Papilledema and Echographically Detectable Retro-orbital Dilatation of the Sub-arachnoidal Space with open Fontanelle - Six Case Reports - Gusek-Schneider, G. C.; Mardin, Christian Y.; Trollmann, Regina; Eyüpoglu, Ilker Yasin; Ganslandt, Oliver Thomas (Klinische Monatsblätter für Augenheilkunde, 2011)
This paper analyses the case reports for three children in which a papilledema occurred before the age of one year. Furthermore, an analysis is also given of three further case reports for children aged less than one year in which, in spite of open fontanelle, no papilledema was found, however, a dilatation of the sub-arachnoidal space was demonstrated echographically. Even in children less than one year of age in which an open fontanelle still exists and in whom a neuro-paediatric clarification of internal hydrocepalus is made, in spite of opththalmoscopically inconspicuous findings for the papilla an echography is indispensable for the evaluation of the sub-arachnoidal space. Here, the early recognition of a dilatation of the retro-bulbar sub-arachnoidal space can possibly prevent the occurrence of a consecutive optic atrophy. At the present time, the data available do not allow the recommendation of an upper age limit for an echographic examination.
EVALuna2:21040

Parecoxib does not suppress thromboxane synthesis in newborn piglets with group B streptococcal sepsis - Nögel, Stephanie; Chada, Martin; Schmidt, Ariana; Bosselmann, Stephan; Kandler, Michael; Schweer, Horst; Watzer, Bernhard; Schneider, Holm; Gessner, André; Rascher, Wolfgang (Prostaglandins & Other Lipid Mediators, 2009)
Group B streptococci (GBS) cause fatal sepsis in newborns. Strong activation of thromboxane synthesis is assumed to correlate with severe pulmonary hypertension. In this study we compared the impact of indomethacin versus parecoxib on hemodynamics and outcome and investigated the pharmacological effects on thromboxane synthesis and EP-3 receptor gene expression. Whereas both parecoxib and indometacin reduced expression of thromboxane synthase and EP-3 receptor in infected lung tissue, parecoxib did not suppress urine levels of thromboxane like indometacin. We presume that COX-2 inhibition in GBS sepsis is associated with enhanced thrombogenicity. © 2009 Elsevier Inc. All rights reserved.
CRIS-Team Scopus Importer:2020-07-01
Keywords: Group b streptococcal sepsis; Parecoxib; Thromboxane

Partial homonymous hemianopia of traumatic origin after riding a high-speed amusement ride - Hohberger, B.; Trollmann, Regina; Rompel, O.; Gölitz, Philipp; Gusek-Schneider, G. C. (Ophthalmologe, 2016)
Amusement park injuries have become more common in recent years. Especially neurological symptoms dominate clinical findings. In this article, the case of a 15-year-old child with homonymous hemianopia due to an atypical intracranial bleeding with subdural hematoma after a giant swing ride is described for the first time.
EVALuna2:21326

Particularities of Crohn's disease in pediatric patients: current status and perspectives regarding imaging modalities - Schreiber-Dietrich, Dagmar; Chiorean, Liliana; Cui, Xin-Wu; Braden, Barbara; Kucharzik, Torsten; Juengert, Joerg; Kosiak, Wojciech; Stenzel, Martin; Dietrich, Christoph F. (Expert Review of Gastroenterology and Hepatology, 2015)
A consensus on the best imaging modality evaluating inflammatory bowel disease in the pediatric population is lacking and it is often unclear which modality to choose in specific clinical circumstances. Children with inflammatory bowel disease are exposed to ionizing radiation from multiple imaging studies performed at initial diagnosis, throughout treatment and during the follow-up period. This paper discusses the value of different imaging techniques in pediatric patients with inflammatory bowel disease and gives a review of the literature. In addition, particular features of inflammatory bowel disease in children including the predilection of affected segments in the gastrointestinal tract are highlighted. Based on current literature knowledge, we encourage an integrative approach to the interpretation of clinical and imaging data for diagnosis and follow-up in daily clinical settings.
EVALuna2:18921

Passive mechanical properties in healthy and infarcted rat left ventricle characterised via a mixture model - Martonová, Denisa; Alkassar, Muhannad; Seufert, Julia; Holz, David; Duong, Minh Tuan; Reischl, Barbara; Friedrich, Oliver; Leyendecker, Sigrid (Journal of the Mechanical Behavior of Biomedical Materials, 2021)
During the cardiac cycle, electrical excitation is coupled with mechanical response of the myocardium. Besides the active contraction, passive mechanics plays an important role, and its behaviour differs in healthy and diseased hearts as well as among different animal species. The aim of this study is the characterisation of passive mechanical properties in healthy and infarcted rat myocardium by means of mechanical testing and subsequent parameter fitting. Elasticity assessments via uniaxial extension tests are performed on healthy and infarcted tissue samples from left ventricular rat myocardium. In order to fully characterise the orthotropic cardiac tissue, our experimental data are combined with other previously published tests in rats – shear tests on healthy myocardium and equibiaxial tests on infarcted tissue. In a first step, we calibrate the Holzapfel-Ogden strain energy function in the healthy case. Sa far, this orthotropic constitutive law for the passive myocardium has been fitted to experimental data in several species, however there is a lack of an appropriate parameter set for the rat. With our determined parameters, a finite element simulation of the end-diastolic filling is performed. In a second step, we propose a model for the infarcted tissue. It is represented as a mixture of intact myocardium and a transversely isotropic scar structure. In our mechanical experiments, the tissue after myocardial infarction shows significantly stiffer behaviour than in the healthy case, and the stiffness correlates with the amount of fibrosis. A similar relationship is observed in the computational simulation of the end-diastolic filling. We conclude that our new proposed material model can capture the behaviour of two kinds of tissues – healthy and infarcted rat myocardium, and its calibration with the fitted parameters represents the experimental data well.<br
CRIS-Team Scopus Importer:2021-04-09
Keywords: Fibrosis; Holzapfel-Ogden strain energy; Incompressibility; Myocardial infarction; Parameter fitting; Passive mechanics; Rat left ventricle

Pathway to assess severe primary IGF-1 deficiency diagnosis in a real-life setting: data from the Global Increlex (R) Registry - Bang, Peter; Polak, Michel; Bossowski, Artur; De Schepper, Jean; Sert, Caroline; Perrot, Valerie; Wölfle, Joachim (HORMONE RESEARCH IN PAEDIATRICS, 2022)
CRIS-Team WoS Importer:2022-10-07

Patientenverfügung und Ethik Beiträge zur guten klinischen Praxis - Frewer, Andreas; Fahr, Uwe; Rascher, Wolfgang (2009)

Patient Experiences and Challenges in the Management of Autoinflammatory Diseases—Data from the International FMF & AID Global Association Survey - Rech, Jürgen; Schett, Georg; Tufan, Abdurrahman; Kuemmerle-Deschner, Jasmin B.; Özen, Seza; Tascilar, Koray; Geck, Leonie; Krickau, Tobias; Cohen, Ellen; Welzel, Tatjana; Kuehn, Marcus; Vetterli, Malena (Journal of Clinical Medicine, 2024)
Background: Autoinflammatory diseases (AIDs) are rare, mostly genetic diseases that affect the innate immune system and are associated with inflammatory symptoms. Both paediatric and adult patients face daily challenges related to their disease, diagnosis and subsequent treatment. For this reason, a survey was developed in collaboration between the FMF & AID Global Association and the Erlangen Center for Periodic Systemic Autoinflammatory Diseases. Methods: The aim of the survey was to collect the personal assessment of affected patients with regard to their current status in terms of diagnostic timeframes, the interpretation of genetic tests, the number of misdiagnoses, and pain and fatigue despite treatment. Results: In total, data from 1043 AID patients (829 adults and 214 children/adolescents) from 52 countries were collected and analyzed. Familial Mediterranean fever (FMF) (521/50%) and Behçet’s disease (311/30%) were the most frequently reported diseases. The average time to diagnosis was 3 years for children/adolescents and 14 years for adults. Prior to the diagnosis of autoinflammatory disease, patients received several misdiagnoses, including psychosomatic disorders. The vast majority of patients reported that genetic testing was available (92%), but only 69% were tested. A total of 217 patients reported that no increase in acute-phase reactants was detected during their disease episodes. The intensity of pain and fatigue was measured in AID patients and found to be high. A total of 88% of respondents received treatment again, while 8% reported no treatment. Conclusions: AID patients, particularly adults, suffer from significant delays in diagnosis, misdiagnosis, and a variety of symptoms, including pain and fatigue. Based on the results presented, raising awareness of these diseases in the wider medical community is crucial to improving patient care and quality of life.
CRIS-Team Scopus Importer:2024-03-22
Keywords: autoinflammatory diseases; Behcet’s disease; diagnosis; familial Mediterranean fever (FMF); fatigue; misdiagnoses; pain; patient survey

