTLA4-LRBA (14), PI3K (six), RAS (five), or NFκB (three) signalling. 19 (5%) patients had other IEIs, 17 (5%) had non-IEI diagnoses, 79 (22%) were unresolved despite extended genetics (ALPID-U), and 191 (53%) had insufficient genetic workup for diagnosis. 16 (10%) of 161 patients with a final diagnosis had somatic mutations. Alternative classification of patients fulfilling common variable immunodeficiency or Evans syndrome criteria did not increase the proportion of genetic diagnoses. INTERPRETATION: The ALPID phenotype defined in this study is enriched for patients with genetic diseases treatable with targeted therapies. The term ALPID might be useful to focus diagnostic and therapeutic efforts by triggering extended genetic analysis and consideration of targeted therapies, including in some children currently classified as having common variable immunodeficiency or Evans syndrome. FUNDING: Deutsche Forschungsgemeinschaft under Germany's Excellence Strategy. TRANSLATION: For the German translation of the abstract see Supplementary Materials section.
CRIS-Team Scopus Importer:2024-02-16

Diagnostic Utility of Interleukin-6 in Early-Onset Sepsis among Term Newborns: Impact of Maternal Risk Factors and CRP Evaluation. - Schleier, Maria; Lubig, Julia; Kehl, Sven; Hébert, Steven; Wölfle, Joachim; van der Donk, Adriana; Bär, Alisa; Reutter, Heiko Martin; Hepp, Tobias; Morhart, Patrick (Children, 2023)
(1) Background: Interleukin-6 (IL-6) levels act as an early infection marker preceding C-reactive protein (CRP) elevation. This study seeks to analyze IL-6 behavior in suspected early-onset sepsis (EOS) cases among term newborns, comparing it to that of CRP and evaluating IL-6's diagnostic utility. We also aim to assess the impact of maternal risk factors on EOS in term newborns, quantifying their influence for informed decision making. (2) Methods: The retrospective data analysis included 533 term newborns who were admitted to our hospital because of suspected EOS. IL-6, CRP, and the impact of maternal risk factors were analyzed in the context of EOS using binomial test, Chi-squared test, logistic and linear regression. (3) Results: In the cases of EOS, both IL-6 and CRP were elevated. The increase in CRP can be predicted by the initial increase in IL-6 levels. Among the assessed risk factors, intrapartum maternal fever (adjusted odds ratio 18.1; 95% CI (1.7-4.1)) was identified as the only risk factor significantly associated with EOS. (4) Conclusions: Employing IL-6 as an early infection marker enhanced EOS diagnostic precision due to its detectable early rise. However, caution is required, as elevations in IL-6 and CRP levels do not exclusively indicate EOS. Increased CRP levels in healthy newborns with maternal risk factors may be attributed to dynamics of vaginal labor.
EVALuna2:549522

Did the COVID-19 Lockdown Affect the Incidence of Pediatric Type 1 Diabetes in Germany? - Tittel, Sascha Rene; Rosenbauer, Joachim; Kamrath, Clemens; Ziegler, Julian; Reschke, Felix; Hammersen, Johanna; Moenkemoeller, Kirsten; Pappa, Angeliki; Kapellen, Thomas; Holl, Reinhard Walter (Diabetes Care, 2020)
CRIS-Team Scopus Importer:2020-11-06

Differences between capillary and venous blood counts in children-A data mining approach - Becker, Mathias; Gscheidmeier, Thomas; Gross, Hans-Juergen; Cario, Holger; Wölfle, Joachim; Rauh, Manfred; Metzler, Markus; Zierk, Jakob (International Journal of Laboratory Hematology, 2022)
Background Capillary sampling of blood counts is a well-established alternative to venipuncture in paediatrics. However, the sampling method has to be considered when interpreting test results, as measurements differ. Ethical and practical considerations prevent simultaneous venous and capillary sample acquisition in comprehensive paediatric cohorts that span all ages for the purpose of a direct method comparison, resulting in uncertainty regarding the interpretation of capillary test results. Methods We applied a data mining method to calculate the differences between capillary and venous blood count analytes using laboratory data collected during patient care. We examined 486 401 blood counts performed between 2010 and 2017 in two German paediatric tertiary care centers in children from birth to 18 years analysed on SYSMEX XE-2100 and SYSMEX XE-5000 devices, and analysed the differences between capillary and venous test results in 15 218 paired samples performed within 24 h. Results We identified the mean systematic differences between capillary and venous (capillary-venous) test results for haemoglobin (+6.5 g/L), haematocrit (+2.38%), platelet count (-7.01 x 10(9)/l), red cell count (+0.18 x 10(12)/L), white cell count (-0.64 x 10(9)/L), mean corpuscular cell volume (+2.07 fl), mean corpuscular haemoglobin (+0.33 pg), mean corpuscular haemoglobin concentration (-4.4 g/L) and red cell distribution width (+0.40%). The effect of age on these mean deltas is negligible, while the levels of test results influence the difference between capillary and venous test results in most analytes. Conclusions Our results improve guidance regarding the interpretation of capillary test results for children of all ages and in both physiological and pathological ranges.
CRIS-Team WoS Importer:2022-05-13

Differential Coassembly of α1-GABAARs Associated with Epileptic Encephalopathy - Hannan, Saad; Affandi, Aida H. B.; Minere, Marielle; Jones, Charlotte; Goh, Pollyanna; Warnes, Gary; Popp, Bernt; Trollmann, Regina; Nizetic, Dean; Smart, Trevor G. (The Journal of Neuroscience, 2020)
GABAA receptors (GABAARs) are profoundly important for controlling neuronal excitability. Spontaneous and familial mutations to these receptors feature prominently in excitability disorders and neurodevelopmental deficits following disruption to GABA-mediated inhibition. Recent genotyping of an individual with severe epilepsy and Williams-Beuren syndrome identified a frameshifting de novo variant in a major GABAAR gene, GABRA1 This truncated the α1 subunit between the third and fourth transmembrane domains and introduced 24 new residues forming the mature protein, α1Lys374Serfs*25 Cell surface expression of mutant murine GABAARs is severely impaired compared with WT, due to retention in the endoplasmic reticulum. Mutant receptors were differentially coexpressed with β3, but not with β2, subunits in mammalian cells. Reduced surface expression was reflected by smaller IPSCs, which may underlie the induction of seizures. The mutant does not have a dominant-negative effect on native neuronal GABAAR expression since GABA current density was unaffected in hippocampal neurons, although mutant receptors exhibited limited GABA sensitivity. To date, the underlying mechanism is unique for epileptogenic variants and involves differential β subunit expression of GABAAR populations, which profoundly affected receptor function and synaptic inhibition.SIGNIFICANCE STATEMENT GABAARs are critical for controlling neural network excitability. They are ubiquitously distributed throughout the brain, and their dysfunction underlies many neurologic disorders, especially epilepsy. Here we report the characterization of an α1-GABAAR variant that results in severe epilepsy. The underlying mechanism is structurally unusual, with the loss of part of the α1 subunit transmembrane domain and part-replacement with nonsense residues. This led to compromised and differential α1 subunit cell surface expression with β subunits resulting in severely reduced synaptic inhibition. Our study reveals that disease-inducing variants can affect GABAAR structure, and consequently subunit assembly and cell surface expression, critically impacting on the efficacy of synaptic inhibition, a property that will orchestrate the extent and duration of neuronal excitability.
CRIS-Team Scopus Importer:2020-07-31
Keywords: epilepsy; GABA-A receptor; inhibition; synaptic transmission; α subunit variant

Differential Diagnosis of Acquired and Hereditary Neuropathies in Children and Adolescents-Consensus-Based Practice Guidelines - Korinthenberg, Rudolf; Trollmann, Regina; Plecko, Barbara; Stettner, Georg M.; Blankenburg, Markus; Weis, Joachim; Schoser, Benedikt; Mueller-Felber, Wolfgang; Lochbuehler, Nina; Hahn, Gabriele; Rudnik-Schoeneborn, Sabine (Children, 2021)
Disorders of the peripheral nerves can be caused by a broad spectrum of acquired or hereditary aetiologies. The objective of these practice guidelines is to provide the reader with information about the differential diagnostic workup for a target-oriented diagnosis. Following an initiative of the German-speaking Society of Neuropaediatrics, delegates from 10 German societies dedicated to neuroscience worked in close co-operation to write this guideline. Applying the Delphi methodology, the authors carried out a formal consensus process to develop practice recommendations. These covered the important diagnostic steps both for acquired neuropathies (traumatic, infectious, inflammatory) and the spectrum of hereditary Charcot-Marie-Tooth (CMT) diseases. Some of our most important recommendations are that: (i) The indication for further diagnostics must be based on the patient's history and clinical findings; (ii) Potential toxic neuropathy also has to be considered; (iii) For focal and regional neuropathies of unknown aetiology, nerve sonography and MRI should be performed; and (iv) For demyelinated hereditary neuropathy, genetic diagnostics should first address PMP22 gene deletion: once that has been excluded, massive parallel sequencing including an analysis of relevant CMT-genes should be performed. This article contains a short version of the guidelines. The full-length text (in German) can be found at the Website of the "Arbeitsgemeinschaft der Wissenschftlichen Medizinischen Fachgesellschaften e.V. (AWMF), Germany.
CRIS-Team WoS Importer:2021-09-03

Differential Diagnosis of Acute Scrotum in Childhood and Adolescence with High-Resolution Duplex Sonography - Deeg, Karl-Heinz (Ultraschall in der Medizin, 2021)
Acute testicular pain in childhood can be caused by testicular torsion, torsion of the appendix testis, or epididymo-orchitis. Quick and reliable diagnosis is essential for determining the further course of action (surgery or conservative approach). The diagnostic tool of choice is high- resolution sonography with a linear transducer (> 10MHz) combined with color and spectral Doppler sonography. The Doppler device settings should include a low pulse repetition frequency (< 4 cm/s), a low wall filter (< 100 Hz), and adequate gain. Comparison with the unaffected healthy testis is essential. The most important of the three diseases is torsion of the spermatic cord because it requires immediate surgical intervention and detorsion. The affected testis is enlarged and has an inhomogeneous echotexture with hypoechoic and hyperechoic areas as well as an associated hydrocele. In testicular torsion, color Doppler shows reduced or absent intratesticular vessels in comparison with the healthy contralateral testis. Spectral Doppler shows decreased flow velocities especially during diastole in intratesticular arteries and an increased resistance index. The investigation should always include imaging of the spermatic cord from the outer inguinal ring to the upper pole of the testis. In contrast to a normal finding, the vessels and the ductus deferens are not displayed as linear tubular structures but in form of a spiral twist. Ultrasound shows a targetlike structure with multiple concentric rings. Color Doppler sonography shows the typical whirlpool sign. In torsion of the appendix testis, the appendix testis is enlarged in the groove between the testis and epididymis. The longitudinal diameter of the appendix testis can be greater than 5 mm. The echogenicity of the torsed appendage can vary between hypoechoic (acute torsion) and hyperechoic (prior torsion). An associated hydrocele of varying size is usually seen. Color Doppler sonography reveals a lack of perfusion of the enlarged appendix testis and increased vascularity of the testis and primarily the epididymis. Epididymo-orchitis is characterized by an enlarged epididymis and/or testis with inhomogeneous echogenicity ( hypoechoic - hyperechoic). Color Doppler sonography shows increased vascularity in comparison with the unaffected testis. Spectral Doppler reveals increased diastolic flow velocities and a decreased resistance index. Idiopathic scrotal edema and an incarcerated inguinal hernia must be ruled out in the differential diagnosis.
CRIS-Team WoS Importer:2021-03-19

Differential effects of low birthweight and intrauterine growth restriction on umbilical cord blood insulin-like growth factor concentrations - Tzschoppe, Anja; Riedel, Christina; Von Kries, Ruediger; Struwe, Ellen; Rascher, Wolfgang; Dörr, Helmuth-Günther; Beckmann, Matthias; Schild, Ralf L.; Goecke, Tamme W.; Flyvbjerg, Allan; Frystyk, Jan; Doetsch, Joerg (Clinical Endocrinology, 2015)
Alterations in the growth hormone-insulin-like growth factor (IGF) axis have been considered as a causal factor for intrauterine growth restriction (IUGR) and for the increased risk of metabolic disease in later life. We compared members of the IGF axis in umbilical cord blood between IUGR neonates, small for gestational age without foetal restriction (SGA) and appropriate for gestational age (AGA) neonates.Prospective controlled multicenter study.Sixteen ultrasound-proven IUGR, 8 SGA and 40 AGA neonates.Concentrations of total IGF-I and total IGF-II by immunoassays, bioactive IGF by cell-based bioassay and IGFBP-I in mixed venous and arterial umbilical cord blood samples at birth. Auxological parameters at birth.IGF-I concentrations in IUGR [17·7 ?g/l (CI 13·8;21·6)] were clearly below those in AGA [48·3 ?g/l (CI 43·7;52·9)] and SGA neonates [36·0 ?g/l (CI 26·6;45·4)]. IGF-II levels were significantly reduced in IUGR [201·4 ?g/l (CI 190·2;212·6)] compared to AGA neonates [231·2 ?g/l (CI 220·6;241·9)]. A trend for lower IGF-II concentrations was observed in IUGR when compared to SGA neonates [232·0 ?g/l (CI 207·2;256·8)]. These differences could not be explained by confounding. For IGFBP-1, a trend towards higher values in IUGR was observed.Low IGF-I cord blood concentrations in hypotrophic neonates after IUGR might not only result from low birthweight per se, but also reflect prenatal placental environment. Alterations of the IGF axis could be in the causal pathway of IUGR and thus constitute a potential surrogate marker for IUGR in the assessment of foetal programming.
EVALuna2:17440

DIFFERENT RESPONSE PATTERN TO AIRCRAFT NOISE EXPOSURE IN RENAL VERSUS SYSTEMIC HEMODYNAMIC - Bosch, Agnes; Ott, C.; Kannenkeril, Dennis; Harazny, J. M.; Striepe, Kristina; Karg, M.; Dienemann, T.; Jung, Susan; Schmieder, Roland (2018)
EVALuna2:202964

Diffuse Encephalopathy Associated with Isolated Cerebral Langerhans Cell Histiocytosis - Rompel, Oliver; Buslei, Rolf; Hammon, Matthias; Dörr, Helmuth-Günther; Chada, Martin; Nikkhah, Guido; Uder, Michael; Trollmann, Regina (Pediatric Neurology, 2016)
Langerhans cell histiocytosis is a rare disease of the monocyte-macrophage system. Abnormalities of the hypothalamic-pituitary region are common in individuals with central nervous system involvement.This six-year-old boy developed rapidly progressive aggressive behavior, central diabetes insipidus, and repeated complex partial seizures. Magnetic resonance imaging revealed a diffuse leukoencephalopathy-like pattern and numerous infratentorial and supratentorial granulomatous nodules in the brain parenchyma along with infundibular and hypothalamic mass lesions. Stereotactic serial biopsies enabled histopathologic and immunohistochemical diagnosis of Langerhans cell histiocytosis.Similar MRI findings have rarely been described in the literature. These findings represent part of the broad neuroradiological spectrum of Langerhans cell histiocytosis of the nervous system in children.
EVALuna2:7341

Digital Workout Versus Team Training: The Impact of the COVID-19 Pandemic on Athletes. - Schneider, Friedemann; Runer, Armin; Burkert, Francesco; Und Aspang, Jesse Seilern; Reider, Simone; Schneider, Holm; Pocecco, Elena (Sports Medicine International Open, 2022)
The aim of the study was to assess the effects of the COVID-19 pandemic on sport practice and to identify measures adopted by individuals and sports organizations to allow a safe return to community sports. An electronic survey was launched worldwide in June 2020 in the German and English languages. The questionnaire collected anonymous data on sporting activity before, during, and after pandemic-induced confinement. Participants classified themselves as either recreational, competitive, or professional sports level athletes. A total of 1336 adults (30.5±11.7 years; 54.0% women) participated in the survey; 68.5% were active athletes, 10.1% coaches, 2.1% officials and 4.3% related medical staff, 3.6% had another function, and 11.4% indicated no regular sports activity. Most participants practiced their sport in Europe (93.8%); the majority (61.0%) was amateur athletes. During confinement, 15.7% could perform their main sport unrestricted, 43.5% stated a reduced amount of time spent on sporting activities, 46.4% a reduced intensity level. Most participants (77.5%) were neither aware of screening measures nor of guidelines for dealing with infected athletes (80.0%) or for return to sports after a coronavirus infection (88.6%). Preventive measures mentioned included basic hygiene, measures to reduce personal contacts or virus transmission, or to improve traceability of infections. During confinement, a higher age (p=0.004) and training in a club setting (p<0.001) were associated with reduced sporting activity, while the availability of online training (p=0.030 ) was linked to both increased extent and intensity levels. A lower age (p=0.001) and recreational sports level (p=0.005) were associated with decreased activity after confinement. Although isolation can be necessary to protect public health, it alters the amount and intensity of physical activity.
EVALuna2:514670

Diminished protein-bound ω-hydroxylated ceramides in the skin of patients with ichthyosis with 12R-lipoxygenase (LOX) or eLOX-3 deficiency - Dick, A.; Tantcheva-Poor, I. .; Oji, V.; Giehl, K. A.; Fischer, J. .; Krieg, P.; Schneider, Holm; Rauh, Manfred (British Journal of Dermatology, 2017)
EVALuna2:34217

Direct and indirect costs and cost drivers of Tuberous sclerosis complex in children, adolescents, and caregivers: A multicenter cohort study - Zoellner, Johann Philipp; Grau, Janina; Schubert-Bast, Susanne; Kurlemann, Gerhard; Hertzberg, Christoph; Wiemer-Kruel, Adelheid; Bast, Thomas; Bertsche, Astrid; Bettendorf, Ulrich; Fiedler, Barbara; Hahn, Andreas; Hartmann, Hans; et al. (Epilepsia, 2021)
CRIS-Team WoS Importer:2021-11-26