Patient preference for therapies in hypertension: a cross-sectional survey of German patients - Schmieder, Roland; Högerl, Karin; Jung, Susan; Bramlage, Peter; Veelken, Roland; Ott, Christian (Clinical Research in Cardiology, 2019)
BACKGROUND: Hypertension is poorly controlled in numerous patients despite effective medication being available. Catheter-based renal denervation (RDN) has emerged as an alternative treatment option. We aimed to assess how likely patients with elevated blood pressure (BP) are to accept RDN as treatment option. METHODS: A questionnaire-based cross-sectional survey was performed in patients with elevated BP in Germany. Data on patient demographics, clinical characteristics and treatment preferences were collected, anonymized and analyzed. RESULTS: One thousand and eleven patients completed the survey. Mean age was 66 years (55% male). If not already on medication (n = 172), 38.2% of patients would prefer RDN. Of those already on drug therapy (n = 839), 28.2% would opt for RDN. Patients who were pro-RDN were younger (p < 0.0001) and more often male (p < 0.0001). Nineteen percent would choose RDN if it lowered systolic BP by at least 20 mmHg, more than 40% if they did not have to take any more pills thereafter, and 30% if it would lower BP by at least 10 mmHg. Experiences of side effects and drug adherence were identified as determinants of patient preference. Physicians were the main source of information regarding medical problems (95.5%) and influence patients' decision regarding therapies (98%). CONCLUSIONS: This survey found that a significant proportion of patients would choose catheter-based RDN over lifelong pharmacotherapy. These patients were younger and more likely to be male but their expectation of the extent of BP decrease with RDN was high. Physicians are key mediators for treatment selection. They need to incorporate patient preferences into shared decision making.
EVALuna2:118640

Patient preferences in genetic newborn screening for rare diseases: study protocol - Martin, Sylvia; Angolini, Emanuele; Audi, Jennifer; Bertini, Enrico; Bruno, Lucia Pia; Coulter, Joshua; Ferlini, Alessandra; Fortunato, Fernanda; Frankova, Vera; Garnier, Nicolas; Grauman, Åsa; Gross, Edith; et al. (BMJ Open, 2024)
Introduction Rare diseases (RDs) collectively impact over 30 million people in Europe. Most individual conditions have a low prevalence which has resulted in a lack of research and expertise in this field, especially regarding genetic newborn screening (gNBS). There is increasing recognition of the importance of incorporating patients’ needs and general public perspectives into the shared decision-making process regarding gNBS. This study is part of the Innovative Medicine Initiative project Screen4Care which aims at shortening the diagnostic journey for RDs by accelerating diagnosis for patients living with RDs through gNBS and the use of digital technologies, such as artificial intelligence and machine learning. Our objective will be to assess expecting parent’s perspectives, attitudes and preferences regarding gNBS for RDs in Italy and Germany. Methods and analysis A mixed method approach will assess perspectives, attitudes and preferences of (1) expecting parents seeking genetic consultation and (2) ‘healthy’ expecting parents from the general population in two countries (Germany and Italy). Focus groups and interviews using the nominal group technique and ranking exercises will be performed (qualitative phase). The results will inform the treatment of attributes to be assessed via a survey and a discrete choice experiment (DCE). The total recruitment sample will be 2084 participants (approximatively 1000 participants in each country for the online survey). A combination of thematic qualitative and logit-based quantitative approaches will be used to analyse the results of the study. Ethics and dissemination This study has been approved by the Erlangen University Ethics Committee (22–246_1-B), the Freiburg University Ethics Committee (23–1005 S1-AV) and clinical centres in Italy (University of FerraraCE: 357/2023/Oss/ AOUFe and Hospedale Bambino Gesu: No.2997 of 2 November 2023, Prot. No. _902) and approved for data storage and handling at the Uppsala University (2022-05806-01). The dissemination of the results will be ensured via scientific journal publication (open access).
CRIS-Team Scopus Importer:2024-05-03

Patient-reported health-related quality of life (HRQOL) following allogeneic stem cell transplantation (SCT) performed early after diagnosis of pediatric chronic myeloid leukemia (CML) - Schleicher, O.; Horndasch, A.; Krumbholz, Manuela; Sembill, S.; Karow, A.; Bremensdorfer, C.; Grabow, D.; Metzler, Markus; Suttorp, M. (BONE MARROW TRANSPLANTATION, 2022)
CRIS-Team WoS Importer:2022-11-25

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)
BackgroundPediatric CML is very rare. Before the introduction of tyrosine kinase inhibitors (TKIs), allogeneic hematopoietic stem cell transplantation (HSCT) from a donor -if available- was the standard cure attempt. Data on the long-term outcome and health-related quality of life (HRQOL) in former pediatric CML patients undergoing HSCT are lacking. Study questionWe investigated long-term survivors' self-reporting to a questionnaire sent out to patients formerly enrolled in pediatric CML-HSCT trials. MethodsIndividuals with CML transplanted at age <18 years were identified from the German Childhood Cancer Registry database. Long-term survivors received a questionnaire based on the SF-36 and FACT-BMT asking them to self-report HRQOL issues. (Ethical vote #541_20 B, Medical Faculty, University of Erlangen-Nurnberg). Results111/171 (64.9%) individuals survived HSCT long-term and 86/111 (77.5%) fulfilled all inclusion criteria and received the questionnaire. 37/86 (43%) participants (24 female, 13 male, median age at HSCT 12 years [range 2-18], median age at the time of the survey 29 years [range 18-43]) responded after a median follow-up period of 19 years (range 4-27) after HSCT. 10/37 (27%) participants underwent no regular medical follow-up examinations. Self-reported symptoms like chronic graft-versus-host disease (cGvHD)-associated organ impairments and conditioning regimen consequences could causatively not sharply be separated in each case. Complains comprised hypothyroidism (N=11, 30%), infertility (N=9, 24%), lung problems, dry eyes (each N=7, 19%), skin alterations (N=6, 17%), hair problems (N=4, 11%), and sexual dysfunction (N=3, 9%). 10 (27%) participants experienced 13 CML relapses after a median interval from HSCT of 31 months (range 2-93). Only one patient underwent 2nd SCT after failure of relapse treatment with TKIs. Six secondary malignancies (dysplastic melanocytic nevus and ALL, basal cell carcinoma (N=2), rhabdomyosarcoma, and thyroid carcinoma developed in 5 (13%) participants. As assessed by the SF-36 questionnaire, impaired physical health was mainly associated with cGvHD. The mental component summary score showed that also participants without cGvHD scored significantly lower than the general population. When assessed by the FACT-BMT, participants with cGvHD scored significantly lower while participants without cGvHD scored even 5 points higher than the data from controls. 18 (49%) participants considered the sequelae of HSCT an obstacle to education. Out of the total cohort, N=20 (54%), N=7 (19%), N=5 (14%), and N=4 (11%) participants worked full time, part-time, were unemployed, or had not yet finalized their education, respectively. 20 (54%) participants lived as singles, 8 (22%) lived in a partnership, 6 (16%) were married, and 3 (8%) had been divorced. Four (11%) participants reported a total number of 7 children. ConclusionThis first assessment of HRQOL in former pediatric patients with CML surviving HSCT for more than two decades demonstrates self-reported satisfactory well-being only in the absence of cGvHD. Research-based on self-reported outcomes sheds light on former patients' perspectives and provides an additional layer of valuable knowledge for pediatric and adult hematologists. Regular follow-up examinations are mandatory helping to avoid that late secondary neoplasias, CML-relapse, and disorders forming the broad range of possible long-term consequences of HSCT are not detected too late.
CRIS-Team WoS Importer:2022-11-04

Pediatric Aspects in Young Rock Climbers - Schöffl, Isabelle; Schöffl, Volker (Springer International Publishing, 2022)
As climbing consists of power and endurance aspects, it represents an ideal activity for children and adolescents. In addition to promoting the entire muscular system, it advances cognitive and mental function. However, the climbers need to be introduced to climbing stepwise according to their capabilities. Their development and individual responsibility need to be reevaluated at regular intervals. High-intensive training modalities used in elite sports should be avoided, as they can increase the risk of early arthrosis in the small finger joints as well as epiphyseal fractures. Finger pain during and after exercise must be recognized as an early warning sign.
CRIS-Team Scopus Importer:2024-12-16
Keywords: Child development; Children; Epiphyseal fracture; Growth

Pediatric Buried Bumper Syndrome: Diagnostic Validity of Transabdominal Ultrasound and Artificial Intelligence - Aguilar, Caroline; Regensburger, Adrian; Knieling, Ferdinand; Wagner, Alexandra; Siebenlist, Gregor; Wölfle, Joachim; Koehler, Henrik; Hörning, André; Jüngert, Jörg M. (Ultraschall in der Medizin, 2021)
Zusammenfassung
CRIS-Team WoS Importer:2021-06-04

Pediatric cardiac MRI: automated left-ventricular volumes and function analysis and effects of manual adjustments - Hammon, Matthias; Janka, Rolf Matthias; Dankerl, Peter; Glöckler, Martin; Kammerer, Ferdinand J.; Dittrich, Sven; Uder, Michael; Rompel, Oliver (Pediatric Radiology, 2015)
Cardiac MRI is an accurate and reproducible technique for the assessment of left ventricular volumes and function. The accuracy of automated segmentation and the effects of manual adjustments have not been determined in children.To evaluate automated segmentation and the effects of manual adjustments for left ventricular parameter quantification in pediatric cardiac MR images.Left ventricular parameters were evaluated in 45 children with suspected myocarditis (age 13.4 ± 3.5 years, range 4-17 years) who underwent cardiac MRI. Dedicated software was used to automatically segment and adjust the parameters. Results of end-diastolic volume, end-systolic volume, stroke volume, myocardial mass, and ejection fraction were documented before and after apex/base adjustment and after apex/base/myocardial contour adjustment.The software successfully detected the left ventricle in 42 of 45 (93.3%) children; failures occurred in the smallest and youngest children. Of those 42 children, automatically segmented end-diastolic volume (EDV) was 151 ± 47 ml, and after apex/base adjustment it was 146 ± 45 ml, after apex/base/myocardial contour adjustment 146 ± 45 ml. The corresponding results for end-systolic volume (ESV) were 66 ± 32 ml, 63 ± 29 ml and 64 ± 28 ml; for stroke volume (SV) they were 85 ± 25 ml, 83 ± 23 ml and 83 ± 23 ml; for ejection fracture (EF) they were 57 ± 10%, 58 ± 9% and 58 ± 9%, and for myocardial mass (MM) they were 104 ± 31 g, 95 ± 31 g and 94 ± 30 g. Statistically significant differences were found when comparing the EDV/ESV/MM results, the EF results after apex/base adjustment and after apex/base/myocardial contour adjustment and the SV results (except for comparing the SVs after apex/base adjustment and after apex/base/myocardial contour adjustment).Automated segmentation for the evaluation of left ventricular parameters in pediatric MR images proved to be feasible. Automated segmentation + apex/base adjustment provided clinically acceptable parameters for the majority of cases.
EVALuna2:14344

Pediatric chronic myeloid leukemia is a unique disease that requires a different approach - Hijiya, Nobuko; Schultz, Kirk R.; Metzler, Markus; Millot, Frederic; Suttorp, Meinolf (Blood, 2016)
Chronic myelogenous leukemia (CML) in children is relatively rare. Because of a lack of robust clinical study evidence, management of CML in children is not standardized and often follows guidelines developed for adults. Children and young adults tend to have a more aggressive clinical presentation than older adults, and prognostic scores for adult CML do not apply to children. CML in children has been considered to have the same biology as in adults, but recent data indicate that some genetic differences exist in pediatric and adult CML. Because children with CML may receive tyrosine kinase inhibitor (TKI) therapy for many decades, and are exposed to TKIs during a period of active growth, morbidities in children with CML may be distinct from those in adults and require careful monitoring. Aggressive strategies, such as eradication of CML stem cells with limited duration and intensive regimens of chemotherapy and TKIs, may be more advantageous in children as a way to avoid lifelong exposure to TKIs and their associated adverse effects. Blood and marrow transplantation in pediatric CML is currently indicated only for recurrent progressive disease, and the acute and long-term toxicities of this option should be carefully evaluated against the complications associated with lifelong use of TKIs.
EVALuna2:33877

Pediatric Colorectal Carcinoma is Associated With Excellent Outcome in the Context of Cancer Predisposition Syndromes - Weber, Marie; Schneider, Dominik T.; Offenmüller, Sonja; Kaatsch, Peter; Einsiedel, Hagen Graf; Benesch, Martin; Claviez, Alexander; Ebinger, Martin; Kramm, Christof; Kratz, Christian; Lawlor, Jennifer; Leuschner, Ivo; et al. (Pediatric Blood & Cancer, 2016)
Colorectal carcinoma (CRC) is the second most common adult cancer in Germany, however, it is extremely rare in children and adolescents. In these patients, previous literature describes aggressive behavior and diagnosis at advanced stage.Thirty-one patients with CRC age <= 18 years and treated between 1990 and 2012 have been identified through the structures and registries of the German Society for Pediatric Oncology and Hematology.The age range was 9-18 years (median 13.5 years); the median follow-up time was 43.9 months (range 1-124 months). Twenty-six patients (84%) were tested for a genetic tumor syndrome (GTS); of these, 11 patients (35% of all patients) tested positive (eight cases of Lynch syndrome, one patient with familial adenomatous polyposis, two patients with constitutional mismatch repair deficiency). An unfavorable histology was reported in 55% of the records (n = 17), a poor differentiation (grade III) in 68% of carcinoma (n = 21). Overall survival (OS) and event-free survival at 5 years was 52.0% and 65.6%, respectively. Five-year survival according to stage was 100% in stage II (n = 2), 100% in stage III (n = 13), and 12.9% in stage IV (n = 15; P < 0.001). Five-year OS in patients with and without a defined GTS was 100% and 36.5% (P = 0.019), respectively.Children and adolescents with CRC are frequently diagnosed in advanced stages and have an unfavorable prognosis. In this study, a high percentage of pediatric CRC patients presented with a tumor predisposition syndrome and showed an especially favorable OS.
EVALuna2:15175

Pediatric Cullen gangrene: Case report of postoperative pyoderma gangrenosum in a preterm infant with a complex gastrointestinal malformation - Diez, Sonja; Syed, Julia; Müller, Hanna; Besendörfer, Manuel; Schellerer, Vera (International Journal of Surgery Case Reports, 2020)
Introduction: Pyoderma gangrenosum (PG) is a rare condition in infants, children and adolescents. The postoperative variant of this rapidly progressive ulceration is known as Cullen gangrene. Only a few case reports of pediatric Cullen gangrene have been published. Presentation of case: We present a male infant (gestational age 31 + 6 weeks) with gastroschisis and intrauterine volvulus. After multiple operations due to his complex gastrointestinal malformation, the patient showed classical symptoms of postoperative PG (PPG) 4 weeks after birth. Diagnosis could be made early in an interdisciplinary approach, differentiating intraabdominal infection (vancomycin resistant enterococcus (VRE), candida albicans) from epifascial occurrence. Treatment with high-dose steroids and immunoglobulins was initiated immediately and led to rapid recovery. Discussion: The unusual combination of a complex gastrointestinal malformation and an intraabdominal infection with VRE and candida albicans made the diagnosis difficult. However, early diagnosis is crucial in the treatment of Cullen gangrene. Conclusion: This is the first case report of Cullen gangrene presenting in an infant (at 4 weeks of age).
CRIS-Team Scopus Importer:2020-01-21
Keywords: Cullen gangrene; Gastroschisis; Pediatric surgery; Pyoderma gangrenosum

Pediatric Extracorporeal Life Support Using a Third Generation Diagonal Pump - Speth, Marlene; Münch, Frank; Purbojo, Ariawan; Glöckler, Martin; Toka, Okan; Cesnjevar, Robert; Rueffer, Andre (Asaio Journal, 2016)
This study reports a single-centre experience of the Medos Deltastream diagonal-pump (DP3) for extracorporeal cardiac, pulmonary, or combined support in a single-center pediatric cohort. Twenty-seven consecutive patients with 28 runs of the DP3 between January 2013 and June 2014 were included for analysis. Median patient age, weight, and duration of support were 278 days (range: 0 days-14.2 years), 7.2 kg (range: 2.5-39 kg), and 8 days (range: 2-69 days). Midline sternotomy (n = 20, 71.4%) or cervical approaches (n = 8, 28.6%) were used for cannulation. The DP3 was employed for either veno-arterial extracorporeal life support (ECLS, n = 16), veno-venous extracorporeal membrane oxygenation (ECMO, n = 5), or ventricular assist devices (right ventricular assist device [RVAD], n = 1; left ventricular assist device [LVAD], n = 1; and univentricular assist device [UNIVAD], n = 5). Three patients initially supported with ECLS were switched to UNIVAD and one patient with UNIVAD was changed to ECLS. Required flow for neonates (n = 8) ranged between 0.2 and 0.75 L/min. Irreversible pump damage occurred in one patient during deairing after air block. Successful weaning, 30 day and hospital survival were 89.3% (n = 25), 85.7% (n = 24), and 71.4% (n = 20). All patients on UNIVAD, who did not require further extracorporeal respiratory assist, survived. In conclusion, the DP3 can be used for individual patient demands and adapted to their most suitable method of support. Meticulous flow adjustments render this pump highly effective for extracorporeal support particularly in pediatric patients.
EVALuna2:25117

Pediatric Mesothelioma Tumors: The European Expert Group Contribution - Orbach, D.; Andre, N.; Brecht, I.; Lopez Almaraz, R.; Ben Ami, T.; Wermersch, S.; Carton, M.; Virgone, C.; Bisogno, G.; Schneider, D.; Bajciova, V.; Reguerre, Y.; et al. (PEDIATRIC BLOOD & CANCER, 2020)
CRIS-Team WoS Importer:2020-12-04