Direct and indirect costs and cost-driving factors of Tuberous sclerosis complex in children, adolescents, and caregivers: a multicenter cohort study - Grau, Janina; Zollner, Johann Philipp; Schubert-Bast, Susanne; Kurlemann, Gerhard; Hertzberg, Christoph; Wiemer-Kruel, Adelheid; Bast, Thomas; Bertsche, Astrid; Bettendorf, Ulrich; Fiedler, Barbara; Hahn, Andreas; Hartmann, Hans; et al. (Orphanet Journal of Rare Diseases, 2021)
Background Tuberous sclerosis complex (TSC), a multisystem genetic disorder, affects many organs and systems, characterized by benign growths. This German multicenter study estimated the disease-specific costs and cost-driving factors associated with various organ manifestations in TSC patients. Methods A validated, three-month, retrospective questionnaire was administered to assess the sociodemographic and clinical characteristics, organ manifestations, direct, indirect, out-of-pocket, and nursing care-level costs, completed by caregivers of patients with TSC throughout Germany. Results The caregivers of 184 patients (mean age 9.8 +/- 5.3 years, range 0.7-21.8 years) submitted questionnaires. The reported TSC disease manifestations included epilepsy (92%), skin disorders (86%), structural brain disorders (83%), heart and circulatory system disorders (67%), kidney and urinary tract disorders (53%), and psychiatric disorders (51%). Genetic variations in TSC2 were reported in 46% of patients, whereas 14% were reported in TSC1. Mean total direct health care costs were EUR 4949 [95% confidence interval (95% CI) EUR 4088-5863, median EUR 2062] per patient over three months. Medication costs represented the largest direct cost category (54% of total direct costs, mean EUR 2658), with mechanistic target of rapamycin (mTOR) inhibitors representing the largest share (47%, EUR 2309). The cost of anti-seizure drugs (ASDs) accounted for a mean of only EUR 260 (5%). Inpatient costs (21%, EUR 1027) and ancillary therapy costs (8%, EUR 407) were also important direct cost components. The mean nursing care-level costs were EUR 1163 (95% CI EUR 1027-1314, median EUR 1635) over three months. Total indirect costs totaled a mean of EUR 2813 (95% CI EUR 2221-3394, median EUR 215) for mothers and EUR 372 (95% CI EUR 193-586, median EUR 0) for fathers. Multiple regression analyses revealed polytherapy with two or more ASDs and the use of mTOR inhibitors as independent cost-driving factors of total direct costs. Disability and psychiatric disease were independent cost-driving factors for total indirect costs as well as for nursing care-level costs. Conclusions This study revealed substantial direct (including medication), nursing care-level, and indirect costs associated with TSC over three months, highlighting the spectrum of organ manifestations and their treatment needs in the German healthcare setting. Trial registration: DRKS, DRKS00016045. Registered 01 March 2019,
CRIS-Team WoS Importer:2021-07-09

Disability Rating in Children and Adolescents with Chronic Myeloid Leukemia - Suttorp, Meinolf; Sembill, Stephanie; Metzler, Markus (Klinische Pädiatrie, 2020)
Background CML comprises only 2-3 % of all diagnosed pediatric leukemias. Mostly diagnosed in chronic phase (CML-CP), the disease progresses without treatment to accelerated phase (CML-AP) and finally to life-limiting blastic phase (CML-BP). Contrasting the therapy of other leukemia types, CML-CP is not treated by intense chemotherapy but with oral drugs - termed tyrosine kinase inhibitors (TKI)- for an unlimited duration. This therapy may be associated with general and developmental-specific side effects. The rarity of pediatric-CML is limiting the experience in assessment of the disability rating (DR) as an administrative health authority procedure.
CRIS-Team WoS Importer:2020-10-30

Discontinuous Galerkin-based approach to define orthotropic tissue structure in computational heart models - Holz, David; Duong, Minh Tuan; Martonová, Denisa; Alkassar, Muhannad; Leyendecker, Sigrid (conference, International Conference on Computational Biomechanics, 2021)

Disparate effects of the combined therapy of empagliflozin and linagliptin versus metformin and insulin glargine on renal haemodynamics in type 2 diabetes - Ott, Christian; Jung, Susan; Kannenkeril, Dennis; Striepe, Kristina; Bosch, Agnes; Korn, M.; Bramlage, P.; Schmieder, Roland (DIABETOLOGIA, 2019)
CRIS-Team WoS Importer:2019-10-11

DISPARATE NITRIC OXIDE ACTIVITY OF THE RETINAL CIRCULATION IN HYPERTENSIVE VS TYPE 2 DIABETES-PATIENTS - Kannenkeril, Dennis; Jung, Susan; Harazny, J. M.; Bosch, Agnes; Ott, Christian; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

Distinct pathways for genetic and epigenetic predisposition in familial and bilateral Wilms tumor - Wegert, Jenny; Appenzeller, Silke; Treger, Taryn D.; Streitenberger, Heike; Ziegler, Barbara; Bausenwein, Sabrina; Vokuhl, Christian; Parks, Conor; Jüttner, Eva; Gramlich, Susanne; Ernestus, Karen; Warman, Steven W.; et al. (Genome Medicine, 2025)
Background: Genetic predisposition is particularly common in children with the kidney cancer, Wilms tumor. In 10% of these children, this manifests as a family history of Wilms tumor or bilateral disease. The frequency and spectrum of underlying changes have not been systematically investigated. Methods: We analyzed 129 children with suspected Wilms tumor predisposition, 20 familial cases, and 109 children with bilateral disease, enrolled over 30 years in the German SIOP93-01/GPOH and SIOP2001 studies. We used whole exome, whole genome, and targeted DNA sequencing, together with MLPA and targeted methylation assays on tumor, blood, and normal kidney to determine predisposing changes. Results: Predisposing variants were identified in 117/129 children, comprising DNA variants (57%) and epigenetic changes (34%). Most children had predisposition variants in genes previously implicated in Wilms tumor: most prominently WT1 (n = 35) and less frequently TRIM28, REST, DIS3L2, CTR9, DICER1, CDC73, and NONO. Nine children carried germline mutations in cancer predisposition genes not considered Wilms tumor predisposition genes, such as CHEK2, CDKN2A, BLM, BRCA2, STK11, and FMN2. Predisposition via epigenetic BWS-IC1 alterations occurred as early somatic events, reflected by partial (mosaic) loss of imprinting or loss of heterozygosity at the IGF2/H19 locus in normal kidney or blood. These patients rarely had a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS). Especially WT1-driven tumors follow a stereotypical pathway of germline WT1 mutations becoming homozygous in renal precursor lesions through 11p LOH, which concomitantly activates imprinted IGF2 expression, with subsequent WNT pathway activation leading to tumor growth. There is a high rate of multicentric tumors, which may have previously been missed in unilateral tumors. While Wilms tumor predisposition genes relied on somatic inactivation of the second allele, this was different for general cancer predisposition genes. The latter cases were often associated with additional oncogenic alterations, similar to tumors with epigenetic predisposition. Conclusions: We identified two main mechanisms of Wilms tumor predisposition: either germline genetic alterations of Wilms tumor and, less frequently, general cancer genes; or postzygotic mosaic imprinting defects activating IGF2. These findings inform future genetic screening and risk assessment of affected children and lend support to liquid biopsy screening for enhanced therapeutic stratification.
CRIS-Team Scopus Importer:2025-05-16
Keywords: BWS; Cancer predisposition; Genomic imprinting; Hereditary cancer; Multicentric tumors; Nephroblastoma; Pediatric cancer; Wilms tumor; WT1

Distinct pattern of genomic breakpoints in CML and BCR::ABL1-positive ALL: analysis of 971 patients - Hovorkova, Lenka; Winkowska, Lucie; Skorepova, Justina; Krumbholz, Manuela; Benesova, Adela; Polivkova, Vaclava; Alten, Julia; Bardini, Michela; Meyer, Claus; Kim, Rathana; Trahair, Toby N.; Clappier, Emmanuelle; et al. (Molecular Cancer, 2024)
Background: The BCR::ABL1 is a hallmark of chronic myeloid leukemia (CML) and is also found in acute lymphoblastic leukemia (ALL). Most genomic breaks on the BCR side occur in two regions - Major and minor - leading to p210 and p190 fusion proteins, respectively. Methods: By multiplex long-distance PCR or next-generation sequencing technology we characterized the BCR::ABL1 genomic fusion in 971 patients (adults and children, with CML and ALL: pediatric ALL: n = 353; pediatric CML: n = 197; adult ALL: n = 166; adult CML: n = 255 patients) and designed “Break-App” web tool to allow visualization and various analyses of the breakpoints. Pearson’s Chi-Squared test, Kolmogorov-Smirnov test and logistic regression were used for statistical analyses. Results: Detailed analysis showed a non-random distribution of breaks in both BCR regions, whereas ABL1 breaks were distributed more evenly. However, we found a significant difference in the distribution of breaks between CML and ALL. We found no association of breakpoints with any type of interspersed repeats or DNA motifs. With a few exceptions, the primary structure of the fusions suggests non-homologous end joining being responsible for the BCR and ABL1 gene fusions. Analysis of reciprocal ABL1::BCR fusions in 453 patients showed mostly balanced translocations without major deletions or duplications. Conclusions: Taken together, our data suggest that physical colocalization and chromatin accessibility, which change with the developmental stage of the cell (hence the difference between ALL and CML), are more critical factors influencing breakpoint localization than presence of specific DNA motifs.
CRIS-Team Scopus Importer:2024-07-12
Keywords: ABL1; Acute lymphoblastic leukemia; BCR; Chronic myeloid leukemia; Genomic breakpoints

Distribution and Cytokine Profile of Peripheral B Cell Subsets Is Perturbed in Pediatric IBD and Partially Restored during a Successful IFX Therapy - Schnell, Alexander; Schwarz, Benedikt; Wahlbuhl, Mandy; Allabauer, Ida; Hess, Merlin; Weber, Simone; Werner, Felix; Schmidt, Hannah; Rechenauer, Tobias; Siebenlist, Gregor; Kaspar, Sonja; Ehrsam, Christoph; et al. (Inflammatory Bowel Diseases, 2021)
Background: The role of B cells in inflammatory bowel disease (IBD) is ambiguous, as B cells may have both pathogenic and protective functions in IBD. We studied B cell subsets before and after initiation of an anti-tumor necrosis factor alpha (anti-TNFα) therapy in pediatric IBD. The aim of the study was to examine the behavior of B cells in pediatric IBD patients undergoing an anti-TNFα therapy and, more specifically, to clarify their association with a successful or an unsuccessful infliximab (IFX) treatment. Methods: A total of N = 42 pediatric IBD patients (Crohn disease, n = 30; ulcerative colitis, n = 12) for whom an anti-TNFα therapy with and without a concomitant azathioprine (AZA) medication was administered were recruited. Fourteen healthy age-matched children served as control patients. Blood samples were collected before initiation of the anti-TNFα therapy, before the fourth infusion at the end of the induction phase, and after 6 and 12 months under therapy maintenance. Flow cytometry (CD20, CD27, CD38, CD138) and intracellular staining (interleukin 10 [IL10], TNFα, granzyme B) were performed. Responders to successful IFX therapy were classified exhibiting a fecal calprotectin level of below 100 μg/g or achieving levels of <10% of the baseline value at initiation than at the end of the 12-month follow-up period. Results: Before initiation of anti-TNFα therapy, flow cytometry revealed increased percentages of naïve B cells whereas transitional B cells were reduced compared with those in the healthy control patients. The IL10-producing B cells of both ulcerative colitis and Crohn disease patients were reduced at the initiation of IFX therapy, whereas TNFα-producing transitional CD24hiCD38hi B cells in ulcerative colitis patients were increased compared with those in healthy control patients. After 12 months of therapy, we detected a significant increase of IL10-producing transitional B cells in responding patients. The IFX trough levels in the responding patients showed a significant increase until 6 months after IFX initiation, attaining mean values of 9.9 μg/mL, whereas the IFX dosage was significantly lower than that in the nonresponding patients. The IFX trough levels in AZA-treated patients reached earlier therapeutic levels than in patients without AZA comedication, whereas during the course of the IFX therapy, comedication with AZA had no significant effect on the outcome. Conclusions: Attaining a normalization of IL10 production among CD24hiCD38hi B cells after 12 months of therapy may represent additional information about the reconstitution of a patient's immune system in responding patients. The achievement of an IFX trough level of 10 μg/mL at 6 months of treatment is associated with a successful anti-TNFα therapy. In addition, AZA comedication supports an earlier achievement of therapeutic IFX trough levels.
CRIS-Team Scopus Importer:2021-02-26
Keywords: children; Crohn disease; TNFα inhibitor; transitional B cells; ulcerative colitis

Distribution of BCR::ABL1 Transcript Types and Response to Therapy in Pediatric Patients with Chronic Myeloid Leukemia - Seiser, Esra; Behrens, Yvonne L.; Lukat, Sabine; Sembill, Stephanie; Karow, Axel; Suttorp, Meinolf; Metzler, Markus; Krumbholz, Manuela (Journal of Molecular Diagnostics, 2025)
Achieving a stable deep molecular response with the option to discontinue tyrosine kinase inhibitor treatment is the new therapeutic goal for patients with chronic myeloid leukemia (CML). Several studies have shown that individuals expressing the BCR::ABL1 e14a2 transcript achieve a major molecular response more rapidly than those with the e13a2 transcript. However, technical issues may have confounded these observations, and data for pediatric patients are limited. This study analyzed the distribution of BCR::ABL1 transcript types and their association with baseline hematologic parameters and tyrosine kinase inhibitor treatment response in 102 pediatric patients with CML. Subgroups were compared on the basis of results from routine multiplex PCR and droplet digital PCR (ddPCR). The dynamics of the transcript types under therapy were evaluated in detail in patients and a CML cell line co-expressing e13a2 + e14a2. ddPCR has identified significantly more patients co-expressing e13a2 + e14a2 than classified on the basis of routine diagnostics. This has implications for the categorization of individual subgroups. Comparing transcript dynamics in individuals or a cell line expressing both variants simultaneously revealed no differences in treatment response. When analyzing clinical data based on the transcript classification of patients, it is important to use methods that detect both variants with equal sensitivity. In ddPCR, the transcript variants' ratio is accurately shown because there is no competitive template amplification, as seen in multiplex and quantitative real-time PCR.
CRIS-Team Scopus Importer:2025-02-28

Diving into the Digital Landscape: Assessing the Quality of Online Information on Neonatal Jaundice for Parents - Baumgartner, Michael; Behr, Anna Lena; Garbe, Anne Christina; Quatember, Christoph; Reutter, Heiko Martin; Wölfle, Joachim; Fahlbusch, Fabian Benedikt; Hanslik, Gregor (Children, 2024)
Background: Hyperbilirubinemia is a common condition in newborns. While mild cases of jaundice are common and typically resolve spontaneously, severe hyperbilirubinemia can lead to serious neurologic complications if left untreated. With the constant adaptation of guidelines, clinical management has significantly improved, and treatment has become routine for pediatricians. However, for parents of affected children, managing the condition is not routine. In today’s digital age, parents often seek additional information by accessing a wide range of medical resources on the internet. While this can be empowering, it also presents challenges, as the quality and accuracy of online medical information can vary widely. Therefore, we analyzed the current quality of information on jaundice found on the internet by parents. Methods: A simulated internet search (using the Google search engine) was conducted from a layperson’s perspective using German (“Neugeborenes Gelbsucht”, “Baby Gelbsucht”) and English (“jaundice newborn”, “jaundice baby”) search terms. Subsequently, the quality of the search results was assessed by two independent neonatologists based on the DISCERN Plus Score, HONcode certification, and the JAMA criteria. Results: Websites targeting non-medical laypersons exhibited significant variability in quality. Notably, the content of English websites was superior to that of websites in the German language. The majority of English sites were predominantly institutional, whereas most German sites were commercially oriented. Conclusions: Although information on jaundice is readily accessible online for non-medical individuals, there were notable differences in quality based on language and significant variability in the quality of information warranting attention from healthcare professionals. Furthermore, German websites providing information on jaundice were often hosted by commercial organizations. We propose that pediatric societies engage in developing and maintaining organization-based medical information to improve online resources for parents.
CRIS-Team Scopus Importer:2024-08-02
Keywords: jaundice; neonatal care; online information

DMBT1 expression and neutrophil-to-lymphocyte ratio during necrotizing enterocolitis are influenced by impaired perfusion due to cardiac anomalies. - Diez, Sonja; Besendörfer, Manuel; Weyerer, Veronika; Hartmann, Arndt; Moosmann, Julia; Weiss, Christel; Renner, Marcus; Müller, Hanna (Molecular and Cellular Pediatrics, 2022)
BACKGROUND: Deleted in malignant brain tumors 1 (DMBT1) is involved in innate immunity and epithelial differentiation. It has been proven to play a role in various states of inflammation or hypoxia of fetal gastrointestinal and pulmonary diseases. Discrimination of pathogenesis in necrotizing enterocolitis (NEC) based on cardiac status improves the understanding of NEC in different patient subgroups. We aimed at examining DMBT1 expressions regarding their association with cardiac status leading to impaired intestinal perfusion, intraoperative bacteria proof, and a fulminant course of NEC. METHODS: Twenty-eight patients with NEC were treated surgically between 2010 and 2019 at our institution. DMBT1 expression was examined in intestinal sections using immunohistochemistry to detect DMBT1 protein. Associations of clinical parameters and DMBT1 expression were analyzed. RESULTS: We examined DMBT1 levels in 10 patients without cardiac defects and 18 patients with persisting ductus arteriosus (PDA) and congenital heart defects (CHD). Compared to patients without cardiac malformations, DMBT1 levels tended to score higher in patients with PDA/CHD (p = 0.2113) and were negatively correlated with C-reactive protein in these infants (p = 0.0172; r = - 0.5533). The number of DMBT1-expressing macrophages was elevated in the PDA/CHD-subgroup (p = 0.0399). Ratios of neutrophils and monocytes to lymphocytes were significantly higher in infants with PDA/CHD (p = 0.0319 and 0.0493). DMBT1 expression was significantly associated with positive bacterial culture of intraoperative swabs (p = 0.0252) and DMBT1 expression of the serosa was associated with a fulminant course of NEC (p = 0.0239). CONCLUSIONS: This study demonstrates that DMBT1 expression may be influenced by cardiac anomalies with an impaired intestinal perfusion in the neonatal intestine. NEC in PDA/CHD infants is associated with more DMBT1-positive macrophages and a significantly elevated neutrophil-to-lymphocyte ratio.
EVALuna2:497662
Keywords: DMBT1; Deleted in malignant brain tumors 1; Necrotizing enterocolitis; Congenital heart disease; Neutrophil-to-lymphocyte ratio; Monocyte-to-lymphocyte ratio

DMBT1 is upregulated in cystic fibrosis, affects ciliary motility, and is reduced by acetylcysteine - Kiefer, Alexander; Plattner, Erika; Ruppel, Renate; Weiss, Christel; Zhou-Suckow, Zhe; Mall, Marcus; Renner, Marcus; Müller, Hanna (Molecular and Cellular Pediatrics, 2022)
Background: Cystic fibrosis (CF) is the most common genetic disorder in the Caucasian population. Despite remarkable improvements in morbidity and mortality during the last decades, the disease still limits survival and reduces quality of life of affected patients. Moreover, CF still represents substantial economic burden for healthcare systems. Inflammation and infection already start in early life and play important roles in pulmonary impairment. The aim of this study is to analyze the potential role of DMBT1, a protein with functions in inflammation, angiogenesis, and epithelial differentiation, in CF. Results: Immunohistochemically DMBT1 protein expression was upregulated in lung tissues of CF patients compared to healthy controls. Additionally, pulmonary expression of Dmbt1 was approximately 6-fold increased in an established transgenic mouse model of CF-like lung disease (ENaC tg) compared to wild-type mice as detected by qRT-PCR. Since acetylcysteine (ACC) has been shown to reduce inflammatory markers in the airways, its potential influence on DMBT1 expression was analyzed. A549 cells stably transfected with an expression plasmid encoding the largest (8kb) DMBT1 variant (DMBT1+ cells) or an empty vector control (DMBT1- cells) and incubated with ACC both showed significantly reduced DMBT1 concentrations in the culture medium (p = 0.0001). To further elucidate the function of DMBT1 in pulmonary airways, respiratory epithelial cells were examined by phase contrast microscopy. Addition of human recombinant DMBT1 resulted in altered cilia motility and irregular beat waves (p < 0.0001) suggesting a potential effect of DMBT1 on airway clearance. Conclusions: DMBT1 is part of inflammatory processes in CF and may be used as a potential biomarker for CF lung disease and a potential tool to monitor CF progression. Furthermore, DMBT1 has a negative effect on ciliary motility thereby possibly compromising airway clearance. Application of ACC, leading to reduced DMBT1 concentrations, could be a potential therapeutic option for CF patients.
CRIS-Team Scopus Importer:2022-03-18
Keywords: Acetylcysteine; Ciliary motility; Cystic fibrosis; DMBT1; Inflammation

DMBT1 is upregulated in lung epithelial cells after hypoxia and changes surfactant ultrastructure - Müller, Hanna; Schmiedl, Andreas; Weiss, Christel; Ai, Maria; Jung, Susan; Renner, Marcus (Pediatric Pulmonology, 2020)
Background: Hypoxia and asphyxia are known to induce surfactant inactivation in newborns. Deleted in Malignant Brain Tumors 1 (DMBT1) is an innate immunity protein with functions in epithelial differentiation and angiogenesis. It was detected in hyaline membranes of infants with respiratory distress syndrome. Human recombinant DMBT1 is able to increase the surface tension of exogenous surfactant preparations in a dose-dependent manner. Methods: Immunohistochemistry was performed on lung sections of infants who died due to pre-, peri- or postnatal hypoxia. The lung epithelial cell line A549 was stably transfected with a DMBT1 (DMBT1+ cells) expression plasmid or with an empty plasmid (DMBT1− cells). The cells were cultured in normoxic or hypoxic conditions, and then DMBT1 as well as HIF-1α RNA expression were analyzed by using real-time-polymerase chain reaction. Human recombinant DMBT1 was added to the modified porcine natural surfactant Curosurf to examine the effect of DMBT1 on surfactant ultrastructure with electron microscopy. Results: DMBT1 expression was upregulated in human lung tissue after fetal/peri-/postnatal hypoxia. In addition, in vitro experiments showed increased DMBT1 RNA expression in A549 cells after hypoxia. HIF-1α was upregulated in both DMBT1+ and DMBT1− cells in response to hypoxia. The addition of human recombinant DMBT1 to Curosurf caused an impaired surfactant ultrastructure. Conclusions: DMBT1 is upregulated in response to hypoxia and there seems to be a link between hypoxia and surfactant inactivation.
CRIS-Team Scopus Importer:2020-08-28
Keywords: DMBT1; hypoxia; lung epithelial cells; surfactant

DNA copy number alterations mark disease progression in paediatric chronic myeloid leukaemia - Van Der Sligte, Naomi E.; Krumbholz, Manuela; Pastorczak, Agata; Scheijen, Blanca; Tauer, Josephine T.; Nowasz, Christina; Sonneveld, Edwin; De Bock, Geertruida H.; Meeuwsen-De Boer, Tiny G. J.; Van Reijmersdal, Simon; Kuiper, Roland P.; Bradtke, Jutta; et al. (British Journal of Haematology, 2014)
Early recognition of children with chronic phase chronic myeloid leukaemia (CML-CP) at risk for developing a lymphoid blast crisis (LyBC) is desirable, because therapy options in CML-LyBC are limited. We used Multiplex Ligation-dependent Probe Amplification to determine whether B-cell lymphoid leukaemia-specific copy number alterations (CNAs) (e.g. IKZF1, PAX5, CDKN2A deletions) could be detected in CML-CP and may be used to predict disease progression to LyBC. CNAs were detected in all patients with CML-LyBC, but in none of the 77 patients with CML-CP. Based on this study we conclude that CNAs remain a hallmark of disease progression.
EVALuna2:18891

DNA methylation and transcription in HERV (K, W, E) and LINE sequences remain unchanged upon foreign DNA insertions - Weber, Stefanie; Jung, Susan; Dörfler, Walter (Epigenomics, 2016)
DNA methylation and transcriptional profiles were determined in the regulatory sequences of the human endogenous retroviral (HERV-K, -W, -E) and LINE-1.2 elements and were compared between non-transgenomic and plasmid-transgenomic cells.DNA methylation profiles in the HERV (K, W, E) and LINE sequences were determined by bisulfite genomic sequencing. The transcription of these genome segments was assessed by quantitative real-time PCR.In HERV-K, HERV-W and LINE-1.2 the levels of DNA methylation ranged between 75 and 98%, while in HERV-E they were around 60%. Nevertheless, the HERV and LINE-1.2 sequences were actively transcribed. No differences were found in comparisons of HERV and LINE-1.2 CpG methylation and transcription patterns between non-transgenomic and plasmid-transgenomic HCT116 cells.The insertion of a 5.6 kbp plasmid into the HCT116 genome had no effect on the HERV and LINE-1.2 methylation and transcription profiles, although other parts of the HCT116 genome had shown marked changes. These repetitive sequences are transcribed, probably because the large number of HERV and LINE-1.2 elements harbor copies with non- or hypo-methylated long terminal repeat sequences.
EVALuna2:8330

Do the exome: A case of Williams-Beuren syndrome with severe epilepsy due to a truncating de novo variant in GABRA1 - Popp, Bernt; Trollmann, Regina; Büttner, Christian; Caliebe, Almuth; Thiel, Christian; Hüffmeier, Ulrike; Reis, André; Zweier, Christiane (European Journal of Medical Genetics, 2016)
Williams-Beuren syndrome (WBS) is a relatively common, clinically recognizable microdeletion syndrome. In most cases the typical heterozygous deletion of 1.5 Mb on chromosome 7q11.23 spanning about 26 genes can be identified. Also some larger or smaller atypical deletions have been reported and associated with additional or atypical phenotypic aspects. We report on an individual with typical WBS due to the common deletion and with refractory infantile spasms. Using trio-exome sequencing, we identified a de novo truncating variant c.1200del, p (Lys401Serfs*25) in GABRA1 as the likely cause of the early onset epilepsy. This unique case not only allows to further define the phenotypic spectrum of infantile epileptic encephalopathy associated with rare de novo GABRA1 variants but exemplifies the need for a sensitive review of unclear associations in clinically defined syndromes and for extended diagnostic work-up in individuals with unusual presentations of a genetically confirmed diagnosis.
EVALuna2:9310

Drug Utilisation and Off-Label Use on a German Neonatal Intensive Care Unit: A Retrospective Cohort Study and 10-Year Comparison - Geißler, Carmen; Schulze, Christopher; Botzenhardt, Sebastian; Rascher, Wolfgang; Neubert, Antje (Pharmacy, 2020)
Pharmacotherapy of neonates is complex and marked to a large extent of off-label use. The implementation of the Paediatric Regulation (2007) gave hope for a change in the safety and efficacy for drugs used in neonatal intensive care units (NICU). This study investigates drug utilisation patterns and off-label use in a German neonatal intensive care unit (NICU) in 2014. A 12-months retrospective, observational cohort study was performed at the NICU of the University Children's Hospital Erlangen, Germany. Licensing status was determined using the Summary of Product Characteristics (SmPC). Results are compared with a similar study conducted 10 years earlier. The study included 204 patients (57.8% male) (2004: 183) and 2274 drug prescriptions were recorded (2004: 1978). The drugs that were mostly prescribed were drugs for the nervous system (2004: 22.6%; 2014: 26.9%) and anti-infectives for systemic use (2004: 26.0%; 2014: 24.9%);34.3% (2004) and 39.2% (2014) of all prescriptions were off-label;62.7% of all patients received at least one off-label or unlicensed drug (2004: 70%). For 13 drugs, the licensing status changed either from off-label to label (n = 9) or vice versa (n = 4). Overall, there was no significant change neither in terms of the drugs used nor regarding their licensing status. Further studies are needed to validate these findings in a European context.
CRIS-Team WoS Importer:2020-10-30

Drug utilisation on a preterm and neonatal intensive care unit in Germany: A prospective, cohort-based analysis - Neubert, Antje; Lukas, Kristin; Leis, Thomas; Dormann, Harald; Brune, Kay; Rascher, Wolfgang (European Journal of Clinical Pharmacology, 2010)
Purpose: This study aims to describe the drug use on a Neonatal Intensive Care Unit (NICU) at a University Children's Hospital in Germany, to investigate the licensing status of the drugs used and to conclude critical areas in neonatal intensive care to support prioritisation of future research. Methods: An 11-month, prospective cohort study was conducted on the NICU at the University Children's Hospital Erlangen, Germany. All products prescribed during the study period were analysed whether or not the SPC contains information on term and preterm neonates. Results: A total of 183 patients (102 male) with a mean gestational age of 33.6 weeks (minimum=24, maximum=42) were included. The mean length of hospitalisation was 19.4 days (minimum=2, maximum=167). On average, patients received 11.1 drugs (minimum=0, maximum=46). The majority of prescriptions were accounted for by antibiotics (n=515), which were received by 90% of all patients, followed by CNS drugs (n=448) and respiratory drugs (n=306). Of all the different drugs prescribed (n=102) only 38% had information regarding their use in patients aged less than 1 month in their SPC. Analgesics and cardiovascular drugs were prescribed frequently, but without having information for use in neonates. Seventy percent of all patients and 100% of very preterm infants received at least one of these drugs. Conclusions: Treatment strategies on a preterm intensive care unit are complex and little information is available for the drugs used. Analgesics and cardiovascular drugs are of major concern. Efforts will have to be made to conduct well-designed and powered studies in this vulnerable population. © 2009 Springer-Verlag.
CRIS-Team Scopus Importer:2025-02-03
Keywords: Drug utilisation; Neonatal intensive care unit; Neonates; Off-label; Preterm; Unlicensed

Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy with Severe Intercalated Disc Derangement in Humans and in Knock-In Mice - Herrmann, Harald; Cabet, Eva; Chevalier, Nicolas R.; Moosmann, Julia; Schultheis, Dorothea; Haas, Jan; Schowalter, Mirjam; Berwanger, Carolin; Weyerer, Veronika; Agaimy, Abbas; Meder, Benjamin; Müller, Oliver J.; et al. (Circulation, 2020)
Background: Mutations in the human desmin gene cause myopathies and cardiomyopathies. This study aimed to elucidate molecular mechanisms initiated by the heterozygous R406W-desmin mutation in the development of a severe and early-onset cardiac phenotype. Methods: We report an adolescent patient who underwent cardiac transplantation as a result of restrictive cardiomyopathy caused by a heterozygous R406W-desmin mutation. Sections of the explanted heart were analyzed with antibodies specific to 406W-desmin and to intercalated disc proteins. Effects of the R406W mutation on the molecular properties of desmin were addressed by cell transfection and in vitro assembly experiments. To prove the genuine deleterious effect of the mutation on heart tissue, we further generated and analyzed R405W-desmin knock-in mice harboring the orthologous form of the human R406W-desmin. Results: Microscopic analysis of the explanted heart revealed desmin aggregates and the absence of desmin filaments at intercalated discs. Structural changes within intercalated discs were revealed by the abnormal organization of desmoplakin, plectin, N-cadherin, and connexin-43. Next-generation sequencing confirmed the DES variant c.1216C>T (p.R406W) as the sole disease-causing mutation. Cell transfection studies disclosed a dual behavior of R406W-desmin with both its integration into the endogenous intermediate filament system and segregation into protein aggregates. In vitro, R406W-desmin formed unusually thick filaments that organized into complex filament aggregates and fibrillar sheets. In contrast, assembly of equimolar mixtures of mutant and wild-type desmin generated chimeric filaments of seemingly normal morphology but with occasional prominent irregularities. Heterozygous and homozygous R405W-desmin knock-in mice develop both a myopathy and a cardiomyopathy. In particular, the main histopathologic results from the patient are recapitulated in the hearts from R405W-desmin knock-in mice of both genotypes. Moreover, whereas heterozygous knock-in mice have a normal life span, homozygous animals die at 3 months of age because of a smooth muscle-related gastrointestinal phenotype. Conclusions: We demonstrate that R406W-desmin provokes its severe cardiotoxic potential by a novel pathomechanism, where the concurrent dual functional states of mutant desmin assembly complexes underlie the uncoupling of desmin filaments from intercalated discs and their structural disorganization.
CRIS-Team Scopus Importer:2020-12-11
Keywords: cardiomyopathies; desmin; desmosomes; intermediate filaments; intestinal pseudo-obstruction; muscle; smooth; muscle; striated

Dual pathways to endochondral osteoblasts: a novel chondrocyte-derived osteoprogenitor cell identified in hypertrophic cartilage - Park, Jung; Gebhardt, Matthias; Golovchenko, Svitlana; Perez-Branguli, Francesc; Hattori, Takako; Hartmann, Christine; Zhou, Xin; Decrombrugghe, Benoit; Stock, Michael; Schneider, Holm; Mark, Klaus (Biology Open, 2015)
According to the general understanding, the chondrocyte lineage terminates with the elimination of late hypertrophic cells by apoptosis in the growth plate. However, recent cell tracking studies have shown that murine hypertrophic chondrocytes can survive beyond "terminal" differentiation and give rise to a progeny of osteoblasts participating in endochondral bone formation. The question how chondrocytes convert into osteoblasts, however, remained open. Following the cell fate of hypertrophic chondrocytes by genetic lineage tracing using BACCol10;Cre induced YFP-reporter gene expression we show that a progeny of Col10Cre-reporter labelled osteoprogenitor cells and osteoblasts appears in the primary spongiosa and participates - depending on the developmental stage - substantially in trabecular, endosteal, and cortical bone formation. YFP(+) trabecular and endosteal cells isolated by FACS expressed Col1a1, osteocalcin and runx2, thus confirming their osteogenic phenotype. In searching for transitory cells between hypertrophic chondrocytes and trabecular osteoblasts we identified by confocal microscopy a novel, small YFP(+)Osx(+) cell type with mitotic activity in the lower hypertrophic zone at the chondro-osseous junction. When isolated from growth plates by fractional enzymatic digestion, these cells termed CDOP (chondrocyte-derived osteoprogenitor) cells expressed bone typical genes and differentiated into osteoblasts in vitro. We propose the Col10Cre-labeled CDOP cells mark the initiation point of a second pathway giving rise to endochondral osteoblasts, alternative to perichondrium derived osteoprogenitor cells. These findings add to current concepts of chondrocyte-osteocyte lineages and give new insight into the complex cartilage-bone transition process in the growth plate.
EVALuna2:10200

Dual source computed tomography in patients with congenital heart disease - Ihlenburg, Katharina Susanne; Rompel, Oliver; Rueffer, Andre; Purbojo, Ariawan; Cesnjevar, Robert; Dittrich, Sven; Glöckler, Martin (Thoracic and Cardiovascular Surgeon, 2014)
The objective of this study was to review our early experience with the dual source computed tomography (DSCT), a recently available scanner technique equipped with two X-ray tubes and two detectors, in the context of congenital cardiac malformations.We reviewed 40 pediatric patients with congenital heart disease (CHD) who underwent DSCT between September 2009 and December 2011 as diagnostic imaging tool for surgical procedures.The median age was 0.36 years (range: 3 days to 44 years). Great vessels (n = 13), cardiac anatomy (n = 13), trachea and vascular rings (n = 7), pulmonary veins (n = 4), and coronary arteries (n = 3) were focused on, which revealed important information for surgery. Scanning quality was affected in only two cases (metal artifacts and tachycardia). Overall median age-specific dose was 1.47 mSv. In patients younger than 1 year (n = 26), median dose was 1.28 mSv.DSCT allows a very rapid scan speed, examinations are performed in spontaneously breathing patients, and the radiation exposure is relatively low. It is very valuable in the setting of complex surgery by revealing the position of anatomical structures in their relation to each other. Missing information can be acquired less invasively in addition to echocardiography and might replace cardiac catheterization for several morphological indications.
EVALuna2:14356