Pediatric Mesothelioma With ALK Fusions: A Molecular and Pathologic Study of 5 Cases - Argani, Pedram; Lian, Derrick W.Q.; Agaimy, Abbas; Metzler, Markus; Wobker, Sara E.; Matoso, Andres; Epstein, Jonathan I.; Sung, Yun Shao; Zhang, Lei; Antonescu, Cristina R. (American Journal of Surgical Pathology, 2021)
Pediatric mesotheliomas are rare and their pathogenesis remains undefined. In this study, we report 5 cases of malignant mesothelioma in children, characterized by fusions involving the anaplastic lymphoma kinase (ALK) gene. Four cases occurred in females involving the abdominal cavity and were characterized by a pure epithelioid morphology. The fifth arose in the tunica vaginalis of a 15-year-old male and displayed a biphasic epithelioid-sarcomatoid phenotype. All cases demonstrated the classic morphologic and immunohistochemical features of malignant mesothelioma, including tubulopapillary architecture and cuboidal epithelioid cells with eosinophilic cytoplasm and uniform nuclei with vesicular chromatin. Immunohistochemically, all cases showed labeling for ALK, cytokeratins, WT1, and calretinin, while lacking expression of adenocarcinoma immunomarkers. Four cases demonstrated weak-moderate labeling for PAX8 protein, which resulted in diagnostic challenges with primary peritoneal serous carcinoma. The ALK genetic abnormalities were investigated by a combination of molecular methods. Archer FusionPlex was performed in 2 cases, showing fusions between ALK with either STRN or TPM1 genes, resulting in a transcript that retained the ALK kinase domain. One case was further studied by DNA targeted sequencing, but no additional genetic alterations were observed. In 1 case, cytogenetic analysis showed the presence of a t(2;15)(p23;q22) and fluorescence in situ hybridization confirmed the ALK gene break-apart. In the remaining 2 cases, ALK gene rearrangements were demonstrated by fluorescence in situ hybridization. Unlike adult mesotheliomas, which are tightly linked to asbestos exposure, often show loss of BAP1 expression and have complex karyotypes, ALK-rearranged mesothelioma appears to be similar to other fusion-positive mesotheliomas, such as those harboring EWSR1/FUS-ATF1 fusions, sharing significant morphologic overlap, occurring in young patients and displaying a simple, translocation-driven genetic profile.
CRIS-Team Scopus Importer:2021-04-23

Pediatric multi-drug-resistant tuberculosis in Germany – diagnostic and therapeutic challenges of an “orphan disease” - Schäfer, Hannah Lena; Barker, Michael; Follmann, Peter; Günther, Annette; Hörning, André; Kaiser-Labusch, Petra; Kerzel, Sebastian; Maier, Christoph; Roth, Samra; Schmidt, Christian; Schütz, Katharina; Stehling, Florian; et al. (European Journal of Pediatrics, 2023)
Delay in diagnosing multidrug-resistant tuberculosis (MDR-pTB) in children prolongs time to effective treatment. Data on risk factors for pediatric MDR from low-incidence countries are scarce. Retrospective nationwide case–control study to analyze MDR-pTB cases in Germany between 2010 and 2020 in comparison to a drug-susceptible (DS)-pTB group. We included 52 MDR cases (24 tuberculosis (TB), 28 TB infection (TBI); mean age 7.3 years) and 56 DS cases (31 TB, 26 TBI; mean age 7.9 years). Groups were similar for sex, household size, and migration background. Compared to the DS group, more children with MDR were born in the Commonwealth of Independent States (CIS) (22% MDR-pTB vs. 13% DS-pTB, n.s.) and had more MDR index cases (94% MDR-pTB, 5% DS-pTB, p < 0.001). The interval between first healthcare contact and initiation of effective therapy was significantly longer in MDR-pTB (47 days) than in DS-pTB (11 days, p < 0.001), correlating with disease progression. Treatment for MDR-pTB was successful in 74%, but 22% experienced long-term adverse effects (e.g., hepatopathy, hearing loss). Conclusions: Close contact to MDR cases or birth in MDR-TB-high-incidence countries are risk factors for MDR-pTB. Early identification of potential MDR index cases by contact investigation, and susceptibility testing in children from high-burden MDR-TB countries are essential for timely diagnosis and treatment, reducing the severity of disease and treatment side effects. Trial Registration: Deutsches Register Klinischer Studien (https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023817), DRKS00023817, 2020–09-08. What is Known: •Management of children with MDR-TB remains challenging due to difficulties in diagnosing MDR-TB (lack of information on MDR index case, lack of microbiological confirmation in paucibacillary disease). •Choice of treatment regimen and monitoring of side effects. What is New: •Children with an MDR-TB index or born in a MDR-TB-high-incidence country are at higher risk of developing MDR-TB in a low incidence country. •The time lag to initiate treatment in MDR-TB is longer than in DS-TB and MDR-TB treatment involves a higher risk of adverse effects in longer treatment regimens especially with injectables.
CRIS-Team Scopus Importer:2023-09-22
Keywords: Children; Germany; Multicenter; Multidrug resistance (MDR); Tuberculosis

Pediatric reference intervals for alkaline phosphatase - Zierk, Jakob; Arzideh, Farhad; Haeckel, Rainer; Cario, Holger; Fruehwald, Michael C.; Gross, Hans-Juergen; Gscheidmeier, Thomas; Hoffmann, Reinhard; Krebs, Alexander; Lichtinghagen, Ralf; Neumann, Michael; Ruf, Hans-Georg; et al. (Clinical Chemistry and Laboratory Medicine, 2017)
BACKGROUND: Interpretation of alkaline phosphatase activity in children is challenging due to extensive changes with growth and puberty leading to distinct sex- and age-specific dynamics. Continuous percentile charts from birth to adulthood allow accurate consideration of these dynamics and seem reasonable for an analyte as closely linked to growth as alkaline phosphatase. However, the ethical and practical challenges unique to pediatric reference intervals have restricted the creation of such percentile charts, resulting in limitations when clinical decisions are based on alkaline phosphatase activity. METHODS: We applied an indirect method to generate percentile charts for alkaline phosphatase activity using clinical laboratory data collected during the clinical care of patients. A total of 361,405 samples from 124,440 patients from six German tertiary care centers and one German laboratory service provider measured between January 2004 and June 2015 were analyzed. Measurement of alkaline phosphatase activity was performed on Roche Cobas analyzers using the IFCC's photometric method. RESULTS: We created percentile charts for alkaline phosphatase activity in girls and boys from birth to 18 years which can be used as reference intervals. Additionally, data tables of age- and sex-specific percentile values allow the incorporation of these results into laboratory information systems. CONCLUSIONS: The percentile charts provided enable the appropriate differential diagnosis of changes in alkaline phosphatase activity due to disease and changes due to physiological development. After local validation, integration of the provided percentile charts into result reporting facilitates precise assessment of alkaline phosphatase dynamics in pediatrics.
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Performance of epimyocardial leads in patients with a single ventricle circulation - Zartner, Peter A.; Mini, Nathalie; Vergnat, Mathieu; Momcilovic, Diana; Schneider, Martin B.; Dittrich, Sven (Pace-Pacing and Clinical Electrophysiology, 2021)
Background Cardiac pacing can be challenging after a Fontan operation, and limited data exist regarding strategies to plan these epimyocardial systems while minimizing the number of surgical procedures.
CRIS-Team WoS Importer:2021-04-02