Dual-source computed tomography of the lung with spectral shaping and advanced iterative reconstruction: potential for maximum radiation dose reduction - Wetzl, Matthias; May, Matthias; Weinmann, Daniel; Hammon, Matthias; Treutlein, Christoph; Zeilinger, Martin; Kiefer, Alexander; Trollmann, Regina; Wölfle, Joachim; Uder, Michael; Rompel, Oliver (Pediatric Radiology, 2020)
Background: Radiation dose at CT should be as low as possible without compromising diagnostic quality. Objective: To assess the potential for maximum dose reduction of pediatric lung dual-source CT with spectral shaping and advanced iterative reconstruction (ADMIRE). Materials and methods: We retrospectively analyzed dual-source CT acquisitions in a full-dose group (FD: 100 kV, 64 reference mAs) and in three groups with spectral shaping and differing reference mAs values (Sn: 100 kV, 96/64/32 reference mAs), each group consisting of 16 patients (age mean 11.5 years, standard deviation 4.8 years, median 12.8 years, range 1.3–18 years). Advanced iterative reconstruction of images was performed with different strengths (FD: ADMIRE Level 2; Sn: ADMIRE Levels 2, 3 and 4). We analyzed dose parameters and measured noise. Diagnostic confidence and detectability of lung lesions as well as anatomical structures were assessed using a Likert scale (from 1 [unacceptable] to 4 [fully acceptable]). Results: Compared to full dose, effective dose was reduced to 16.7% in the Sn 96 group, 11.1% in Sn64, and 5.5% in Sn32 (P<0.001). Noise values of Sn64ADM4 did not statistically differ from those in FDADM2 (45.7 vs. 38.9 Hounsfield units [HU]; P=0.132), whereas noise was significantly higher in Sn32ADM4 compared to Sn64ADM4 (61.5 HU; P<0.001). A Likert score >3 was reached in Sn64ADM4 regarding diagnostic confidence (3.2) and detectability of lung lesions (3.3). For detectability of most anatomical structures, no significant differences were found between FDAM2 and Sn64ADM4 (P≥0.05). Conclusion: In pediatric lung dual-source CT, spectral shaping together with ADMIRE 4 enable radiation dose reduction to about 10% of a full-dose protocol while maintaining an acceptable diagnostic quality.
CRIS-Team Scopus Importer:2020-06-26
Keywords: Adolescents; Advanced iterative reconstruction; Children; Dual-source computed tomography; Lung; Radiation dose reduction; Spectral shaping; Tin prefiltration

Dynamic reference intervals for coagulation parameters from infancy to adolescence - Weidhofer, Christina; Meyer, Elias; Ristl, Robin; Wiedemann, Helmut; Cadamuro, Janne; Kipman, Ulrike; Zierk, Jakob; Male, Christoph; Quehenberger, Peter; Haschke-Becher, Elisabeth; Einwallner, Elisa (Clinica Chimica Acta, 2018)
INTRODUCTION: Practical and ethical challenges as well as time and costs have restricted the generation of pediatric reference intervals. Therefore, pediatric reference intervals on coagulation parameters based on solid evidence are still scarce. Furthermore, reference intervals by age-group cannot reflect the dynamics of age and sex specific coagulation values during childhood. This study is the first to close this gap and provide continuous age and sex dependent reference intervals during childhood in hemostasis. METHODS: We used an innovative indirect method for providing continuous reference intervals for five common coagulation parameters: Activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin clotting time (TT), fibrinogen (FIB) and antithrombin (AT). Calculations were performed using retrospective laboratory data from pediatric patients between 2005 and 2015 of two major Austrian hospitals, resulting in a total of 195.360 measurements (aPTT: 55,100; PT: 35,492; TT: 35,295; FIB: 49,789; AT: 19,684). RESULTS: This multicenter study provides calculations of continuous reference intervals for five common coagulation parameters in a large pediatric cohort, accounting for age and gender. CONCLUSION: To the best of our knowledge, this is the first multicenter study, determining continuous pediatric coagulation reference intervals based on a large retrospective dataset.
EVALuna2:35510

DYNC2LI1 mutations broaden the clinical spectrum of dynein-2 defects - Keßler, Kristin; Wunderlich, Ina; Uebe, Steffen; Falk, Nathalie; Gießl, Andreas; Brandstätter, Johann Helmut; Popp, Bernt; Klinger, Patricia; Ekici, Arif Bülent; Sticht, Heinrich; Dörr, Helmuth-Günther; Reis, André; et al. (Scientific Reports, 2015)
Skeletal ciliopathies are a heterogeneous group of autosomal recessive osteochondrodysplasias caused by defects in formation, maintenance and function of the primary cilium. Mutations in the underlying genes affect the molecular motors, intraflagellar transport complexes (IFT), or the basal body. The more severe phenotypes are caused by defects of genes of the dynein-2 complex, where mutations in DYNC2H1, WDR34 and WDR60 have been identified. In a patient with a Jeune-like phenotype we performed exome sequencing and identified compound heterozygous missense and nonsense mutations in DYNC2LI1 segregating with the phenotype. DYNC2LI1 is ubiquitously expressed and interacts with DYNC2H1 to form the dynein-2 complex important for retrograde IFT. Using DYNC2LI1 siRNA knockdown in fibroblasts we identified a significantly reduced cilia length proposed to affect cilia function. In addition, depletion of DYNC2LI1 induced altered cilia morphology with broadened ciliary tips and accumulation of IFT-B complex proteins in accordance with retrograde IFT defects. Our results expand the clinical spectrum of ciliopathies caused by defects of the dynein-2 complex.
EVALuna2:9281

Dysregulation of the polyamine system in favour of its catabolism is a common mechanism after kidney injury - Sieckmann, T.; Ogel, N.; Kelterborn, S.; Boivin, F.; Schley, Gunnar; Fahling, M.; Ashraf, M. I.; Reichel, M.; Vigolo, E.; Knauf, F.; Rosenberger, C.; Aigner, F.; et al. (ACTA PHYSIOLOGICA, 2022)
CRIS-Team WoS Importer:2022-10-07

EARLY CHILDHOOD HEIGHT-ADJUSTED TOTAL KIDNEY VOLUME AS A RISK MARKER OF KIDNEY SURVIVAL IN AUTOSOMAL RECESSIVE POLYCYSTIC KIDNEY DISEASE (ARPKD) - Burgmaier, Kathrin; Kilian, Samuel; Arbeiter, Klaus; Atmis, Bahriye; Buescher, Anja; Derichs, Ute; Dursun, Ismail; Duzova, Ali; Eid, Loai; Galiano, Matthias; Gessner, Michaela; Gokce, Ibrahim; et al. (PEDIATRIC NEPHROLOGY, 2021)
CRIS-Team WoS Importer:2021-10-01

Early Clinical Experience of a Novel Mobile Driving Unit for Pediatric VAD Support - Miera, O.; Sandica, E.; Dittrich, Sven; Schmitt, K. R.; Hermann, M.; Blanz, U.; Cesnjevar, Robert; Haas, N. (JOURNAL OF HEART AND LUNG TRANSPLANTATION, 2021)
CRIS-Team WoS Importer:2021-04-23

Early MDO with a Virtually Planned Distractor in a Neonate with Pierre Robin Sequence - Lutz, Rainer; Olmos, Manuel; Schmidt, Joachim; Morhart, Patrick; Nobis, Christopher-Philipp; Möst, Tobias; Kesting, Marco Rainer; Weber, Manuel (Plastic and Reconstructive Surgery Global Open, 2022)
Pierre Robin sequence (PRS) is characterized by mandibular micrognathia, glossoptosis, and airway obstruction. We report a case of a female infant with PRS in combination with deletion of chromosome 4q and cardiac insufficiency due to an atrioventricular septum defect. The child was transferred to our center from a peripheral hospital with respiratory insufficiency. Initially, respiration was ensured using a continuous positive airway pressure (CPAP) device because a Tuebingen plate was not tolerated. After a pediatric cardiac surgery intervention, CPAP ventilation proved to be insufficient, and the young patient had to be resuscitated and endotracheal intubation was required for recurrent severe respiratory failure. To avoid tracheostomy, an interdisciplinary decision was made to perform an early mandibular distraction. In the fifth week of life, two patient-specific internal distractors were implanted after prior virtual surgery planning. This approach allows for shorter surgical time through preoperative vector planning and fabrication of a patient-specific distractor, in combination with reduced morbidity through maximum protection of adjacent structures such as the tooth follicles and inferior alveolar nerves. An advancement of the mandible by 15mm could be achieved within 2 weeks. Thereafter, the small patient could be extubated successfully, and there was no further episode of major respiratory insufficiency. We demonstrate that mandibular early distraction with a patient-specific distractor is a successful method to treat severe respiratory insufficiency in PRS, and it can prevent the necessity for tracheostomy with the resulting disadvantages. We provide details concerning our therapeutic algorithm, metric analyses, and a discussion of relevant literature.
CRIS-Team WoS Importer:2022-06-17

Early start of growth hormone is associated with positive effects on auxology and metabolism in Prader-Willi-syndrome - Magill, Lucy; Laemmer, Constanze; Wölfle, Joachim; Fimmers, Rolf; Gohlke, Bettina (Orphanet Journal of Rare Diseases, 2020)
Background: Prader-Willi-Syndrome (PWS) is characterized by hypothalamic-pituitary dysfunction. Recent research suggests starting growth hormone-treatment (GHT) as soon as possible. The aim of this study is to analyze possible differences in auxological parameters, carbohydrate and lipid metabolism between two groups of children with PWS that started GHT either during or after their first year of life. Study design: Retrospective longitudinal study of 62 children (31 males) with genetically confirmed PWS. Upon diagnosis all children were offered GHT, some started immediately, others commenced later. Cohort A (n = 21; 11 males) started GHT at 0.3-0.99 yrs. (mean 0.72 yrs) and Cohort B (n = 41; 20 males) commenced GHT at 1.02-2.54 yrs. (mean 1.42 yrs) of age. Fasting morning blood samples and auxological parameters were obtained before the start of therapy and semi-annually thereafter. Differences between the two cohorts were estimated with a linear mixed-effect model. Results: Mean length/height-SDSPWS differed significantly between the groups [1 yr: A: 0.37 (±0.83) vs B: 0.05 (±0.56); 5 yrs.: A: 0.81 (±0.67) vs B: 0.54 (±0.64); p = 0.012]. No significant differences were found in BMI, lean body mass or body fat. Low-density cholesterol was significantly lower in A than in B [LDL: 1 yr: A: 79 (±20) mg/dl vs B: 90 (±19) mg/dl; 5 yrs.: A: 91(±18) mg/dl vs 104 (±26) mg/dl; p = 0.024]. We found significant differences in the glucose homeostasis between the groups [fasting insulin: p = 0.012; HOMA-IR: p = 0.006; HbA1c: p < 0.001; blood glucose: p = 0.022]. Conclusions: An early start of GHT during the first year of life seems to have a favorable effect on height-SDS and metabolic parameters.
CRIS-Team Scopus Importer:2020-10-23
Keywords: Carbohydrate and lipid metabolism; Growth hormone therapy; Insulin-like growth factor-I; Prader-Willi-syndrome

Early vascular parameters in the micro- and macrocirculation in type 2 diabetes - Kannenkeril, Dennis; Bosch, Agnes; Harazny, Joanna; Karg, Marina; Jung, Susan; Ott, Christian; Schmieder, Roland (Cardiovascular Diabetology, 2018)
BACKGROUND: Diabetes converts from a metabolic disorder into a predominantly vascular disease, once its duration extends over several years or/and when additional cardiovascular risk factors such as hypertension coexist. In a cross-sectional analysis we analyzed various vascular parameters in the renal, retinal and systemic circulation, with the goal to identify which vascular parameter of early organ damage is the earliest that can be clinically detected. METHODS: In 111 patients with type 2 diabetes (T2DM) (off any anti-diabetic medication for at least 4 weeks) and 54 subjects without T2DM we compared various parameters of early vascular remodeling in the same patient: urinary albumin creatinine ratio ([UACR], early morning spot urine) and estimated glomerular filtration rate (eGFR), retinal capillary flow (RCF) and intercapillary distance (ICD) as parameters of capillary rarefaction, wall-to-lumen ratio (WLR) of the retinal arterioles [all assessed by Scanning Laser Doppler Flowmetry], and central systolic pressure (cSBP) and central pulse pressure (cPP) [measured by pulse wave analysis, Syphygmocor] both reflecting vascular stiffness of large arteries. RESULTS: Compared to subjects without T2DM, patients with T2DM (diabetes duration: median 48 months, interquartile range 24-88 months) were older (59.8 ± 7.3 vs 43.4 ± 12.9 years, p < 0.001), more females (33.3 vs 20.4%, p < 0.001), but 24-h systolic and diastolic blood pressure did not differ between the two groups. The analysis adjusted for age, gender and cardiovascular risk factors revealed that ICD (23.9 ± 5.1 vs 20.8 ± 3.5 µm, p value = 0.001) and cPP (41.8 ± 11.7 vs 34.8 ± 10.6 mmHg, p value < 0.001) were significantly higher and eGFR (91.7 ± 9.9 vs 95.9 ± 17.3 ml/min/1.73 m2, p value < 0.001) was significantly lower in patients with T2DM than in subjects without T2DM. CONCLUSION: These data suggest that at similar blood pressure capillary rarefaction in the retinal circulation (ICD), decreased eGFR in the renal circulation and increased central pulse pressure (cPP) of large arteries are earlier detectable than other vascular remodeling parameters of the micro- (WLR, RCF, UACR) and macrocirculation (cSBP) in patients with T2DM. Trial registration Trial registration number: NCT02471963, Date of registration: June 15, 2015, retrospectively registered; Trial registration number: NCT01319357, Date of registration: March 21, 2011, retrospectively registered; Trial registration number: NCT02383238, Date of registration: March 9, 2015, retrospectively registered; Trial registration number: NCT00152698, Date of registration: September 9, 2005, prospectively registered; Trial registration number: NCT00136188, Date of registration: August 26, 2005, prospectively registered.
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Ectodermal dysplasias: Classification and organization by phenotype, genotype and molecular pathway - Wright, John Timothy; Fete, Mary; Schneider, Holm; Zinser, Madelaine; Koster, Maranke I.; Clarke, Angus J.; Hadj-Rabia, Smail; Tadini, Gianluca; Pagnan, Nina; Visinoni, Atila F.; Bergendal, Birgitta; Abbott, Becky; et al. (American Journal of Medical Genetics Part A, 2019)
An international advisory group met at the National Institutes of Health in Bethesda, Maryland in 2017, to discuss a new classification system for the ectodermal dysplasias (EDs) that would integrate both clinical and molecular information. We propose the following, a working definition of the EDs building on previous classification systems and incorporating current approaches to diagnosis: EDs are genetic conditions affecting the development and/or homeostasis of two or more ectodermal derivatives, including hair, teeth, nails, and certain glands. Genetic variations in genes known to be associated with EDs that affect only one derivative of the ectoderm (attenuated phenotype) will be grouped as non-syndromic traits of the causative gene (e.g., non-syndromic hypodontia or missing teeth associated with pathogenic variants of EDA "ectodysplasin"). Information for categorization and cataloging includes the phenotypic features, Online Mendelian Inheritance in Man number, mode of inheritance, genetic alteration, major developmental pathways involved (e.g., EDA, WNT "wingless-type," TP63 "tumor protein p63") or the components of complex molecular structures (e.g., connexins, keratins, cadherins).
CRIS-Team WoS Importer:2019-02-27

Ectodermal dysplasias: New perspectives on the treatment of so far immedicable genetic disorders - Schneider, Holm (Frontiers in Genetics, 2022)
The past decade has witnessed an expansion of molecular approaches facilitating the differential diagnosis of ectodermal dysplasias, a group of genetic diseases characterized by the lack or malformation of hair, teeth, nails, and certain eccrine glands. Moreover, advances in translational research have increased the therapeutic opportunities for such rare diseases, and new dental, surgical, and ophthalmic treatment options are likely to offer relief to many individuals affected by ectodermal dysplasias. In X-linked hypohidrotic ectodermal dysplasia (XLHED), the genetic deficiency of the signaling molecule ectodysplasin A1 (EDA1) may even be overcome before birth by administration of a recombinant replacement protein. This has been shown at least for the key problem of male subjects with XLHED, the nearly complete absence of sweat glands and perspiration which can lead to life-threatening hyperthermia. Prenatal treatment of six boys by injection of an EDA1 replacement protein into the amniotic fluid consistently induced the development of functional sweat glands. Normal ability to sweat has so far persisted for > 5 years in the two oldest boys treated in utero. Thus, timely replacement of a missing protein appears to be a promising therapeutic strategy for the most frequent ectodermal dysplasia and possibly additional congenital disorders.
CRIS-Team WoS Importer:2022-09-30

Ectodysplasin A1 Deficiency Leads to Osteopetrosis-like Changes in Bones of the Skull Associated with Diminished Osteoclastic Activity - Schweikl, Christine; Maier-Wohlfart, Sigrun; Schneider, Holm; Park, Jung (International Journal of Molecular Sciences, 2022)
Pathogenic variants of the gene Eda cause X-linked hypohidrotic ectodermal dysplasia (XLHED), which is characterized by structural abnormalities or lack of ectodermal appendages. Signs of dysplasia are not restricted to derivatives of the ectodermal layer, but mesodermal abnormalities, such as craniofacial dysmorphism, are also frequently observed, suggesting close reciprocal interactions between the ectoderm and mesoderm; however, a causal link has remained unsubstantiated. We investigated the functional impact of defective ectodysplasin A1 (Eda1) signaling on postnatal bone homeostasis in Eda1-deficient Tabby mice. Interestingly, Eda1 was detected in wild-type mouse calvariae throughout postnatal lifetime. In calvariae, bone-lining Osterix (Osx)+ osteoblasts stained positive for Eda1, and osteoclasts were revealed as Eda receptor (Edar)-positive. Moreover, adult Eda1-deficient calvarial bone showed osteopetrosis-like changes with significantly diminished marrow space, which was maintained during adulthood. Concomitantly with osteopetrosis-like changes, Tabby calvarial bone and Tabby bone marrow-derived osteoclasts had far less osteoclastic activity-associated co-enzymes including cathepsin K, Mmp9, Trap, and Tcirg1 (V-type proton ATPase a3 subunit) compared with wild-type calvariae in vivo or osteoclasts in vitro, indicating that Eda1 deficiency may affect the activity of osteoclasts. Finally, we confirmed that nuclear Nfatc1-positive osteoclasts were strongly diminished during mature osteoclastic differentiation under M-CSF and RANKL in the Tabby model, while Fc-EDA treatment of Tabby-derived osteoclasts significantly increased nuclear translocation of Nfatc1. Furthermore, we identified enhanced Nfatc1 and NF-κB transcriptional activity following Fc-EDA treatment in vitro using luciferase assays. Overall, the results indicate that diminished expressions of osteoclastic activity-associated co-enzymes may lead to disturbed bone homeostasis in Tabby calvariae postnatally.
CRIS-Team Scopus Importer:2022-11-04
Keywords: bone; ectodermal dysplasia; ectodysplasin A1; NF-κB; NFAT; osteoclast differentiation; osteopetrosis

Ectodysplasin A in Biological Fluids and Diagnosis of Ectodermal Dysplasia - Podzus, J.; Kowalczyk-Quintas, C.; Schuepbach-Mallepell, S.; Willen, L.; Staehlin, G.; Vigolo, M.; Tardivel, A.; Headon, D.; Kirby, N.; Mikkola, M. L.; Schneider, Holm; Schneider, P. (Journal of Dental Research, 2017)
The tumor necrosis factor (TNF) family ligand ectodysplasin A (EDA) is produced as 2 full-length splice variants, EDA1 and EDA2, that bind to EDA receptor (EDAR) and X-linked EDA receptor (XEDAR/EDA2R), respectively. Inactivating mutations in Eda or Edar cause hypohidrotic ectodermal dysplasia (HED), a condition characterized by malformations of the teeth, hair and glands, with milder deficiencies affecting only the teeth. EDA acts early during the development of ectodermal appendages-as early as the embryonic placode stage-and plays a role in adult appendage function. In this study, the authors measured EDA in serum, saliva and dried blood spots. The authors detected 3- to 4-fold higher levels of circulating EDA in cord blood than in adult sera. A receptor binding-competent form of EDA1 was the main form of EDA but a minor fraction of EDA2 was also found in fetal bovine serum. Sera of EDA-deficient patients contained either background EDA levels or low levels of EDA that could not bind to recombinant EDAR. The serum of a patient with a V262F missense mutation in Eda, which caused a milder form of X-linked HED (XLHED), contained low levels of EDA capable of binding to EDAR. In 2 mildly affected carriers, intermediate levels of EDA were detected, whereas a severely affected carrier had no active EDA in the serum. Small amounts of EDA were also detectable in normal adult saliva. Finally, EDA could be measured in spots of wild-type adult or cord blood dried onto filter paper at levels significantly higher than that measured in EDA-deficient blood. Measurement of EDA levels combined with receptor-binding assays might be of relevance to aid in the diagnosis of total or partial EDA deficiencies.
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Editorial: Gene, Cell and Protein Replacement Therapy for Genetic Muscle, Bone and Skin Disorders - Schneider, Holm; De Luca, Michele (Frontiers in Genetics, 2021)
CRIS-Team Scopus Importer:2021-11-12
Keywords: duchenne muscular dystrophy (DMD); ectodermal dysplasia; epidermolysis bullosa; gene therapy; myogenic cell transplantation; protein replacement

Effect and safety of treatment with ACE-inhibitor Enalapril and β-blocker metoprolol on the onset of left ventricular dysfunction in Duchenne muscular dystrophy - A randomized, double-blind, placebo-controlled trial - Dittrich, Sven; Graf, Erika; Trollmann, Regina; Neudorf, Ulrich; Schara, Ulrike; Heilmann, Antje; Von Der Hagen, Maja; Stiller, Brigitte; Kirschner, Janbernd; Pozza, Robert Dalla; Müller-Felber, Wolfgang; Weiss, Katja; et al. (Orphanet Journal of Rare Diseases, 2019)
Background: X-linked Duchenne muscular dystrophy (DMD), the most frequent human hereditary skeletal muscle myopathy, inevitably leads to progressive dilated cardiomyopathy. We assessed the effect and safety of a combined treatment with the ACE-inhibitor enalapril and the β-blocker metoprolol in a German cohort of infantile and juvenile DMD patients with preserved left ventricular function. Methods Trial design: Sixteen weeks single-arm open run-in therapy with enalapril and metoprolol followed by a two-arm 1:1 randomized double-blind placebo-controlled treatment in a multicenter setting. Inclusion criteria: DMD boys aged 10-14 years with left ventricular fractional shortening [LV-FS] ≥ 30% in echocardiography. Primary endpoint: time from randomization to first occurrence of LV-FS < 28%. Secondary: changes of a) LV-FS from baseline, b) blood pressure, c), heart rate and autonomic function in ECG and Holter-ECG, e) cardiac biomarkers and neurohumeral serum parameters, f) quality of life, and g) adverse events. Results: From 3/2010 to 12/2013, 38 patients from 10 sites were centrally randomized after run-in, with 21 patients continuing enalapril and metoprolol medication and 17 patients receiving placebo. Until end of study 12/2015, LV-FS < 28% was reached in 6/21 versus 7/17 patients. Cox regression adjusted for LV-FS after run-in showed a statistically non-significant benefit for medication over placebo (hazard ratio: 0.38; 95% confidence interval: 0.12 to 1.22; p = 0.10). Analysis of secondary outcome measures revealed a time-dependent deterioration of LV-FS with no statistically significant differences between the two study arms. Blood pressure, maximal heart rate and mean-NN values were significantly lower at the end of open run-in treatment compared to baseline. Outcome analysis 19 months after randomization displayed significantly lower maximum heart rate and higher noradrenalin and renin values in the intervention group. No difference between treatments was seen for quality of life. As a single, yet important adverse event, the reversible deterioration of walking abilities of one DMD patient during the run-in period was observed. Conclusions: Our analysis of enalapril and metoprolol treatment in DMD patients with preserved left ventricular function is suggestive to delay the progression of the intrinsic cardiomyopathy to left ventricular failure, but did not reach statistical significance, probably due to insufficient sample size. Clinical trial registration: DRKS-number 00000115, EudraCT-number 2009-009871-36.
CRIS-Team Scopus Importer:2019-05-21
Keywords: ACE-inhibitors; Cardiomyopathy; Duchenne muscular dystrophy; ß-blockers

Effectiveness and safety of rhIGF1 therapy in patients with or without Laron syndrome - Bang, Peter; Wölfle, Joachim; Perrot, Valerie; Sert, Caroline; Polak, Michel (European Journal of Endocrinology, 2021)
Objective: The European Increlex® Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin, Increlex®) therapy in patients with severe primary IGF1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS). Design: Ongoing, open-label, observational registry (NCT00903110). Methods: Children and adolescents receiving rhIGF1 therapy from 10 European countries were enrolled in 2008-2017 (n = 242). The treatment-naïve/prepubertal (NPP) cohort (n = 138) was divided into subgroups based on reported genetic diagnosis of LS (n = 21) or non-LS (n = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score (SDS) gain ≥ 0.3). Assessments included change in height and weight over 5 years and adverse events (AEs). Results: Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years' treatment (P < 0.05). In the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P < 0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 years vs 7.00 years) at baseline and height SDS gain in year 1 (0.64 vs 0.70), although NPP-non-LS-responders were taller (P < 0.001) at baseline. BMI SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common. Conclusions: In most NPP children with SPIGFD, with or without LS, rhIGF1 therapy promotes linear growth. The safety profile was consistent with previous studies.
CRIS-Team Scopus Importer:2021-02-05

Effectiveness of structured, multidisciplinary long-term care for pediatric cancer survivors: protocol of the multicenter, randomized-controlled AELKI study - Schmidt, Hannah; Baust, Katja; Calaminus, Gabriele; Hohls, Lisa; Tetzner, Katharina; Griech, Nicole; Haugke, Henrike; Baltus, Hannah; Elsner, Susanne; Katalinic, Alexander; Becker, Hera; Cytera, Chirine; et al. (Trials, 2024)
Background: In Germany, around 2.250 children and adolescents are diagnosed with cancer each year. Despite generally positive long-term survival rates, many patients must cope with late effects of the disease and its treatment. This highlights the need for a well-structured, long-term approach addressing both physical and mental health issues. Currently, the German healthcare system lacks such comprehensive structures. Our study aims to evaluate the effectiveness of a structured, multidisciplinary long-term approach compared to conventional “treatment as usual” (TAU). Methods: A prospective, multicenter study with ten pediatric university clinics in Germany will be conducted. The cluster-randomization takes place at the clinic level. Children and adolescents who completed their cancer treatment at least five years ago and their parents will be eligible to participate. While the control group (CG) receives TAU, the intervention group (IG) participates in a structured program. This program includes risk-based medical treatment and psychosocial interventions tailored to each patient’s individual needs within a two-month timeframe. The primary outcome is the improvement of self-efficacy. Secondary outcomes are satisfaction with health care, improvement of health-related quality of life (HRQoL), reduction of mental health problems, and improvement of transition readiness. Discussion: This approach has the potential to optimize the health care for individuals who survived cancer during childhood or adolescence. It addresses the challenges of overuse, underuse, and misuse of health care resources. By considering both medical and psychosocial factors and promoting increased self-efficacy, independent from parental involvement, it may facilitate a smoother transition to adult medicine and enhance adherence to lifelong aftercare. If proven successful, this approach will contribute to the integration of multidisciplinary strategies into standard healthcare practice. Trial registration: German Clinical Trials Register DRKS00029269. Registered on December 23, 2022.
CRIS-Team Scopus Importer:2024-09-20
Keywords: Cancer; Children and adolescent; Long-term care; Multidisciplinary; Psychosocial

Effect of empagliflozin on ketone bodies in patients with stable chronic heart failure - Pietschner, Robert; Kolwelter, Julie; Bosch, Agnes; Striepe, Kristina; Jung, Susan; Kannenkeril, Dennis; Ott, C.; Schiffer, Mario; Achenbach, Stephan; Schmieder, Roland (Cardiovascular Diabetology, 2021)
Background: Recent studies indicated that sodium glucose cotransporter (SGLT)2 inhibition increases levels of ketone bodies in the blood in patients with type 1 and 2 diabetes. Other studies suggested that in patients with chronic heart failure (CHF), increased myocardial oxygen demand can be provided by ketone bodies as a fuel substrate. Experimental studies reported that ketone bodies, specifically beta-hydroxybutyrate (β-OHB) may increase blood pressure (BP) by impairing endothelium-dependant relaxation, thereby leading to increased vascular stiffness. In our study we assessed whether the SGLT 2 inhibition with empagliflozin increases ketone bodies in patients with stable CHF and whether such an increase impairs BP and vascular function. Methods: In a prospective, double blind, placebo controlled, parallel-group single centre study 75 patients with CHF (left ventricular ejection fraction 39.0 ± 8.2%) were randomised (2:1) to the SGLT-2 inhibitor empagliflozin 10 mg orally once daily or to placebo, 72 patients completed the study. After a run-in phase we evaluated at baseline BP by 24 h ambulatory blood pressure (ABP) monitoring, vascular stiffness parameters by the SphygmoCor system (AtCor Medical, Sydney, NSW, Australia) and fasting metabolic parameters, including β-OHB by an enzymatic assay (Beckman Coulter DxC 700 AU). The same measurements were repeated 12 weeks after treatment. In 19 of the 72 patients serum levels of β-OHB were beneath the lower border of our assay (< 0.05 mmol/l) therefore being excluded from the subsequent analysis. Results: In patients with stable CHF, treatment with empagliflozin (n = 36) was followed by an increase of β-OHB by 33.39% (p = 0.017), reduction in 24 h systolic (p = 0.038) and diastolic (p = 0.085) ABP, weight loss (p = 0.003) and decrease of central systolic BP (p = 0.008) and central pulse pressure (p = 0.008). The increase in β-OHB was related to an attenuated decrease of empagliflozin-induced 24 h systolic (r = 0.321, p = 0.069) and diastolic (r = 0.516, p = 0.002) ABP and less reduction of central systolic BP (r = 0.470, p = 0.009) and central pulse pressure (r = 0.391, p = 0.033). No significant changes were seen in any of these parameters after 12 weeks of treatment in the placebo group (n = 17). Conclusion: In patients with stable CHF ketone bodies as assessed by β-OHB increased after treatment with empagliflozin. This increase led to an attenuation of the beneficial effects of empagliflozin on BP and vascular parameters. Trial registration The study was registered at http://www.clinicaltrials.gov (NCT03128528).
CRIS-Team Scopus Importer:2021-11-19

Effect of maternal smoking on stress physiology in healthy neonates - Haslinger, C.; Bamert, H.; Rauh, Manfred; Burkhardt, T.; Schaffer, L. (Journal of Perinatology, 2018)
OBJECTIVE: To assess the impact of maternal smoking during pregnancy (MSDP) on the neonatal hypothalamic-pituitary-adrenal axis. STUDY DESIGN: In a prospective observational study, salivary cortisol and cortisone levels were measured at the fourth day of life during resting conditions and in response to a pain-induced stress event in healthy neonates whose mothers smoked cigarettes during each stage of pregnancy and compared with controls. RESULTS: Neonates in the control group (n=70) exhibited a physiologic stress response with a significant increase in cortisol (1.3 to 2.1 ng ml-1; P<0.05) and cortisone (11.8 to 17.8 ng ml-1; P<0.05) from baseline levels, whereas in neonates from mothers who smoked (n=33), cortisol (0.9 to 0.8 ng ml-1; P=0.77) and cortisone (11.5 to 13.0; P=0.19) stress response was not significantly different from baseline levels. A two-way analysis of variance confirmed these findings in both groups. CONCLUSIONS: Healthy neonates whose mothers smoked during pregnancy show a blunted stress response on the fourth day of life. Thus, MSDP leads to a dysregulation of the HPA axis with continued effects in neonatal life. This might explain long-term consequences of MSDP such as overweight, diabetes mellitus and modification of blood pressure control mechanisms in adult life.
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Effect of nusinersen on motor, respiratory and bulbar function in early-onset spinal muscular atrophy - Pechmann, Astrid; Behrens, Max; Doernbrack, Katharina; Tassoni, Adrian; Stein, Sabine; Vogt, Sibylle; Zoeller, Daniela; Bernert, Gunther; Hagenacker, Tim; Schara-Schmidt, Ulrike; Schwersenz, Inge; Walter, Maggie C.; et al. (Brain, 2022)
5q-associated spinal muscular atrophy is a rare neuromuscular disorder with the leading symptom of a proximal muscle weakness. Three different drugs have been approved by the European Medicines Agency and Food and Drug Administration for the treatment of spinal muscular atrophy patients, however, long-term experience is still scarce. In contrast to clinical trial data with restricted patient populations and short observation periods, we report here real-world evidence on a broad spectrum of patients with early-onset spinal muscular atrophy treated with nusinersen focusing on effects regarding motor milestones, and respiratory and bulbar insufficiency during the first years of treatment. Within the SMArtCARE registry, all patients under treatment with nusinersen who never had the ability to sit independently before the start of treatment were identified for data analysis. The primary outcome of this analysis was the change in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders and motor milestones considering World Health Organization criteria. Further, we evaluated data on the need for ventilator support and tube feeding, and mortality. In total, 143 patients with early-onset spinal muscular atrophy were included in the data analysis with a follow-up period of up to 38 months. We observed major improvements in motor function evaluated with the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders. Improvements were greater in children >2 years of age at start of treatment than in older children. 24.5% of children gained the ability to sit independently. Major improvements were observed during the first 14 months of treatment. The need for intermittent ventilator support and tube feeding increased despite treatment with nusinersen. Our findings confirm the increasing real-world evidence that treatment with nusinersen has a dramatic influence on disease progression and survival in patients with early-onset spinal muscular atrophy. Major improvements in motor function are seen in children younger than 2 years at the start of treatment. Bulbar and respiratory function needs to be closely monitored, as these functions do not improve equivalent to motor function.
CRIS-Team WoS Importer:2023-01-27

Effect of Psychosocial Factors on Growth - Gohlke, Bettina C.; Bettendorf, Markus; Binder, Gerhard; Hauffa, Berthold; Reinehr, Thomas; Dörr, Helmuth-Günther; Wölfle, Joachim (Klinische Pädiatrie, 2021)
Background Genes, hormones and factors such as nutrition and psychosocial environment affect growth. Objective What is the significance of various psychosocial factors on growth? Methods Evaluation of results of a working meeting of paediatric endocrinologist with current literature research. Results Psychosocial deprivation in children can be associated with growth hormone deficiency (GHD) and short stature. GHD can be reversed by a change of environment and psychosocial support. War and migration are often associated with underweight, growth disturbances and poor health care. These factors can improve after the end of conflicts, but children often remain too short. Consumption of alcohol or opiates during pregnancy are associated with lower birth weight and increased risk of early and small for gestational age (SGA) childbirth. Children with attention deficit hyperactivity disorder show a slight slowdown in growth after they started stimulant therapy. However, they reach normal adult height. Conclusions In children with idiopathic short stature, psychosocial causes should be taken into account in the differential diagnosis. Notably there is an increased risk of growth disturbances in children from conflict regions or after prenatal drug exposure.
CRIS-Team WoS Importer:2021-12-24

Effects of blue- and red-enriched light on attention and sleep in typically developing adolescents - Studer, Petra; Brucker, Judith M.; Haag, Cornelia; Van Doren, Jessica; Moll, Gunther; Heinrich, Hartmut; Kratz, Oliver (Physiology & behavior, 2019)
Differential effects of blue- and red-enriched light on attention and sleep have been primarily described in adults. In our cross-over study in typically developing adolescents (11-17 years old), we found attention enhancing effects of blue- compared to red-enriched light in the morning (high intensity of ca. 10001x, short duration: < 1 h) in two of three attention tasks: e.g. better performance in math tests and reduced reaction time variability in a computerized attention test. In our pilot study, actigraphy measures of sleep indicated slight benefits for red- compared to blue-enriched light in the evening: tendencies toward a lower number of phases with movement activity after sleep onset in the complete sample and shorter sleep onset latency in a subgroup with later evening exposure times. These findings point to the relevance of light concepts regarding attention and sleep in typically developing adolescents. Such concepts should be developed and tested further in attention demanding contexts (at school) and for therapeutic purposes in adolescents with impaired attention or impaired circadian rhythms.
CRIS-Team WoS Importer:2019-02-21