Performance of stented biological valves for right ventricular outflow tract reconstruction - Buchholz, Christian; Mayr, Andreas; Purbojo, Ariawan; Glöckler, Martin; Toka, Okan; Cesnjevar, Robert; Rueffer, Andre (Interactive Cardiovascular and Thoracic Surgery, 2016)
This retrospective single-centre review presents mid- and long-term results of stented biological valves (SBVs) in the pulmonary position.Fifty-two SBVs (17 Carpentier-Edwards Supraannular; 13 Carpentier-Edwards Perimount; 12 St. Jude Medical Trifecta; 4 Sorin Mitroflow; 4 Sorin Soprano; 2 Sorin More) were implanted between 2000 and 2015. The median valve size, patient age and weight were 23 mm (range 19-27), 22.8 years (range 5-77) and 62.0 kg (range 14-110), respectively. The main cardiac diagnosis was tetralogy of Fallot in 26 patients (50%). Forty-four patients (85%) had previous cardiac surgery; 12 patients (23%) had previous conduit or biological valve replacement. Valve degeneration was defined as a valvular peak pressure gradient >50 mmHg or pulmonary valve regurgitation more than moderate.The mean follow-up was 7.9 ± 5.5 years. Two patients died after 5.8 and 6.1 years of causes not related to SBVs. Eleven SBVs (21%) had to be replaced surgically (n = 6) or interventionally (n = 5) after 9.0 ± 4.1 years due to valve degeneration (n = 8), endocarditis (n = 2) or right ventricular dysfunction (n = 1). The rates of freedom from valve replacement were 100%, 92% [95% confidence interval (CI) 79-97], 81% (CI 64-91) and 60% (CI 40-78) after 1, 5, 10 and 15 years, respectively. Successful interventional valve-in-valve implantation resulted in 100% freedom from surgical valve replacement in all patients older than 19.1 years. Multivariate analysis identified patient age <19.1 years (P = 0.007) as a risk factor for earlier valve degeneration.SBVs in the pulmonary position showed encouraging long-term results in mature patients. The design of SBVs enables interventional valve implantation, postponing the need for reoperation.
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Permissive hypercapnia in extremely low birthweight infants (PHELBI): a randomised controlled multicentre trial - Thome, Ulrich H.; Genzel-Boroviczeny, Orsolya; Bohnhorst, Bettina; Schmid, Manuel; Fuchs, Hans; Rohde, Oliver; Avenarius, Stefan; Topf, Hans-Georg; Zimmermann, Andrea; Faas, Dirk; Timme, Katharina; Kleinlein, Barbara; et al. (The Lancet Respiratory Medicine, 2015)
Tolerating higher partial pressure of carbon dioxide (pCO2) in mechanically ventilated, extremely low birthweight infants might reduce ventilator-induced lung injury and bronchopulmonary dysplasia. We aimed to test the hypothesis that higher target ranges for pCO2 decrease the rate of bronchopulmonary dysplasia or death.In this randomised multicentre trial, we recruited infants from 16 tertiary care perinatal centres in Germany with birthweight between 400 g and 1000 g and gestational age 23-28 weeks plus 6 days, who needed endotracheal intubation and mechanical ventilation within 24 h of birth. Infants were randomly assigned to either a high target or control group. The high target group aimed at pCO2 values of 55-65 mm Hg on postnatal days 1-3, 60-70 mm Hg on days 4-6, and 65-75 mm Hg on days 7-14, and the control target at pCO2 40-50 mmHg on days 1-3, 45-55 mm Hg on days 4-6, and 50-60 mm Hg on days 7-14. The primary outcome was death or moderate to severe bronchopulmonary dysplasia, defined as need for mechanical pressure support or supplemental oxygen at 36 weeks postmenstrual age. Cranial ultrasonograms were assessed centrally by a masked paediatric radiologist. This trial is registered with the ISRCTN registry, number ISRCTN56143743.Between March 1, 2008, and July 31, 2012, we recruited 362 patients of whom three dropped out, leaving 179 patients in the high target and 180 in the control group. The trial was stopped after an interim analysis (n=359). The rate of bronchopulmonary dysplasia or death in the high target group (65/179 [36%]) did not differ significantly from the control group (54/180 [30%]; p=0·18). Mortality was 25 (14%) in the high target group and 19 (11%; p=0·32) in the control group, grade 3-4 intraventricular haemorrhage was 26 (15%) and 21 (12%; p=0·30), and the rate of severe retinopathy recorded was 20 (11%) and 26 (14%; p=0·36).Targeting a higher pCO2 did not decrease the rate of bronchopulmonary dysplasia or death in ventilated preterm infants. The rates of mortality, intraventricular haemorrhage, and retinopathy did not differ between groups. These results suggest that higher pCO2 targets than in the slightly hypercapnic control group do not confer increased benefits such as lung protection.Deutsche Forschungsgemeinschaft.
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Pharmacodynamic Effect of mTOR Inhibition-based Immunosuppressive Therapy on T- and B-cell Subsets After Renal Transplantation - Wei, Xinyi; Weber, Sabine; Yin, Decheng; Allabauer, Ida; Jobst-Schwan, Tilman; Wiesener, Michael; Schiffer, Mario; Dudziak, Diana; Lehmann, Christian; Wölfle, Joachim; Hörning, André (Transplantation Direct, 2024)
Background. The mammalian target of rapamycin inhibitor (mTORi) therapy after kidney transplantation is solely monitored pharmacokinetically, not necessarily reflecting PI3K-Akt-mTOR pathway blockade efficacy leading to potential under- or overimmunosuppression. Methods. In this cross-sectional study, phosphoflow cytometry was used to determine the efficacy of mTOR inhibition in peripheral T- and B-lymphocyte subsets by assessing p70S6 kinase (p70S6K) phosphorylation in renal transplant recipients upon treatment with a combination of either mTORi and calcineurin inhibitors (n = 18), or mTORi with mycophenolic acid (n = 9). Nine dialysis patients with end-stage renal disease and 17 healthy age-matched volunteers served as controls. Results. mTORi treatment reduced p70S6K phosphorylation in CD4+, CD8+ T, and CD19+ B cells compared with healthy controls (HCs). Subpopulation analysis of CD4+ T cells and CD19+ B cells revealed a significant reduction of p70S6K phosphorylation in CD4+CD45RA−CD25− Th cells (P < 0.05), CD24hiCD38hi transitional B cells (P < 0.001), CD24+CD38− memory B cells (P < 0.001), and CD24intCD38int-naive B cells (P < 0.05) upon mTORi treatment, whereas CD4+CD45RA−CD25++CD127− regulatory T cells and CD24−CD38hi plasmablasts were not affected. Compared with mTORi + mycophenolic acid therapy, mTORi + calcineurin inhibitor treatment exhibited an even stronger inhibition of p70S6K phosphorylation in CD4+CD45RA−CD25− Th cells and CD8+ T cells. However, trough levels of mTORi did not correlate with p70S6K phosphorylation. Conclusions. mTORi selectively inhibited p70S6K phosphorylation in select lymphocyte subtypes. Assessing p70S6K phosphorylation by phosphoflow cytometry may serve as an approach to understand cell subset specific effects of mTORi providing detailed pharmacodynamic information for individualizing immunosuppression.
CRIS-Team Scopus Importer:2024-07-19

Pharmacokinetic–pharmacodynamic modeling of maintenance therapy for childhood acute lymphoblastic leukemia - Gebhard, Anna; Lilienthal, Patrick; Metzler, Markus; Rauh, Manfred; Sager, Sebastian; Schmiegelow, Kjeld; Toksvang, Linea Natalie; Zierk, Jakob (Scientific Reports, 2023)
In the treatment of childhood acute lymphoblastic leukemia (ALL), current protocols combine initial high-dose multiagent chemotherapy with prolonged oral therapy with 6-mercaptopurine (6MP) and low-dose methotrexate (MTX) maintenance therapy. Decades of research on ALL treatment have resulted in survival rates of approximately 90%. However, dose-response relationships vary widely between patients and insight into the influencing factors, that would allow for improved personalized treatment management, is insufficient. We use a detailed data set with measurements of thioguanine nucleotides and MTX in red blood cells and absolute neutrophil count (ANC) to develop pharmacokinetic models for 6MP and MTX, as well as a pharmacokinetic–pharmacodynamic (PKPD) model capable of predicting individual ANC levels and thus contributing to the development of personalized treatment strategies. Here, we show that integrating metabolite measurements in red blood cells into the full PKPD model improves results when less data is available, but that model predictions are comparable to those of a fixed pharmacokinetic model when data availability is not limited, providing further evidence of the quality of existing models. With this comprehensive model development leading to dynamics similar to simpler models, we validate the suitability of this model structure and provide a foundation for further exploration of maintenance therapy strategies through simulation and optimization.
CRIS-Team Scopus Importer:2023-09-08

Pharmacologic stabilization of hypoxia-inducible transcription factors protects developing mouse brain from hypoxia-induced apoptotic cell death - Trollmann, Regina; Richter, Markus; Jung, Susan; Walkinshaw, G.; Brackmann, Florian (Neuroscience, 2014)
Accumulation of hypoxia-inducible transcription factors (HIFs) by prolyl-4-hydroxylase inhibitors (PHI) has been suggested to induce neuroprotection in the ischemic rodent brain. We aimed to investigate in vivo effects of a novel PHI on HIF-regulated neurotrophic and pro-apoptotic factors in the developing normoxic and hypoxic mouse brain.Neonatal mice (P7) were treated with PHI FG-4497 (30-100mg/kg, i.p.) followed by exposure to systemic hypoxia (8% O2, 6h) 4h later. Cerebral expression of HIF?-subunits, specific neurotrophic and vasoactive target genes (vascular endothelial growth factor (VEGF), adrenomedullin (ADM), erythropoietin (EPO), inducible nitric oxide synthase (iNOS)) as well as pro-apoptotic (BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 gene (BNIP3), immediate early response 3 (IER3)) and migratory factors (chemokine receptor 4 (CXCR4), stromal cell-derived factor 1 (SDF-1)) was determined (quantitative real-time (RT)., Western blot analysis) in comparison to controls. Apoptotic cell death was analyzed by terminal desoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) and cleaved caspase 3 (CC3) staining.Under normoxic conditions, FG-4497 treatment significantly induced the accumulation of both HIF-1? and HIF-2? isoforms in developing mouse brain. In addition, there was a significant up-regulation of HIF target genes (VEGF, ADM, EPO, CXCR4, p<0.01) with FG-4497 treatment compared to controls supporting functional activation of the HIF proteins. Under hypoxia, differential target gene activation was observed in the developing brain including additive effects of FG-4497 and hypoxia on mRNA expression of VEGF and ADM as well as a dose-dependent down-regulation of iNOS. BNIP3 but not IER3 mRNA levels significantly increased in hypoxic brains pre-treated with high-dose FG-4497 compared to controls. Of special interest, FG-4497 treatment significantly diminished apoptotic cell death, quantified by TUNEL and CC3-positive cells, in hypoxic developing brains compared to controls.PHI treatment modulates neurotrophic factors known to be crucially involved in hypoxia-induced cerebral adaptive mechanisms as well as early brain maturation. Pre-treatment with FG-4497 seems to protect the developing brain from hypoxia-induced apoptosis. Present observations provide basic information for further evaluation of neuroprotective properties of PHI treatment in hypoxic injury of the developing brain. However, potential effects on maturational processes need special attention in experimental research targeting HIF-dependent neuroprotective interventions during the very early stage of brain development.
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Pharmacology and pharmacokinetics of imatinib in pediatric patients - Suttorp, Meinolf; Bornhaeuser, Martin; Metzler, Markus; Schleyer, Eberhard; Millot, Frederic (Expert Review of Clinical Pharmacology, 2018)
INTRODUCTION: The tyrosine kinase inhibitor (TKI) imatinib was rationally designed to target BCR-ABL1 which is constitutively activated in chronic myeloid leukemia (CML). Following the tremendous success in adults, imatinib also became licensed for treatment of CML in minors. The rarity of pediatric CML hampers the conduction of formal trials. Thus, imatinib is still the single TKI approved for CML treatment in childhood. Areas covered: This review attempts to provide an overview of the literature on pharmacology, pharmacokinetic, and pharmacogenetic of imatinib concerning pediatric CML treatment. Articles were identified through a PubMed search and by reviewing abstracts from relevant hematology congresses. Additional information was provided from the authors' libraries and expertise and from our own measurements of imatinib trough plasma levels in children. Pharmacokinetic variables (e.g. alpha 1-acid glycoprotein binding, drug-drug/food-drug interactions via cytochrome P450 3A4/5, cellular uptake mediated via OCT-1-influx variations and P-glycoprotein-mediated drug efflux) still await to be addressed in pediatric patients systematically. Expert commentary: TKI response rates vary among different individuals and pharmacokinetic variables all can influence CML treatment success. Adherence to imatinib intake may be the most prominent factor influencing treatment outcome in teenagers thus pointing towards the potential benefits of regular drug monitoring.
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PHENOCOPIESOF CLINICALLY DIAGNOSED ARPKD REVEALED IN CHILDREN - Halawi, Abdul; Burgmaier, Kathrin; Buescher, Anja; Dursun, Ismail; Galiano, Matthias; Gessner, Michaela; Gokce, Ibrahim; Kowalewska, Claudia; Mekahli, Djalila; Mir, Sevgi; Shroff, Rukshana; Stabouli, Stella; et al. (PEDIATRIC NEPHROLOGY, 2021)
CRIS-Team WoS Importer:2021-10-01