Effects of glucose concentration in the tumor microenvironment on Non Small Lung Cancer (NSCLC) Progression - Gähler, Alexander; Hohenberger, Katja; Tausche, Patrick; Chiriac, Mircea-Teodor; Rauh, Manfred; Trufa, Denis; Geppert, Carol-Immanuel; Rieker, Ralf; Sirbu, Horia; Neurath-Finotto, Susetta (JOURNAL OF IMMUNOLOGY, 2021)
CRIS-Team WoS Importer:2021-12-03

Effects of Levetiracetam and Sulthiame on EEG in benign epilepsy with centrotemporal spikes: A randomized controlled trial - Tacke, Moritz; Borggraefe, Ingo; Gerstl, Lucia; Heinen, Florian; Vill, Katharina; Bonfert, Michaela; Bast, Thomas; Neubauer, Bernd Axel; Baumeister, Friedrich; Baethmann, Martina; Bentele, Karl; Blank, Christian; et al. (Seizure-European Journal of Epilepsy, 2018)
PURPOSE: BECTS (benign childhood epilepsy with centrotemporal spikes) is associated with characteristic EEG findings. This study examines the influence of anti-convulsive treatment on the EEG. METHODS: In a randomized controlled trial including 43 children with BECTS, EEGs were performed prior to treatment with either Sulthiame or Levetiracetam as well as three times under treatment. Using the spike-wave-index, the degree of EEG pathology was quantified. The EEG before and after initiation of treatment was analyzed. Both treatment arms were compared and the EEG of the children that were to develop recurrent seizures was compared with those that were successfully treated. RESULTS: Regardless of the treatment agent, the spike-wave-index was reduced significantly under treatment. There were no differences between the two treatment groups. In an additional analysis, the EEG characteristics of the children with recurrent seizures differed statistically significant from those that did not have any further seizures. CONCLUSION: Both Sulthiame and Levetiracetam influence the EEG of children with BECTS. Persistent EEG pathologies are associated with treatment failures.
EVALuna2:35718

Effects of long-term methylphenidate use on growth and blood pressure: results of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) - Mccarthy, Suzanne; Neubert, Antje; Man, Kenneth K. C.; Banaschewski, Tobias; Buitelaar, Jan; Carucci, Sara; Coghill, David; Danckaerts, Marina; Falissard, Bruno; Garas, Peter; Haege, Alexander; Hollis, Chris; et al. (BMC Psychiatry, 2018)
BACKGROUND: Concerns have been raised over the safety of methylphenidate (MPH), with regard to adverse effects on growth and blood pressure. Our study investigates whether, and to what extent, methylphenidate use in boys with ADHD is associated with having low body mass index (BMI), having low height, and increased systolic and diastolic blood pressure. METHODS: Data used for this study stem from the German KiGGS dataset. Three different groups of boys aged 6-15 years were included in the analysis: ADHD patients who used MPH for less than 12 months; ADHD patients who used MPH for 12 months or more; and ADHD patients without current MPH treatment. Each of these three groups was compared to a non-ADHD control group regarding low weight (BMI ≤ 3rd percentile), low height (≤3rd percentile) and raised systolic and diastolic blood pressure. For growth outcomes, boys were categorized according to age (< 11 years/≥11 years, to account for pubertal maturation). Multivariable logistic regression was conducted to test for associations. RESULTS: 4244 boys were included in the study; MPH < 12 months: n = 65 (n = 36 < 11 years), MPH ≥ 12 months: n = 53 (n = 22 < 11 years), ADHD controls: n = 320 (n = 132 < 11 years), non-ADHD controls: n = 3806 (n = 2003 < 11 years). Pre-pubertal boys with MPH use less than 12 months and pubertal/postpubertal boys with MPH use of 12 months or greater were significantly more likely to have a BMI ≤ 3rd percentile compared to non-ADHD controls. Boys from the ADHD control group were significantly less likely to have a raised systolic blood pressure compared to non-ADHD controls. Beyond that, no significant between group differences were observed for any other growth and BP parameter. CONCLUSION: The analyses of the KiGGS dataset showed that MPH use in boys with ADHD is associated with low BMI. However, this effect was only observed in certain groups. Furthermore, our analysis was unable to confirm that MPH use is also associated with low height (≤3rd percentile) and changes in blood pressure.
EVALuna2:35837

EFFECTS OF THE NO SYNTHASE INHIBITOR RONOPTERIN (VAS203) ON MICRO- AND MACROCIRCULATION IN HEALTHY VOLUNTEERS - Ott, Christian; Bosch, Agnes; Jung, Susan; Kannenkeril, Dennis; Schinzel, R.; Tegtmeier, F.; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2019)
CRIS-Team WoS Importer:2019-09-20

Effects of the STAMP-inhibitor asciminib on T cell activation and metabolic fitness compared to tyrosine kinase inhibition by imatinib, dasatinib, and nilotinib - Häselbarth, Lukas; Karow, Axel; Mentz, Kristin; Böttcher, Martin; Roche-Lancaster, Oisin; Krumbholz, Manuela; Jitschin, Regina; Mougiakakos, Dimitrios; Metzler, Markus (Cancer Immunology, Immunotherapy, 2023)
T cell function is central to immune reconstitution and control of residual chronic myeloid leukemia (CML) cells after treatment initiation and is associated with achieving deep molecular response as a prerequisite for treatment-free remission, the ultimate therapeutic goal in CML. ATP-pocket-binding tyrosine kinase inhibitors (TKIs) like imatinib, dasatinib, and nilotinib are widely used for treating CML, but they have shown to inhibit T cell function as an “off-target” effect. Therefore, we tested asciminib, the first-in-class BCR::ABL1 fusion protein inhibitor specifically targeting the ABL myristoyl pocket (STAMP) and compared its effects on T cell function with imatinib, dasatinib, and nilotinib. Whereas all four TKIs inhibited the expression of the co-stimulatory protein CD28, the amino acid transporter CD98, proliferation, and secretion of pro-inflammatory cytokines IFNγ, IL-6, and IL-17A upon T cell stimulation, asciminib had less impact on PD-1, activation markers, and IL-2 secretion. T cells treated with asciminib and the other TKIs maintained their ability to mobilize their respiratory capacity and glycolytic reserve, which is an important surrogate for metabolic fitness and flexibility. Overall, we found milder inhibitory effects of asciminib on T cell activation, which might be beneficial for the immunological control of residual CML cells.
CRIS-Team Scopus Importer:2023-01-13
Keywords: Activity; Asciminib; CML; Metabolism; T cell; TKI

Efficacy and safety of gene therapy with onasemnogene abeparvovec in children with spinal muscular atrophy in the D-A-CH-region: a population-based observational study - Weiß, Claudia; Becker, Lena Luise; Friese, Johannes; Blaschek, Astrid; Hahn, Andreas; Illsinger, Sabine; Schwartz, Oliver; Bernert, Günther; Hagen, Maja von der; Husain, Ralf A.; Goldhahn, Klaus; Kirschner, Janbernd; et al. (The Lancet Regional Health - Europe, 2024)
Background: Real-world data on gene addition therapy (GAT) with onasemnogene abeparvovec (OA), including all age groups and with or without symptoms of the disease before treatment are needed to provide families with evidence-based advice and realistic therapeutic goals. Aim of this study is therefore a population-based analysis of all patients with SMA treated with OA across Germany, Austria and Switzerland (D-A-CH). Methods: This observational study included individuals with Spinal Muscular Atrophy (SMA) treated with OA in 29 specialized neuromuscular centers in the D-A-CH-region. A standardized data set including WHO gross motor milestones, SMA validated motor assessments, need for nutritional and respiratory support, and adverse events was collected using the SMArtCARE registry and the Swiss-Reg-NMD. Outcome data were analyzed using a prespecified statistical analysis plan including potential predictors such as age at GAT, SMN2 copy number, past treatment, and symptom status. Findings: 343 individuals with SMA (46% male, 54% female) with a mean age at OA of 14.0 months (range 0–90, IQR 20.0 months) were included in the analysis. 79 (23%) patients were clinically presymptomatic at the time of treatment. 172 (50%) patients received SMN2 splice-modifying drugs prior to GAT (risdiplam: n = 16, nusinersen: n = 154, both: n = 2). Functional motor improvement correlated with lower age at GAT, with the best motor outcome in those younger than 6 weeks, carrying 3 SMN2 copies, and being clinically presymptomatic at time of treatment. The likelihood of requiring ventilation or nutritional support showed a significantly increase with older age at the time of GAT and remained stable thereafter. Pre-treatment had no effect on disease trajectories. Liver-related adverse events occurred significantly less frequently up to 8 months of age. All other adverse events showed an even distribution across all age and weight groups. Interpretation: Overall, motor, respiratory, and nutritional outcome were dependent on timing of GAT and initial symptom status. It was best in presymptomatic children treated within the first six weeks of life, but functional motor scores also increased significantly after treatment in all age groups up to 24 months. Additionally, OA was best tolerated when administered at a young age. Our study therefore highlights the need for SMA newborn screening and immediate treatment to achieve the best possible benefit-risk ratio. Funding: The SMArtCARE and Swiss-Reg-NMD registries are funded by different sources (see acknowledgements).
CRIS-Team Scopus Importer:2024-10-18
Keywords: Gene addition therapy; Gene therapy; Onasemnogene abeparvovec; SMA; Spinal muscular atrophy; Zolgensma

Efficacy, Retention and Tolerability of Everolimus in Patients with Tuberous Sclerosis Complex: A Survey-Based Study on Patients' Perspectives - Willems, Laurent M.; Rosenow, Felix; Schubert-Bast, Susanne; Kurlemann, Gerhard; Zoellner, Johann Philipp; Bast, Thomas; Bertsche, Astrid; Bettendorf, Ulrich; Ebrahimi-Fakhari, Daniel; Grau, Janina; Hahn, Andreas; Hartmann, Hans; et al. (Cns Drugs, 2021)
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/m(2) (median: 5.6 mg/m(2), range 2.0-15.1 mg/m(2)) in children and adolescents and 4 +/- 2.1 mg/m(2) (median: 3.7 mg/m(2), range 0.8-10.1 mg/m(2)) 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.
CRIS-Team WoS Importer:2021-07-30

Efficacy, tolerability, and retention of fenfluramine for the treatment of seizures in patients with Dravet syndrome: Compassionate use program in Germany - Strzelczyk, Adam; Pringsheim, Milka; Mayer, Thomas; Polster, Tilman; Klotz, Kerstin A.; Muhle, Hiltrud; Alber, Michael; Trollmann, Regina; Spors, Hartwig; Kluger, Gerhard; Kurlemann, Gerhard; Schubert-Bast, Susanne (Epilepsia, 2021)
Objective: Dravet syndrome (DS) is a rare but severe drug-resistant epilepsy. Before the approval of fenfluramine (FFA) for the treatment of seizures in DS, patients in Germany could receive treatment under a compassionate use program (CUP). Methods: We conducted a multicenter, retrospective, observational study to describe the efficacy, tolerability, and retention of FFA within the CUP. Patients received add-on therapy with oral FFA gradually titrated to a target dose between.13 and.7 mg/kg/day. Results: Overall, 78 patients with DS (median age = 8.0 years, range = 2.1–46.0; 53% female, median concomitant antiseizure medications [ASMs] = 3) were treated with FFA for a median duration of 255.5 days (range = 31–572). Responder rates (a ≥50% reduction; n = 78) and seizure-freedom rates at 3 months were 68% and 14% for total seizures, respectively, and 67% and 23% for generalized tonic–clonic seizures. Responder rates were consistent at 6 and 12 months (n = 66 and n = 43, respectively). Median seizure days per month significantly decreased from 10.0 (range =.5–30) to 3.0 (range = 0–30) in the 3-month period before and after FFA treatment (p <.001). Significantly fewer patients reported at least one episode of status epilepticus (28% vs. 14% patients before and after FFA initiation, p =.005). During FFA treatment, 35 (45%) patients were able to discontinue a concomitant ASM. At the last follow-up date, 66 (85%) patients remained on treatment with FFA. The most common adverse events were somnolence (36%), decreased appetite (22%), and ataxia (8%). Forty-eight (62%) patients were reported as having a meaningful global clinical improvement. Significance: In a large cohort of patients, FFA demonstrated efficacy across a range of outcomes including clinically significant reductions in convulsive seizures, and was well tolerated, providing valuable information for real-world practice.
CRIS-Team Scopus Importer:2021-08-20
Keywords: Clinical Global Impression of Change; convulsive seizures; Dravet syndrome; fenfluramine; real-world; status epilepticus

Efficiency of translation termination in humans is highly dependent upon nucleotides in the neighbourhood of a (premature) termination codon - Pacho, Frederic; Zambruno, Giovanna; Calabresi, Valentina; Kiritsi, Dimitra; Schneider, Holm (Journal of Medical Genetics, 2011)
Background Spontaneous read-through of a premature termination codon (PTC) has so far not been observed in patients carrying nonsense mutations. This report describes a patient with junctional epidermolysis bullosa who was expected to die because of compound heterozygous nonsense mutations in the gene LAMA3 (R943X/R1159X), but was rescued by spontaneous readthrough of the R943X allele. Results and conclusion FACS analysis of cells carrying various PTCs surrounded by their natural neighbouring codons revealed significant reporter gene expression despite the PTC only for this patient's genetic context. Gene expression could be abolished by replacing the first or third nucleotide before, or one of the two nucleotides following the PTC. Site-directed mutagenesis was used to identify genotypes allowing PTC read-through. The genetic context of the LAMA3 mutation R943X is close to a hypothetical consensus sequence for maximum PTC read-through. Bioinformatic analysis showed that this consensus sequence is present in four sequences from the NCBI reference database, each of which contains another in-frame termination codon three or four codons apart. This indicates strong selective pressure against leaky termination codons in the human genome. This patient's mutated full length mRNA escaped nonsensemediated decay, leading to LAMA3 mRNA levels similar to those of a healthy control, and full length laminin a3 could be detected in culture supernatant of the patient's keratinocytes. Immunofluorescence analyses of skin biopsies and continuous clinical improvement of the patient's condition suggested accumulation of intact laminin-332 in the epidermal basement membrane. These findings provide important clues for the prediction of PTC read-through in human genetic disease.
CRIS-Team Scopus Importer:2020-07-01

Einstufung des Grades der Schwerbehinderung bei Kindern und Jugendlichen mit Chronischer Myeloischer Leukämie - Suttorp, Meinolf; Sembill, Stephanie; Metzler, Markus (TumorDiagnostik & Therapie, 2021)
Background CML comprises only 2-3% of all diagnosed pediatric leukemias. Mostly diagnosed in chronic phase (CML-CP), the disease progresses without treatment to accelerated phase (CML-AP) and finally to life-limiting blastic phase (CML-BP). Contrasting the therapy of other leukemia types, CML-CP is not treated by intense chemotherapy but with oral drugs -termed tyrosine kinase inhibitors (TKI)- for an unlimited duration. This therapy may be associated with general and developmentalspecific side effects. The rarity of pediatric-CML is limiting the experience in assessment of the disability rating (DR) as an administrative health authority procedure. Methods A questionnaire was sent out evaluating the procedures and results associated with the application of a disabled person's pass. Results 34 out of 70 patients (49%; median age 11 yrs., range 3-17 yrs.; CML-CP/-AP/-BP: N=28/3/3) replied to the questionnaire. Median duration of TKI therapy was 33 months (range 4-163) and associated in 71% (24/34) of the patients with side effects. 5/34 (15%) patients did not apply for a pass. DR 100 was assigned to all patients with CML-BP and to 2/3 patients with CML-AP; the 3rd patient was assigned DR 60. In the 21 patients with CML-CP the assigned DR varied from 20-100; 9/28 patients (32%) were assigned to DR 50. Special identifier label H (helpless) was assigned to 5/28 patients (18%) with CML-CP. Conclusion Compared to other pediatric malignancies, the broad range of DR in CML-CP points to unsureness when assessing the limitations exerted by the disease and its therapy. Guidelines for adults with CML offer little orientation only as pediatric patients frequently suffer from developmental-specific side effects.
Created from Fastlane, Scopus look-up
Keywords: Chronic Myeloid Leukemia; disability rating; Pediatric CML; TKI side Effects

Ektope Lage einer Schilddrüse im Zungengrund – Zufallsdiagnose bei einem 6‑jährigen Mädchen - Albrecht, Andrea; Penger, Theresa; Marx, Martin; Jüngert, Jörg M.; Kuwert, Torsten; Dörr, Helmuth-Günther (Monatsschrift Kinderheilkunde, 2020)
Background: An ectopic thyroid gland is a rare anomaly due to the incomplete descent of the thyroid gland during the embryonic developmental migration process. The ectopic thyroid tissue is normally located in the area from the tongue to the diaphragm but lingual and sublingual locations preferentially occur. In a child with congenital hypothyroidism, which was detected during neonatal screening, the ectopic gland could be diagnosed during the further clarification. Case report: This article reports on the case of a girl who was presented to the pediatrician for clarification of chronic abdominal pain at the age of 6 years and 3 months. As an incidental finding the pediatrician diagnosed a subclinical hypothyroidism (serum TSH 23.3 mU/l, fT3 and fT4 normal) and initiated treatment with L‑thyroxine (L-T4). The psychomotor, growth and weight development had always been age-appropriate. At the initial presentation in this outpatient department the girl was 6 years and 5 months old, was clinically and biochemically euthyroid, and the body measurements were normal. The thyroid autoantibodies were inconspicuous. The ultrasound scan revealed a small lingual thyroid-like tissue (volume 0.9 ml) with no thyroid tissue in the typical site. A thyroid scintigraphy confirmed the diagnosis. Under the weight-adapted medication with L‑thyroxine the patient never developed symptoms of hypothyroidism and the volume of the lingual thyroid did not increase. The patient is currently 11 years and 8 months old (height 146.9 cm, weight 33.3 kg, Tanner stage B 2) and attends a grammar school. Conclusion: A thyroid gland at the base of the tongue is a rare cause of latent hypothyroidism and is difficult to diagnose when there is a lack of clinical symptoms. It can be detected at any age as an incidental finding.
CRIS-Team Scopus Importer:2020-05-05
Keywords: Ectopic lingual thyroid; Incidental finding; Rare disease; Subclinical hypothyroidism; Thyroid ultrasound

Electric Field-Induced Osteogenic Differentiation on TiO2 Nanotubular Layer - Park, Jung Hyun; Mazare, Anca Valentina; Schneider, Holm; Mark, Klaus; Fischer, Michael; Schmuki, Patrik (Tissue Engineering - Part C: Methods, 2016)
On biocompatible implant surfaces, cellular behavior and fate of stem cells are determined not only by microenvironmental signals but also by electrochemical signals. The potential of electric fields (EFs) to stimulate bone growth and bone healing has been widely demonstrated, but the molecular mechanism linking EFs to osteogenic differentiation has remained elusive. Here we show that constant EFs triggered osteogenic induction of mesenchymal stem cells (MSCs) on a defined nanotubular TiO2 substrate. EFs stimulate the formation of plasma membrane protrusions and the transport of connexin 43 to these protrusions. Connexin 43 is required for the EF-induced lasting intracellular calcium increase, which rapidly propagates to neighboring cells by gap junctions. This enables simultaneous osteogenic induction following downstream calcineurin/CAMKII/NFAT signaling. We propose that connexin 43-mediated, EF-induced osteogenic differentiation of MSCs on a defined nanotubular titanium oxide surface may give new insight on therapeutic interventions for bone regeneration and tissue engineering approaches.
EVALuna2:10221

Elektronische Verordnungssysteme auf pädiatrischen Normalstationen - Wimmer, Stefan; Toni, Irmgard (Monatsschrift Kinderheilkunde, 2022)
Background: Computerized physician order entry (CPOE) systems are used more and more frequently in pediatric hospitals. The reasons are optimized patient care and documentation as well as the potential reduction of adverse drug reactions (ADR) caused by medication errors; however, for the implementation on pediatric wards special technical requirements for the software have to be considered to avoid danger to patients due to software or user errors. Aim of the study: The available literature on the use of CPOE systems on general pediatric wards was analyzed with respect to the influence on ADR. Methods: A structured literature search with defined inclusion criteria was carried out in PubMed. Results: Out of 181 search results 4 studies met the inclusion criteria. None of the three studies from the USA and the one from Hong Kong could show a significant reduction of clinically relevant ADRs or medication errors with harm; however, three studies reported a significant positive effect on potentially harmful medication errors. These results correspond to our own data that have so far not been published in a journal. Discussion: Overall, the available studies showed a positive effect on the frequency of medication errors. The use of CPOE systems seems to be meaningful on general pediatric wards on condition that the software is suitable and the personnel are comprehensively trained.
CRIS-Team Scopus Importer:2022-02-11
Keywords: Adverse drug reaction; Clinical decision support; Documentation; Medication error; Patient care

Elevated n-3/n-6 PUFA ratio in early life diet reverses adverse intrauterine kidney programming in female rats - Voggel, Jenny; Fink, Gregor; Zelck, Magdalena; Wohlfarth, Maria; Post, Julia M.; Bindila, Laura; Rauh, Manfred; Amann, Kerstin Ute; Alcazar, Miguel A. Alejandre; Doetsch, Joerg; Nuesken, Kai-Dietrich; Nuesken, Eva (Journal of Lipid Research, 2022)
Intrauterine growth restriction (IUGR) predisposes to chronic kidney disease via activation of proinflammatory pathways, and omega-3 PUFAs (n-3 PUFAs) have anti-inflammatory properties. In female rats, we investigated 1) how an elevated di-etary n-3/n-6 PUFA ratio (1:1) during postnatal kidney development modifies kidney phospholipid (PL) and arachidonic acid (AA) metabolite content and 2) whether the diet counteracts adverse molecular pro-tein signatures expected in IUGR kidneys. IUGR was induced by bilateral uterine vessel ligation or intra-uterine stress through sham operation 3.5 days before term. Control (C) offspring were born after uncom-promised pregnancy. On postnatal (P) days P2-P39, rats were fed control (n-3/n-6 PUFA ratio 1:20) or n-3 PUFA intervention diet (N3PUFA; ratio 1:1). Plasma parameters (P33), kidney cortex lipidomics and pro-teomics, as well as histology (P39) were studied. We found that the intervention diet tripled PL-DHA content (PC 40:6; P < 0.01) and lowered both PL-AA content (PC 38:4 and lyso-phosphatidylcholine 20:4; P < 0.05) and AA metabolites (HETEs, dihydrox-yeicosatrienoic acids, and epoxyeicosatrienoic acids) to 25% in all offspring groups. After ligation, our network analysis of differentially expressed proteins identified an adverse molecular signature indicating inflammation and hypercoagulability. N3PUFA diet reversed 61 protein alterations (P < 0.05), thus miti-gating adverse IUGR signatures. In conclusion, an elevated n-3/n-6 PUFA ratio in early diet strongly reduces proinflammatory PLs and mediators while increasing DHA-containing PLs regardless of prior intrauterine conditions. Counteracting a proin-flammatory hypercoagulable protein signature in young adult IUGR individuals through early diet intervention may be a feasible strategy to prevent developmentally programmed kidney damage in later life.
CRIS-Team WoS Importer:2022-12-02

Elexacaftor – Tezacaftor – Ivacaftor treatment improves systemic infection parameters and Pseudomonas aeruginosa colonization rate in patients with cystic fibrosis a monocentric observational study - Schnell, Alexander; Hober, Hannah; Kaiser, Natalie; Ruppel, Renate; Geppert, Annika; Tremel, Christina; Sobel, Julia; Plattner, Erika; Wölfle, Joachim; Hörning, André (Heliyon, 2023)
Background & aims: The CFTR-modulating therapy Elexaftor – Tezacaftor - Ivacaftor (ETI) has been widely prescribed since its approval in 2020 in the European Union. The aim of this study was to methodically evaluate the effects of an ETI treatment on clinical, biochemical data and Pseudomonas colonization in order to demonstrate its efficacy. Methods: This prospective monocentric study comprised 69 patients diagnosed with cystic fibrosis aged at least 12 years and treated with ETI between September 2020 and November 2021. Clinical and laboratory data of each patient and study visit were collected before and after 24 weeks of ETI treatment. Follow-up status of Pseudomonas aeruginosa (PsA) colonization was assessed after one year of therapy by regularly determined sputum or throat swab samples. Results: Marked improvements biochemical markers of systemic inflammation as white blood cell count, levels of immunoglobulins A, G and M and albumin within 24 weeks of therapy were observed. ETI treatment proved to be effective as seen by amelioration of lung function and sweat chloride concentration. Assessment of PsA colonization status revealed a conversion from a positive to negative detection in 36% of the cases after one year of therapy. Conclusions: ETI treatment effectively improves systemic inflammation parameters and shows promising results in PsA status conversion.
CRIS-Team Scopus Importer:2023-06-02
Keywords: CFTR modulator; Clinical data; Cystic fibrosis; Elexacaftor; ETI; Inflammation markers; Ivacaftor; Kaftrio; Tezacaftor

Emerging technologies in paediatric laboratory medicine - Mak, Chloe; Papassotiriou, Ioannis; Zierk, Jakob; Kohse, Klaus P.; Greaves, Ronda F.; Geaghan, Sharon M.D.; Lang, Tim; Loh, Tze Ping (Journal of Laboratory Medicine, 2021)
CRIS-Team Scopus Importer:2021-10-29

ENGRAFTMENT, DIFFERENTIATION AND BIOLOGICAL EFFECTS OF CORD BLOOD-DERIVED CLONAL CELLS ADMINISTERED INTRAVENOUSLY TO NEWBORN RATS WITH HYPOXIC-ISCHEMIC BRAIN INJURY - Yang, Xiaojun; Griesmaier, E.; Wegleiter, K.; Schlager, G. W.; Weisbach, Volker Günter; Keller, M.; Park, J.; Schneider, Holm (2016)
EVALuna2:34012

Enhancing refiner - Improving performance of reference interval estimation for skewed distributions - Ammer, Tatjana; Schutzenmeister, A.; Prokosch, Hans-Ulrich; Rauh, Manfred; Zierk, Jakob; Rank, C. M. (CLINICA CHIMICA ACTA, 2022)
CRIS-Team WoS Importer:2022-07-08

Enteral Nutrition Therapies in Children with Crohn's Disease - Current Strategies and Possible Modes of Action Enterale Ernährungstherapien beim pädiatrischen M. Crohn Anwendungen und Wirkweise - Hörning, André; Schmidt-Choudhury, Anjona (Aktuelle Ernährungsmedizin, 2023)
Nutrition has an essential effect on the occurence and course of disease in inflammatory bowel disease. Several factors as for example breast feeding, fiber intake from fruit as well as the so called mediterranian diet have been identified as being protective with regard to developing IBD. On the other hand, intake of high levels of sugar, raw meat or ultraprocessed food is associated with a higher risk for a manifestation of IBD in genetically predisposed children. Nevertheless, the underlying mechanisms how exclusion diets alone or in combination with medication modulate intestinal microbiota lead to mucosal healing still have to be elucidated. Since there already exists knowledge on the influence of nutrition on treating or preventing IBD this should be implicated in therapeutic and prevention strategies.
CRIS-Team Scopus Importer:2023-06-23
Keywords: CDED; EET; IBD; microbiota; nutrition

Enzymatic lipid oxidation by eosinophils propagates coagulation, hemostasis, and thrombotic disease. - Uderhardt, Stefan; Ackermann, Jochen A.; Fillep, Tobias; Hammond, Victoria J.; Willeit, Johann; Santer, Peter; Mayr, Manuel; Biburger, Markus; Miller, Meike; Zellner, Katie R.; Stark, Konstantin; Zarbock, Alexander; et al. (Journal of Experimental Medicine, 2017)
Blood coagulation is essential for physiological hemostasis but simultaneously contributes to thrombotic disease. However, molecular and cellular events controlling initiation and propagation of coagulation are still incompletely understood. In this study, we demonstrate an unexpected role of eosinophils during plasmatic coagulation, hemostasis, and thrombosis. Using a large-scale epidemiological approach, we identified eosinophil cationic protein as an independent and predictive risk factor for thrombotic events in humans. Concurrent experiments showed that eosinophils contributed to intravascular thrombosis by exhibiting a strong endogenous thrombin-generation capacity that relied on the enzymatic generation and active provision of a procoagulant phospholipid surface enriched in 12/15-lipoxygenase-derived hydroxyeicosatetraenoic acid-phosphatidylethanolamines. Our findings reveal a previously unrecognized role of eosinophils and enzymatic lipid oxidation as regulatory elements that facilitate both hemostasis and thrombosis in response to vascular injury, thus identifying promising new targets for the treatment of thrombotic disease.

Eosinophilic esophagitis—an underestimated food allergy? Eosinophile Ösophagitis – Eine unterschätzte Nahrungsmittelallergie? - Hörning, André; Madisch, A. (Die Dermatologie, 2025)
Eosinophilic oesophagitis (EoE) is a chronic T2-inflammatory disease and can be figuratively referred to as atopic dermatitis of the oesophagus. It is an immune-mediated disease caused by food allergens and is histologically defined by eosinophilic infiltration and clinically characterised by symptoms of oesophageal dysfunction. In addition to reducing the currently still considerable diagnostic latency, the focus is on prioritising existing and new treatment options with the aim of ensuring effective patient care with improved quality of life in the long term.
CRIS-Team Scopus Importer:2025-06-06
Keywords: Elimination diet; Eosinophilic infiltration; Esophageal dysfunction; Food allergens; Quality of life

Epicutaneous Application of Imiquimod to Model Psoriasis-Like Skin Disease Induces Water-Saving Aestivation Motifs and Vascular Inflammation - Wild, Johannes; Ringen, Julia; Bieler, Tabea; Knopp, Tanja; Lagrange, Jérémy; Molitor, Michael; Sies, Katharina; Kropp, Angela; Keller, Karsten; Daiber, Andreas; Münzel, Thomas; Rauh, Manfred; et al. (Journal of Investigative Dermatology, 2022)
CRIS-Team Scopus Importer:2022-10-28

Epidemiological Survey and Retrospective Analysis of Salmonella Infections between 2000 and 2017 in Warmia and Masuria Voivodship in Poland - Dmochowska, Paula; Von Brzezinski, Maria Spyczak; Zelazowski, Jacek; Wojtkiewicz, Joanna; Jung, Susan; Harazny, Joanna M. (Medicina, 2019)
Background and Objectives: Salmonellosis is a major foodborne bacterial infection throughout the world. Epidemiological surveillance is one of the key factors to reduce the number of infections caused by this pathogen in both humans and animals. The first outcome measure was the prevalence of non-typhoid Salmonella (NTS) infections between 2000 and 2017 among the population of the predominantly agricultural and touristic Polish region of Warmia and Masuria (WaM). The second outcome measure was the comparison of the NTS hospitalization rate of all registered NTS cases, an investigation of the monthly reports of infections, and the exploration of the annual minimal and maximal NTS infection number in WaM in the above-mentioned time period. The last outcome was a comparison of the prevalence of NTS infections in the region and in its administrative districts by considering both rural and urban municipalities three years before and three years after the accession of Poland into the European Union (EU) in 2004. Materials and Methods: The total number of infections and hospitalizations in the 19 districts of the WaM voivodship in Poland was registered monthly between 2000-2017 by the Provincial Sanitary-Epidemiological Station in Olsztyn, Poland. Results: Between 2000 and 2017, the number of diagnosed salmonellosis cases decreased significantly in WaM; the decrease was higher in urban districts than in rural ones, and the ratio of hospitalizations and the total number of NTS cases increased significantly across all districts. The lowest number of cases was reported in the winter months and was stable from 2007, whereas the highest number was reported in the summer months with a higher tendency of outbreaks. Conclusion: The falling number of salmonellosis cases in 2000-2017 in WaM reflects the general trend in Poland and Europe. The decrease of NTS infections in WaM is related to the accession of Poland into the EU.
CRIS-Team WoS Importer:2019-04-30

Epidemiology of inherited epidermolysis bullosa in Germany - Has, Cristina; Hess, Moritz; Anemueller, Waltraud; Blume-Peytavi, Ulrike; Emmert, Steffen; Foelster-Holst, Regina; Frank, Jorge; Giehl, Kathrin; Guenther, Claudia; Hammersen, Johanna; Hillmann, Kathrin; Hoeflein, Bettina; et al. (Journal of the European Academy of Dermatology and Venereology, 2022)
Background Epidermolysis bullosa (EB) is a rare genetic disorder manifesting with skin and mucosal membrane blistering in different degrees of severity. Objective Epidemiological data from different countries have been published, but none are available from Germany. Methods In this population-based cross-sectional study, people living with EB in Germany were identified using the following sources: academic hospitals, diagnostic laboratories and patient organization. Results Our study indicates an overall EB incidence of 45 per million live births in Germany. With 14.23 per million live births for junctional EB, the incidence is higher than in other countries, possibly reflecting the availability of early molecular genetic diagnostics in severely affected neonates. Dystrophic EB was assessed at 15.58 cases per million live births. The relatively low incidence found for EB simplex, 14.93 per million live births, could be explained by late or missed diagnosis, but also by 33% of cases remaining not otherwise specified. Using log-linear models, we estimated a prevalence of 54 per million for all EB types, 2.44 for junctional EB, 12.16 for dystrophic EB and 28.44 per million for EB simplex. These figures are comparable to previously reported data from other countries. Conclusions Altogether, there are at least 2000 patients with EB in the German population. These results should support national policies and pharmaceutical companies in decision-making, allow more precise planning of drug development and clinical trials, and aid patient advocacy groups in their effort to improve quality of life of people with this orphan disease.
CRIS-Team WoS Importer:2022-11-11

Epidemiology of inherited Epidermolysis bullosa in Germany - Has, Cristina; Hess, Moritz; Anemueller, Waltraud; Blume-Peytavi, Ulrike; Emmert, Steffen; Foelster-Holst, Regina; Frank, Jorge; Giehl, Kathrin; Günther, Claudia; Hammersen, Johanna; Hillmann, Kathrin; Hoeflein, Bettina; et al. (Journal of the European Academy of Dermatology and Venereology, 2023)

Equal cerebral perfusion during extended aortic coarctation repair - Rüffer, André; Knieling, Ferdinand; Cesnjevar, Robert; Regensburger, Adrian; Purbojo, Ariawan; Dittrich, Sven; Münch, Frank; Wölfle, Joachim; Jüngert, Jörg M. (European Journal of Cardio-Thoracic Surgery, 2021)
OBJECTIVES: Aortic coarctation with distal aortic arch hypoplasia can be effectively addressed by coarctation resection with extended end-to-end-anastomosis (REEEA). Particularly, when unilateral cerebral perfusion (UCP) is established by clamping of left-sided supra-aortic vessels, the extent of cerebral blood flow distribution during repair remains undetermined, so far. Transfontanellar contrast-enhanced ultrasound (T-CEUS) can be utilized for real-time visualization and quantitative evaluation of cerebral blood flow. This study quantitatively evaluates cerebral perfusion during REEEA by using intraoperative T-CEUS. METHODS: In a prospective study, 9 infants with open fontanelle undergoing REEEA [median age: 13 days (range 1-34) and median weight 3.1 kg (range 2.2-4.4)] were intraoperatively examined with T-CEUS at 3 consecutive time-points: before skin incision, during UCP and after skin suture. A software-based analysis of 11 parameters was used for data evaluation. Absolute and relative blood flow in contralateral hemispheres was measured in side-by-side comparison, and referenced to baseline measurements. RESULTS: No side-depend absolute or relative cerebral perfusion differences were found during REEEA, except for an increased relative 'wash-out-rate' (P = 0.0013) in favour of the right hemisphere after surgery. Compared to ipsilateral baseline levels, 'rise time' was transiently increased in right (P = 0.0277) and 'time-to-peak' in both hemispheres (right: P = 0.0403 and left: P = 0.0286), all during UCP. CONCLUSIONS: The use of T-CEUS provided evidence for homogenous distribution of contrast agent in both hemispheres during UCP. T-CEUS can be utilized for the postprocedural evaluation of cerebral perfusion during congenital cardiac surgery. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov Unique, Identifier: NCT03215628.
CRIS-Team Scopus Importer:2022-02-11
Keywords: Aortic coarctation; Cerebral perfusion; Extended end-to-end-anastomosis