Phenylbutyrate Treatment in a Boy With MCT8 Deficiency: Improvement of Thyroid Function Tests and Possible Hepatotoxicity. - Schreiner, Felix; Vollbach, Heike; Sonntag, Niklas; Schempp, Vera; Gohlke, Bettina; Friese, Johannes; Wölfle, Joachim; Braun, Doreen; Schweizer, Ulrich (Journal of Clinical Endocrinology and Metabolism, 2025)
CONTEXT: Monocarboxylate transporter 8 (MCT8) deficiency is a rare X-chromosomal inherited disease leading to severe cognitive impairment, muscular hypotonia, and symptoms of peripheral thyrotoxicosis. Experimental approaches aiming to functionally rescue mutant MCT8 activity by the chemical chaperone phenylbutyrate (PB) demonstrated promising effects in vitro for several MCT8 missense mutations. OBJECTIVE: The objective was to evaluate biochemical and clinical effects of PB in doses equivalent to those approved for the treatment of urea cycle disorders in a boy with MCT8 deficiency due to a novel MCT8 missense mutation c.703G>T (p.V235L). RESULTS: During a treatment period of 13 months, PB led to a significant decrease of elevated thyrotropin and triiodothyronine (T3) serum concentrations, while free thyroxine (fT4) increased. The weight z-score of the toddler remained remarkably stable during the treatment period. Neurodevelopmental assessments (BSID-III) revealed a slight increase of gross motor skills from developmental age 4 to 6 months. However, increasing liver enzyme serum activities and accumulation of phenylacetate in urine led to treatment interruptions and dose alterations. In vitro analyses in MDCK1 cells confirmed the pathogenicity of MCT8 p.V235L. However, while PB increased expression of the mutant protein, it did not rescue T3 transport, suggesting a PB effect on thyroid function tests independent of restoring MCT8 activity. CONCLUSION: In a clinical attempt of PB treatment in MCT8 deficiency we observed a significant improvement of thyroid hormone function tests, tendencies toward body weight stabilization and slight neurodevelopmental improvement. Hepatotoxicity of PB may be a limiting factor in MCT8 deficiency and requires further investigation.
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Phosphate Intoxication after Application of Enema - a Life-threatening Iatrogenic Complication - Marek, I.; Benz, Kerstin; Kusnik, Stefan; Morhart, P.; Botzenhardt, S.; Toni, I.; Rascher, Wolfgang (Klinische Pädiatrie, 2015)
Enemas are used in pediatric patients with constipation. Retention of phosphate containing enemas with prolonged resorption or reduced renal elimination of phosphate can result in life-threatening hyperphosphatemia with subsequent lethal hypocalcemia and acidosis.We report the case of a 6-month-old child who received phosphate-containing enema to treat acute aggravation of constipation. The used enema here was not licensed for this age group. Phosphate intoxication resulted (phosphate 19.87 mmol/l) and presented like a sepsis. Hyperphosphatemia was treated by hemodialysis. A non-diagnosed Hirschsprung disease had led to prolonged resorption of phosphate containing enema and to an ileus and toxic megacolon that had to be operated.Insufficient elimination of phosphate containing enema can result in lethal or life threatening hyperphosphatemia, hypocalcemia and metabolic acidosis. These can be treated efficaciously by hemodialysis. Because of the high risk of intoxication in using enemas containing phosphate in infants or in patients with gastrointestinal or renal comorbidities, physicians treating constipation should choose enemas without phosphate but with ingredients with lower risk like glycerol or sorbitol in this age group.
EVALuna2:18933

PKD1L1 Is Involved in Congenital Chylothorax - Whitchurch, Jonathan B.; Schneider, Sophia; Hilger, Alina Christine; Köllges, Ricarda; Stegmann, Jil D.; Waffenschmidt, Lea; Dyer, Laura; Thiele, Holger; Dhabhai, Bhanupriya; Dakal, Tikam Chand; Müller, Andreas; Norris, Dominic P.; et al. (Cells, 2024)
Besides visceral heterotaxia, Pkd1l1 null mouse embryos exhibit general edema and perinatal lethality. In humans, congenital chylothorax (CCT) is a frequent cause of fetal hydrops. In 2021, Correa and colleagues reported ultrarare compound heterozygous variants in PKD1L1 exhibiting in two consecutive fetuses with severe hydrops, implicating a direct role of PKD1L1 in fetal hydrops formation. Here, we performed an exome survey and identified ultrarare compound heterozygous variants in PKD1L1 in two of the five case-parent trios with CCT. In one family, the affected carried the ultrarare missense variants c.1543G>A(p.Gly515Arg) and c.3845T>A(p.Val1282Glu). In the other family, the affected carried the ultrarare loss-of-function variant (LoF) c.863delA(p.Asn288Thrfs*3) and the ultrarare missense variant c.6549G>T(p.Gln2183His). Investigation of the variants' impact on PKD1L1 protein localization suggests the missense variants cause protein dysfunction and the LoF variant causes protein mislocalization. Further analysis of Pkd1l1 mutant mouse embryos revealed about 20% of Pkd1l1-/- embryos display general edema and pleural effusion at 14.5 dpc. Immunofluorescence staining at 14.5 dpc in Pkd1l1-/- embryos displayed both normal and massively altered lymphatic vessel morphologies. Together, our studies suggest the implication of PKD1L1 in congenital lymphatic anomalies, including CCTs.
CRIS-Team Scopus Importer:2024-02-02
Keywords: chylothorax; congenital; PKD1L1; pleural effusion

Plasma concentrations of the amyloid-? peptides in young volunteers: the influence of the APOE genotype - Zimmermann, Rüdiger; Huber, Ellen; Schamber, Christine; Lelental, Natalia; Mroczko, Barbara; Brandner, Sebastian; Maler, Juan Manuel; Oberstein, Timo; Szmitkowski, Maciej; Rauh, Manfred; Kornhuber, Johannes; Lewczuk, Piotr (Journal of Alzheimer's Disease, 2014)
Changes in the concentrations of amyloid-? (A?) in the body fluids are the earliest alterations observed in Alzheimer's disease (AD), however, there is a lack of data about how early these alterations occur, before the onset of the clinical symptoms. APOE genotype is the most recognized genetic risk/protective factor of AD, meaning that a group of non-demented persons carrying ?4 allele is enriched in the subjects who will develop AD, compared to the group of non-carriers. Therefore, we studied the plasma concentrations of A? peptides (A?1-42, A?1-40, A?x-42, and A?x-40), and the APOE genotype in 173 young volunteers (average age, 28 ± 7.6 years) without memory deficits, in order to see whether the non-demented group of subjects at risk already characterize with A? changes three-to-four decades before the age at which dementia usually occurs. We did not find statistically significant differences among the groups of ?4 carriers, ?3 homozygotes, and ?2 carriers. We conclude that the APOE genotype does not influence the metabolism of the A? peptides in young persons without memory deficits.
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Plasma Metabolome Profiling for the Diagnosis of Catecholamine Producing Tumors - März, Juliane; Kurlbaum, Max; Roche-Lancaster, Oisin; Deutschbein, Timo; Peitzsch, Mirko; Prehn, Cornelia; Weismann, Dirk; Robledo, Mercedes; Adamski, Jerzy; Fassnacht, Martin; Kunz, Meik; Kroiss, Matthias (Frontiers in Endocrinology, 2021)
Context: Pheochromocytomas and paragangliomas (PPGL) cause catecholamine excess leading to a characteristic clinical phenotype. Intra-individual changes at metabolome level have been described after surgical PPGL removal. The value of metabolomics for the diagnosis of PPGL has not been studied yet. Objective: Evaluation of quantitative metabolomics as a diagnostic tool for PPGL. Design: Targeted metabolomics by liquid chromatography-tandem mass spectrometry of plasma specimens and statistical modeling using ML-based feature selection approaches in a clinically well characterized cohort study. Patients: Prospectively enrolled patients (n=36, 17 female) from the Prospective Monoamine-producing Tumor Study (PMT) with hormonally active PPGL and 36 matched controls in whom PPGL was rigorously excluded. Results: Among 188 measured metabolites, only without considering false discovery rate, 4 exhibited statistically significant differences between patients with PPGL and controls (histidine p=0.004, threonine p=0.008, lyso PC a C28:0 p=0.044, sum of hexoses p=0.018). Weak, but significant correlations for histidine, threonine and lyso PC a C28:0 with total urine catecholamine levels were identified. Only the sum of hexoses (reflecting glucose) showed significant correlations with plasma metanephrines. By using ML-based feature selection approaches, we identified diagnostic signatures which all exhibited low accuracy and sensitivity. The best predictive value (sensitivity 87.5%, accuracy 67.3%) was obtained by using Gradient Boosting Machine Modelling. Conclusions: The diabetogenic effect of catecholamine excess dominates the plasma metabolome in PPGL patients. While curative surgery for PPGL led to normalization of catecholamine-induced alterations of metabolomics in individual patients, plasma metabolomics are not useful for diagnostic purposes, most likely due to inter-individual variability.
CRIS-Team Scopus Importer:2021-10-01
Keywords: adrenal; catecholamines; feature selection; machine learning; mass spectronomy; paraganglioma; pheochromocytoma; targeted metabolomics

Pleiotropic effects under combined therapy with empagliflozin and linagliptin compared to metformin and insulin glargine in patients with type 2 diabetes - Jung, Susan; Ott, Christian; Kannenkeril, Dennis; Bosch, Agnes; Karg, M.; Striepe, Kristina; Bramlage, P.; Schmieder, Roland (DIABETOLOGIA, 2019)
CRIS-Team WoS Importer:2019-10-11

Point of Care detection of anti-infliximab antibodies in inflammatory bowel disease patients treated with the biosimilar SB2: performance comparison with ELISA - Atreya, Raja; Schmitt, H.; Fischer, Sven Moritz; Neurath, Markus; Rekalde, X.; Nagore, D.; Ametzazurra, A. (JOURNAL OF CROHNS & COLITIS, 2019)
CRIS-Team WoS Importer:2019-03-20

Postnatal management of preterm infants with spinal muscular atrophy: experience from German newborn screening - Trollmann, Regina; Johannsen, Jessika; Vill, Katharina; Köhler, Cornelia; Hahn, Andreas; Illsinger, Sabine; Pechmann, Astrid; Hagen, Maja von der; Müller-Felber, Wolfgang (Orphanet Journal of Rare Diseases, 2024)
Background: The introduction of newborn screening (NBS) for spinal muscular atrophy (SMA) has increased the early diagnosis of 5q-associated SMA in presymptomatic and symptomatic preterm infants. National and international recommendations for treating preterms and newborns < 38 weeks of gestational age are unavailable. Our retrospective multicentre study aimed to evaluate the postnatal clinical course of preterm infants with 5q-associated SMA diagnosed since the implementation of NBS in Germany in 2021 and to summarize the German experience regarding the decision-making process for available treatment regimens for preterm infants with ≤ 3 survival of motor neuron 2 (SMN2) copies. Results: Twelve preterm infants with 5q-associated SMA and a mean gestational age of 34.0 weeks (range: 26.1–36.8) and birth weight of 2022 g (range: 645–3370) were reported from 8/20 German SMA NBS follow-up centers using a pseudonymized questionnaire. Confirmatory diagnosis, including SMN2 copy number, was completed on average on postnatal day 13. All patients had a biallelic deletion of exon 7 or exons 7 and 8 of the survival of motor neuron 1 (SMN1) gene, with SMN2 copy numbers of two in 10 patients and three in two patients. The neonatal course was complicated by respiratory distress due to prematurity (n = 2), sepsis (n = 2), and jaundice (n = 2). At birth, 11 preterm infants (91.6%) were presymptomatic. However, the neurological status of one patient deteriorated at five weeks of age (postconceptional age of 41.8 weeks) prior to the start of treatment. Disease-modifying treatments were initiated in all patients at a mean postconceptional age of 38.8 weeks, with the majority receiving onasemnogene abeparvovec (83.3%, including 2 patients with prior risdiplam bridge therapy). Notably, consensus among participating experts from German neuromuscular centers resulted in 83.3% of patients receiving disease-modifying treatment at term. Conclusions: Premature infants with SMA require interdisciplinary care in close collaboration with the neuromuscular center. SMA NBS facilitates early initiation of disease-modifying therapy, ideally during the presymptomatic phase, which significantly influences the prognosis of the newborn.
CRIS-Team Scopus Importer:2024-10-04
Keywords: 5q-SMA; Newborn screening; Nusinersen; Onasemnogene Abeparvovec; Preterm infants; Risdiplam; SMA treatment; Spinal muscular atrophy

Postoperative pain in small-for-gestational age infants after hernia repair, orchidopexy and urethral reconstruction surgery: A pilot study - Schüssler, Stephanie C.; Kußmann, Franziska; Fahlbusch, Fabian B.; Münster, Tino; Hirsch, Karin; Carbon, Roman; Albrecht, Sven; Dötsch, Jörg; Rascher, Wolfgang (Early Human Development, 2019)
Background: Small-for-gestational-age (SGA) birth bears an enhanced risk of developing hypertension, obesity, insulin resistance and mental health disorders in later life as a consequence of adaptive processes in utero. Only a small number of studies on pain perception in SGA infants exist. These are indicative of a blunted stress response to pain in SGA newborns. Aim: We initiated a pilot study investigating differences in postoperative pain perception between SGA and appropriate-for-gestational-age (AGA) infants. Methods: Pain and alertness levels of 10 formerly SGA and 14 AGA infants at the age 0.5–2 years were evaluated by the FLACC scale, Steward and Aldrete Scores following hernia repair, reconstructive surgery of hypospadia and orchidopexy. In addition, the postoperative consumption of non-steroidal anti-inflammatory drugs was compared between SGA and AGA. Results: Postoperative pain and alertness levels were not significantly different in SGA and AGA children. We did not observe significant group differences regarding the consumption of non-steroidal anti-inflammatory drugs. Conclusion: While previous studies were suggestive of a suppressed stress response to pain in SGA newborns, these findings did not fully translate into an altered response to pain beyond the newborn age. Further studies in a larger cohort seem necessary to verify this finding.
CRIS-Team Scopus Importer:2019-07-16

Potential for Radiation Dose Reduction in Dual-Source Computed Tomography of the Lung in the Pediatric and Adolescent Population Compared to Digital Radiography - Wetzl, Matthias; May, Matthias; Weinmann, Daniel; Hammon, Matthias; Kopp, Markus; Ruppel, Renate; Trollmann, Regina; Wölfle, Joachim; Uder, Michael; Rompel, Oliver (Diagnostics, 2021)
Low-dose dual-source computed tomography (DSCT) protocols for the evaluation of lung diseases in children and adolescents are of importance since this age group is particularly prone to radiation damage. The aim of this study was to evaluate image quality of low-dose DSCT of the lung and to assess the potential of radiation dose reduction compared to digital radiographs (DR). Three groups, each consisting of 19 patients, were examined with different DSCT protocols using tin prefiltration (Sn96/64/32 ref. mAs at 100 kV). Different strengths of iterative reconstruction were applied (ADMIRE 2/3/4). DSCT groups were compared to 19 matched patients examined with posterior-anterior DR. Diagnostic confidence, detectability of anatomical structures and small lung lesions were evaluated on a 4-point Likert scale (LS 1 = unacceptable, 4 = fully acceptable; a value >= 3 was considered acceptable). Effective dose (ED) was 31-/21-/9-fold higher in Sn96/Sn64/Sn32 compared to DR. Diagnostic confidence was sufficient in Sn96/Sn64 (LS 3.4/3.2), reduced in Sn32 (LS 2.7) and the worst in DR (LS 2.4). In DSCT, detectability of small anatomical structures was always superior to DR (p < 0.05). Mean lesion size ranged from 5.1-7 mm; detectability was acceptable in all DSCT groups (LS 3.0-3.4) and superior to DR (LS 1.9; p < 0.05). Substantial dose lowering in DSCT of the pediatric lung enables acceptable detectability of small lung lesions with a radiation dose being about 10-fold higher compared to DR.
CRIS-Team WoS Importer:2021-03-12

Precise variant interpretation, phenotype ascertainment, and genotype–phenotype correlation of children in the EARLY PRO-TECT Alport trial - Boeckhaus, Jan; Hoefele, Julia; Riedhammer, Korbinian M.; Tönshoff, Burkhard; Ehren, Rasmus; Pape, Lars; Latta, Kay; Fehrenbach, Henry; Lange-Sperandio, Baerbel; Kettwig, Matthias; Hoyer, Peter; Staude, Hagen; et al. (Clinical Genetics, 2020)
Early initiation of therapy in patients with Alport syndrome (AS) slows down renal failure by many years. Genotype–phenotype correlations propose that the location and character of the individual's variant correlate with the renal outcome and any extra renal manifestations. In-depth clinical and genetic data of 60/62 children who participated in the EARLY PRO-TECT Alport trial were analyzed. Genetic variants were interpreted according to current guidelines and criteria. Genetically solved patients with X-linked inheritance were then classified according to the severity of their COL4A5 variant into less-severe, intermediate, and severe groups and disease progress was compared. Almost 90% of patients were found to carry (likely) pathogenic variants and classified as genetically solved cases. Patients in the less-severe group demonstrated a borderline significant difference in disease progress compared to those in the severe group (p = 0.05). While having only limited power according to its sample size, an obvious strength is the precise clinical and genetic data of this well ascertained cohort. As in published data differences in clinical progress were shown between patients with COL4A5 less-severe and severe variants. Therefore, clinical and segregational data are important for variant (re)classification. Genetic testing should be mandatory allowing early diagnosis and therapy of AS.
CRIS-Team Scopus Importer:2020-10-30
Keywords: Alport syndrome; COL4A3; COL4A4; COL4A5; hereditary kidney disease