Eradication of Ventricular Assist Device Driveline Infection in Paediatric Patients with Taurolidine - Weichsel, Johannes; Baldauf, Benito; Bonnemeier, Hendrik; Lau, Ernest W.; Dittrich, Sven; Cesnjevar, Robert (Journal of Cardiovascular Development and Disease, 2022)
Ventricular assist devices (VADs) are used to provide mechanical circulatory support to patients with end-stage heart failure. The driveline connecting the external power source to the pump(s) of the intra-corporal VAD breaches the protective skin barrier and provides a track for microbes to invade the interior of the patient's body. Driveline infection constitutes a major and potentially fatal vulnerability of VAD therapy. Driveline infection cannot traditionally be salvaged and requires the extraction of the entire VAD system. We report here the successful eradication of a VAD driveline infection with a taurolidine-containing antimicrobial solution used for preventing the infection of cardiac implantable electronic devices. If replicated in more cases, the novel treatment concept described here may provide a valuable alternative management strategy of salvage rather than explantation for VAD driveline infection.
CRIS-Team WoS Importer:2022-02-04

Erratum: Zahn et al. Manipulation of medicinal products for oral administration to paediatric patients at a german university hospital: An observational study. Pharmaceutics 2020, 12, 583 - Zahn, Julia; Hörning, André; Trollmann, Regina; Rascher, Wolfgang; Neubert, Antje (Pharmaceutics, 2021)
The authors wish to make the following corrections to the affiliation and acknowledgments part [1]. The affiliation of all of the authors of “Department of Paediatrics and Adolescent Medicine, Universitätsklinikum Erlangen, 91054 Erlangen, Germany”, should be “Department of Paediatrics and Adolescent Medicine, Universitätsklinikum Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany”. The updated “Acknowledgments” section is as follows “The authors would like to thank the nursing staff for a valuable exchange on the subject of manipulation and the opportunity to observe dispensing of medicines in clinical practice. The present work was performed in (partial) fulfilment of the requirements for obtaining the degree Dr. rer. biol. hum.”. The authors would like to apologize for any inconvenience caused to the readers by these changes.
CRIS-Team Scopus Importer:2021-08-06

Erratum zu: Arzneimittel für neuartige Therapien – Perspektiven, Chancen, Herausforderungen: Stellungnahme der Deutschen Gesellschaft für Kinder- und Jugendmedizin e. V. (DGKJ) (Monatsschrift Kinderheilkunde, (2020), 10.1007/s00112-020-01056-x) (Monatsschrift Kinderheilkunde, (2020), 10.1007/s00112-020-01068-7) - Rascher, Wolfgang; Klingebiel, Thomas; Herting, Egbert; Hoffmann, Georg F.; Berner, Reinhard; Krägeloh-Mann, Ingeborg; Gärtner, Jutta; Zepp, Fred; Schara, Ulrike (Monatsschrift Kinderheilkunde, 2021)
CRIS-Team Scopus Importer:2021-01-15

Erratum zu: Die intrazerebrale Gentherapie des Aromatischen-L-Aminosäure-Decarboxylase-Mangels mit Eladocagene exuparvovec. Eine Stellungnahme der Gesellschaft für Neuropädiatrie (GNP), der Arbeitsgemeinschaft pädiatrischer Stoffwechselstörungen (APS), der Deutschen Gesellschaft für Neurochirurgie (DGNC) und der Deutschen Gesellschaft für Kinder- und Jugendmedizin (DGKJ) - Opladen, Thomas; Brennenstuhl, Heiko; Kuseyri Hübschmann, Oya; Call, Debora; Green, Kim; Schara, Ulrike; Rascher, Wolfgang; Hövel, Annegret; Assmann, Birgit; Kölker, Stefan; Westhoff, Jens H.; Walter, Magdalena; et al. (Monatsschrift Kinderheilkunde, 2022)
CRIS-Team Scopus Importer:2022-10-14

Erster epileptischer Anfall und Epilepsien im Erwachsenenalter: Kurzfassung S2k-Leitlinie der Deutschen Gesellschaft für Neurologie in Zusammenarbeit mit der Deutschen Gesellschaft für Epileptologie - Holtkamp, Martin; May, Theodor W.; Berkenfeld, Ralf; Bien, Christian G.; Coban, Ingrid; Knake, Susanne; Michaelis, Rosa; Rémi, Jan; Seeck, Margitta; Surges, Rainer; Weber, Yvonne; Baum, Petra; et al. (Clinical Epileptology, 2024)
The new S2k guideline “First epileptic seizure and epilepsies in adulthood” provides recommendations on clinically relevant issues in five major topics: management of first epileptic seizures, pharmacotherapy, epilepsy surgery, complementary and supportive treatment, and psychosocial aspects. For the topic management of first epileptic seizures, the guideline provides recommendations on identifying the two major differential diagnoses, syncope and psychogenic non-epileptic seizure. The importance of additional examinations such as EEG, MRI and cerebrospinal fluid for syndromic classification and etiological allocation is discussed. Recommendations on neuropsychological and psychiatric screening tests are also given. The topic pharmacotherapy issues recommendations on antiseizure medication in monotherapy for focal, generalized and unclassified epilepsies; patient groups with special challenges such as the aged, women of childbearing potential and people with mental retardation are emphasized. Further issues are indications for measuring serum concentrations of antiseizure medication and possible risks of switching manufacturers. In the topic epilepsy surgery, indications for presurgical assessment and the multiple therapeutic approaches, such as resection, laser ablation, and neurostimulation are presented. Recommendations on postoperative management of patients, including rehabilitation and psychosocial counselling, are given. The topic complementary and supportive therapeutic approaches comprises recommendations on the diagnostics and treatment of common psychiatric comorbidities of epilepsy, such as anxiety disorder, depression and psychosis. Another important issue is the management of psychogenic non-epileptic seizures as a neuropsychiatric differential diagnosis or comorbidity of epileptic seizures. Furthermore, recommendations on the potential role of ketogenic diet and on acupuncture, homeopathy and other complementary approaches are made. The recommendations on psychosocial aspects comprise practical issues, such as fitness to drive a car, training and occupation, medical rehabilitation, sport, transition, patients’ self-help, education programs for patients and next of kin, adherence, advise on SUDEP.
CRIS-Team Scopus Importer:2024-03-22
Keywords: Consensus; Epilepsy surgery; Pharmacotherapy; Psychosocial aspects; Recommendations

Erythroderma and Hypernatraemic Dehydration in Newborn - A Case report of Netherton Syndrome - Anneser, Verena; Mueller, Fabian; Wild, Florian; Metze, Dieter; Schneider, Holm; Steinhoff, Martin; Seeliger, Stephan (Klinische Pädiatrie, 2020)
Netherton syndrome (NS) is a rare, severe, autosomal recessive form of congenital ichthyosis, associated with a characteristic defect in the hair shaft (Trichorrhexis invaginata), erythroderma, and a pronounced atopic disposition due to an altered immune system. Its incidence is about 1:100,000 to 1: 200,000. The disease is caused by mutations in the gene SPINK5 (5q31-q32) which codes for the serine protease inhibitor LEKTI. Affected newborns show a non-uniform picture of generalized erythroderma with scaling of the skin and sometimes even present as Collodion babys. A serious complication during early infancy is hypernatremic dehydration resulting from the inadequate barrier function of the skin. The mucocutaneous barrier dysfunction also leads to recurrent infections, atopy, diarrhea, and intestinal malabsorption with concomitant failure to thrive.
CRIS-Team WoS Importer:2020-06-05

Establishment of Reference Intervals for Alkaline Phosphatase in Pakistani Children Using a Data Mining Approach - Ahmed, Sibtain; Zierk, Jakob; Khan, Aysha Habib (Labmedicine, 2019)
OBJECTIVE: To establish reference intervals (RIs) for alkaline phosphatase (ALP) levels in Pakistani children using an indirect data mining approach. METHODS: ALP levels analyzed on a Siemens Advia 1800 analyzer using the International Federation of Clinical Chemistry's photometric method for both inpatients and outpatients aged 1 to 17 years between January 2013 and December 2017, including patients from intensive care units and specialty units, were retrieved. RIs were calculated using a previously validated indirect algorithm developed by the German Society of Clinical Chemistry and Laboratory Medicine's Working Group on Guide Limits. RESULTS: From a total of 108,845 results, after the exclusion of patients with multiple specimens, RIs were calculated for 24,628 males and 18,083 females with stratification into fine-grained age groups. These RIs demonstrate the complex age- and sex-related ALP dynamics occurring during physiological development. CONCLUSION: The population-specific RIs serve to allow an accurate understanding of the fluctuations in analyte activity with increasing age and to support clinical decision making.
EVALuna2:210520

Establishment of Specialized Pediatric Palliative Home Care in the Medical Valley of the European Metropolitan Area Nuremberg - Hébert, Steven; Gravou-Apostolatou, Chara; Rascher, Wolfgang (Klinische Pädiatrie, 2017)
Background As part of the 2007 health reform in Germany the structure of outpatient palliative care for children and adolescents was adopted for the first time and then implemented in Erlangen-Nuremberg in 2009. Methods The introduction of Pediatric Palliative Home Care (PPHC) at the Hospital for Children and Adolescents at the University of Erlangen-Nuremberg was retrospectively analyzed between the years 2009 to 2014. Referring medical records (paper-based and electronic) were evaluated systematically. Results Considering 69 patients within this study, 44 (63.8%) died during the investigated period and 61% of these Patients deceased at home. 60 patients (87%) had a written emergency plan, which was jointly developed with patients and particularly their parents and relatives in cooperation with the PPHC team. Over the years and with increasing experience, the number and duration of emergency hospitalization decreased. Even complex therapies, such as patient-controlled analgesia with PCA pump could be implemented on an outpatient basis. Conclusion The descriptive cohort study demonstrates that palliative care for children, despite the medical and structural complexity is possible in an ambulatory setting. It allows a similar, if not better care, compared to inpatient palliative care for children and adolescents, not only for the affected patients, but also for their families.
EVALuna2:34224

Etiology, Risk Factors and Diagnosis of Back Pain in Children and Adolescents: Evidence-and Consensus-Based Interdisciplinary Recommendations - Frosch, Michael; Mauritz, Maximilian D.; Bielack, Stefan; Blödt, Susanne; Dirksen, Uta; Dobe, Michael; Geiger, Florian; Häfner, Renate; Höfel, Lea; Hübner-Möhler, Bettina; von Kalle, Thekla; Lawrenz, Burkhard; et al. (Children, 2022)
Using a structured approach and expert consensus, we developed an evidence-based guideline on the diagnosis of back pain and the treatment of non-specific back pain in children and adolescents. The first part comprises etiology, risk factors, and diagnosis. The second part, published in the same issue, includes treatment and prevention. A comprehensive and systematic literature search was conducted to identify relevant guidelines and studies. Based on the findings of this literature search, recommendations on risk factors and diagnosis were formulated and voted on by experts in a structured consensus-building process. Notable red flags for specific back pain and evidence-based risk factors for non-specific back pain in children and adolescents were identified. Only three evidence-based recommendations could be formulated for causes, red flags, and risk factors for back pain, while two recommendations are based on expert consensus. Regarding diagnostics, eight expert consensus recommendations and one evidence-based recommendation could be provided. Despite the importance of adequate diagnosis for the treatment of back pain in children and adolescents, results of this work confirm the deficit in research investment in this area.
CRIS-Team Scopus Importer:2022-03-04
Keywords: Adolescents; Back pain; Children; Diagnosis; Etiology; Evidence-based; Guideline; Risk factors

ETOPOSIDE FOR PRIMARY HLH - BETTER THAN ITS REPUTATION - Lehmberg, Kai; Ledig, Svea; Wustrau, Katharina; Kontny, Udo; Westphal, Silke; Hundsdoerfer, Patrick; Jorch, Norbert; Scheer-Preiss, Johanna; Schneider, Dominik; Ghosh, Sujal; Naumann-Bartsch, Nora; Holzinger, Dirk; et al. (PEDIATRIC BLOOD & CANCER, 2023)
CRIS-Team WoS Importer:2023-02-24

European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB): An Update on the Pediatric CEUS Registry on Behalf of the "EFSUMB Pediatric CEUS Registry Working Group" - Dietrich, Christoph F.; Augustiniene, Rasa; Batko, Tomasz; Cantisani, Vito; Cekuolis, Andrius; Deganello, Annamaria; Dong, Yi; Franke, Doris; Harkanyi, Zoltan; Humphries, Paul D.; Jedrzejczyk, Maciej; Jüngert, Jörg M.; et al. (Ultraschall in der Medizin, 2021)
Zusammenfassung
CRIS-Team WoS Importer:2021-04-02

European guidelines for the management of arterial hypertension 2018-what has changed? - Jung, Susan; Schmieder, Roland (Internist, 2019)
BackgroundIn November 2017, the latest American guidelines for the management of arterial hypertension were published. With these guidelines lowering the threshold for hypertension to 130/80mmHg, the latest European guidelines were expected with excitement.ObjectivesThis article gives an overview on the European Society of Cardiology (ESC) and European Society of Hypertension (ESH) 2018 guidelines for the management of arterial hypertension, thereby identifying the most relevant changes in comparison to previous guidelines.Current dataThe latest 2018 ESC/ESH guidelines adhere to the previous definition of hypertension, in which ablood pressure of 140/90mmHg is considered as threshold for diagnosis. In contrast, there was achange in blood pressure treatment target from below 140/90 to between 120-129/70-79mmHg in patients<65years if well tolerated. Among patients65years, asystolic blood pressure between 130 and 139mmHg is recommended, whereas adiastolic blood pressure between 70 and 79mmHg should be targeted. Additionally the guidelines recommend the use of fixed dose combinations as first choice instead of monotherapy to improve adherence. Interventional treatment strategies should only be applied in carefully selected patients at experienced centers and are not recommended outside of clinical studies and registers. Furthermore, the chapters regarding initiation of blood pressure-lowering therapy and clinical evaluation as well as management of hypertension emergencies have been outlined.ConclusionsThe latest European guidelines for the management of hypertension include several changes. One of the most important aspects is thatin contrast to the American guidelinesthe threshold for diagnosis remains at 140/90mmHg, whereas treatment target range has been lowered by roughly 10mmHg and single pill fixed dose combinations are recommended.
CRIS-Team WoS Importer:2019-02-21

Evaluating the Use of Neonatal Colonization Screening for Empiric Antibiotic Therapy of Sepsis and Pneumonia - Bär, Alisa; Schmitt-Grohé, Sabina; Held, Jürgen; Lubig, Julia; Hanslik, Gregor; Fahlbusch, Fabian; Reutter, Heiko Martin; Wölfle, Joachim; van der Donk, Adriana; Schleier, Maria; Hepp, Tobias; Morhart, Patrick (Antibiotics, 2023)
(1) Background: Since 2013, weekly screening for multidrug-resistant Gram-negative (MDRGN) bacteria has been performed in German neonatal intensive care units (NICU). National guidelines recommend considering these colonization analyses for antibiotic treatment regimens. Our retrospective single center study provides insight into the clinical dichotomy of bacterial colonization and infection rates in neonates. (2) Methods: We analyzed microbiological data of neonates admitted to our tertiary level NICU over nine years. Colonization with MDRGN/Serratia marcescens (SERMA) was compared to microbiological findings in sepsis and pneumonia. (3) Results: We analyzed 917 blood and 1799 tracheal aspirate samples. After applying criteria from the Nosocomial Infection Surveillance for Neonates (NEO-KISS), we included 52 and 55 cases of sepsis and pneumonia, respectively; 19.2% of sepsis patients and 34.5% of pneumonia patients had a prior colonization with MDRGN bacteria or SERMA. In these patients, sepsis was not attributable to MDRGN bacteria yet one SERMA, while in pneumonias, ten MDRGN bacteria and one SERMA were identified. We identified late-onset pneumonia and cesarean section as risk factors for MDRGN/SERMA acquisition. (4) Conclusions: Colonization screening is a useful tool for hygiene surveillance. However, our data suggest that consideration of colonization with MDRGN/SERMA might promote extensive use of last resort antibiotics in neonates.
CRIS-Team Scopus Importer:2023-03-10
Keywords: colonization; MDR; MDRGN; multidrug-resistant bacteria; multidrug-resistant Gram-negative bacteria; neonatal infection; neonates; pneumonia; screening; sepsis

Evaluation and implementation of multidisciplinary, standardized, guideline-based long-term follow-up care for adult survivors of childhood cancer in Germany: protocol of a prospective, multi-center, nationwide study (LE-Na) - Cytera, C.; Baust, K.; Borgmann-Staudt, A.; Calaminus, G.; Egger-Heidrich, K.; Faber, J.; Grabow, D.; Halbsguth, T.; Kock-Schopenhauer, A.; König, I. R.; Michaelis, S.; Neumann, A.; et al. (BMC Cancer, 2025)
Background: Late effects can occur years to decades after cancer therapy, resulting in morbidity and reduced health-related quality of life. Clinical long-term follow-up (LTFU) enables timely diagnosis and treatment of these sequelae. So far, only a minority of childhood cancer survivors (CCS) in Germany regularly visit LTFU care facilities. The LE-Na study aims to: 1. implement and/or improve LTFU care structures for adult CCS in Germany, 2. inform former patients about late effects and LTFU care centers, 3. create a basis for future research by building up a central database, consent management and infrastructure, 4. establish a clinical LTFU cohort of adult CCS in Germany, 5. evaluate the implementation of the LFTU care, 6. enable the expansion of LTFU care structures nationwide, 7. integrate the developed LTFU care structures into the standard health care system. Methods: Within five years, approximately 5000 CCS will be invited to visit one of the 10 LTFU centers in Germany. Study participants are either contacted by the German Childhood Cancer Registry (GCCR), transitioned from the local pediatric oncology care unit, or recruited via media. They are assigned to one of three different risk groups based on an evidence-based risk stratification and receive standardized multidisciplinary follow-up care. Primary outcomes are satisfaction with the LTFU care offer as well as degree of health-related self-efficacy expectation. They will be assessed at two time points. A scientific evaluation of the implemented LTFU care will be enabled by a waitlist control group. The harmonized outcome data are documented in a standardized database. Discussion: By addressing CCS in Germany who have not received standardized LTFU care yet, the LE-Na study expects to improve nationwide LTFU care and therewith patient’s satisfaction with the LTFU care offer as well as their health-related self-efficacy expectation.
CRIS-Team Scopus Importer:2025-06-06
Keywords: Childhood cancer survivors; Late effects; Long-term follow-up