Precision of handheld multispectral optoacoustic tomography for muscle imaging - Wagner, Anna; Danko, Vera; Federle, Anna; Klett, Daniel; Simon, David; Heiß, Rafael; Jüngert, Jörg M.; Uder, Michael; Schett, Georg; Neurath, Markus; Wölfle, Joachim; Waldner, Maximilian; et al. (Photoacoustics, 2021)
Photo-or optoacoustic imaging (OAI) allows quantitative imaging of target tissues. Using multi-wavelength illumination with subsequent ultrasound detection, it may visualize a variety of different chromophores at centimeter depth. Despite its non-invasive, label-free advantages, the precision of repeated measurements for clinical applications is still elusive. We present a multilayer analysis of n = 1920 imaging datasets obtained from a prospective clinical trial (NCT03979157) in n = 10 healthy adult volunteers. All datasets were analyzed for 13 single wavelengths (SWL) between 660 nm–1210 nm and five MSOT-parameters (deoxygenated/oxygenated/total hemoglobin, collagen and lipid) by a semi-automated batch mode software. Intraclass correlation coefficients (ICC) were good to excellent for intrarater (SWL: 0.82–0.92; MSOT-parameter: 0.72−0.92) and interrater reproducibility (SWL: 0.79−0.87; MSOT-parameter: 0.78−0.86), with the exception for MSOT-parameter lipid (interrater ICC: 0.56). Results were stable over time, but exercise-related effects as well as inter-and intramuscular variability were observed. The findings of this study provide a framework for further clinical OAI implementation.
CRIS-Team Scopus Importer:2020-12-25
Keywords: MSOT; Multispectral optoacoustic tomography; Muscle imaging; Optoacoustics; Photoacoustics

Preconceptual Counseling, Prenatal Care and peripartum Management of Female Patients with Ullrich-Turner Syndrome and a High-risk cardiovascular Profile - Pontones, Constanza; Lubrich, Hannah; Schwenke, E.; Cupisti, Susanne; Dittrich, Ralf; Kehl, Sven; Beckmann, Matthias; Fahlbusch, C.; Oppelt, Patricia (GEBURTSHILFE UND FRAUENHEILKUNDE, 2020)
CRIS-Team WoS Importer:2020-10-30

Predicting complications in paediatric ulcerative colitis: A longitudinal multicentre cohort study - Claßen, Merle; Schiller, Benjamin; Däbritz, Jan; Buderus, Stephan; Bufler, Philip; Claßen, Martin; Dammann, Söhnke; de Laffolie, Jan; Friedt, Michael; Hauer, Almuthe Christina; Keller, Klaus Michael; Krahl, Andreas; et al. (Alimentary Pharmacology & Therapeutics, 2024)
Background: To prevent complications of paediatric ulcerative colitis (UC), it is critical to understand their predictors. The Paediatric Inflammatory Bowel Disease Ahead (PIBD Ahead) program identified the relevant outcomes and their potential predictors. However, external validation of these results in larger cohorts is required. Aims: The aim of this study is to investigate these outcomes and their predictors. Methods: We included 743 patients aged under 18 years with UC from the multicentre German-Austrian CEDATA-GPGE registry. We performed Cox regressions, Kaplan–Meier estimator, and receiver operating characteristics curve analyses to analyse predictors of poor outcomes. Results: Older age at diagnosis was associated with relapse, hospitalisation, the use of immunomodulators, use of biologics, and therapy escalation. Higher disease activity, as in acute severe colitis in the first 3 months, was significantly associated with further acute severe colitis and the need for biologics. Upper gastrointestinal tract involvement was a risk factor for the need of intravenous corticosteroids and biologics. A faecal calprotectin of >685 μg/g was associated with a higher risk of subsequent acute severe colitis with a sensitivity of 79.0% and a specificity of 59.1%. A lower haematocrit at diagnosis was predictive of the use of biologics. Colectomy was rare. Conclusions: This study validates predictors of poor outcomes in paediatric patients with UC. Our results might help physicians to anticipate poor outcomes and initiate appropriate treatment strategies at an early stage.
CRIS-Team Scopus Importer:2024-09-20

Prediction of High Bell Stages of Necrotizing Enterocolitis Using a Mathematic Formula for Risk Determination - Diez, Sonja; Bell, Lea Emilia; Moosmann, Julia; Weiss, Christel; Müller, Hanna; Besendörfer, Manuel (Children, 2022)
Necrotizing enterocolitis (NEC) continues to cause high morbidity and mortality. Identifying early predictors for severe NEC is essential to improve therapy and optimize timing for surgical intervention. We present a retrospective study of patients with NEC, treated between 2010 and 2020, trying to identify factors influencing the severity of NEC. Within the study period, 88 affected infants with NEC or NEC-like symptoms are analyzed. A multiple logistic regression analysis reveals the following three independent predictors for NEC in Bell stage III: red blood cell transfusion (p = 0.027 with odds ratio (OR) = 3.298), sonographic findings (p = 0.037; OR = 6.496 for patients with positive vs. patients without pathological findings) and cardiac anatomy (p = 0.015; OR = 1.922 for patients with patent ductus arteriosus (PDA) vs. patients with congenital heart disease (CHD); OR = 5.478/OR = 2.850 for patients with CHD/PDA vs. patients without cardiac disease). Results are summarized in a clinical score for daily application in clinical routine. The score is easy to apply and combines clinically established parameters, helping to determine the timing of surgical intervention.
CRIS-Team Scopus Importer:2022-05-13
Keywords: Bell stage; clinical score; congenital heart disease; fulminant NEC; NEC; necrotizing enterocolitis

Prediction of phenotypes by secretory biomarkers and machine learning in patients with chronic rhinosinusitis - Becker, Mathias; Kist, A. M.; Wendler, O.; Pesold, V. V.; Bleier, B. S.; Mueller, S. K. (European Review for Medical and Pharmacological Sciences, 2025)
OBJECTIVE: Chronic rhinosinusitis (CRS) has traditionally been classified phenotypically according to the presence (CRSwNP) or absence (CRSsNP) of nasal polyps. However, the phenotypic dichotomy does not represent the complexity of the disease. Current research thus focuses on identifying underlying inflammatory mechanisms and distinguishing different endotypes. The objectives of this study were 1) to identify maximally predictive non-invasive biomarkers from nasal mucus, 2) to apply machine learning algorithms to use mucus-derived biomarkers to classify phenotype, and 3) to determine the feature importance of each mucus biomarker to phenotypes. PATIENTS AND METHODS: This is an IRB-approved study of 103 CRS patients (37 CRSsNP, 66 CRSwNP). Nasal mucus was collected using merocele sponges after a 3-week steroid washout period. The nasal mucus was then examined for twelve cytokines/inflammatory protein biomarkers, including interferon (IFN)-γ, interleukin (IL)-4, -5, -17A, -22, immunoglobulin (Ig) E, cystatin-SA (CST-2), eosinophilic cationic protein (ECP), matrix metalloproteinase-9 (MMP-9), pappalysin-A (PAPP-A), periostin, and serpin E1. Protein concentrations were determined by ELISAs and Luminex assays. For phenotype classification, different artificial intelligence algorithms in increasing complexity, including t-distributed stochastic neighbor embedding (t-SNE), Adaboost, and XGBoost, were applied to the data from the biomarker analysis. RESULTS: TThe analysis showed that IL-5 is a non-invasive marker to distinguish between the two phenotypic clusters. This was true for immune cell-derived proteins, and all proteins were analyzed conjointly. Periostin and CST-2 showed the highest feature importance for the epithelial- and tissue-derived proteins. The combination of IL-5, IgE, IL-17, and periostin showed the highest accuracy for prediction. CONCLUSIONS: Nasal mucus can predict phenotypes similar to tissue, with IL-5 as the main trigger for clustering. Periostin and CST-2 may be part of important targetable pathways. Future efforts will be directed at determining how these markers may be used to guide therapeutic choices and individualize treatment.
CRIS-Team Scopus Importer:2025-02-28

Predictors of transient congenital primary hypothyroidism: data from the German registry for congenital hypothyroidism (AQUAPE “HypoDok”) - Matejek, Nicola; Tittel, Sascha R.; Haberland, Holger; Rohrer, Tilman; Busemann, Eva-Maria; Jorch, Norbert; Schwab, Karl-Otfried; Wölfle, Joachim; Holl, Reinhard W.; Bettendorf, Markus (European Journal of Pediatrics, 2021)
Neonatal screening for congenital primary hypothyroidism (CH) may not distinguish between transient (TCH) and permanent dysfunction (PCH), causing potential overtreatment and concerns in affected families. To specify the indication for interruption of therapy, we analysed the German registry “HypoDok” for infants with CH, which oversees 1625 patients from 49 participating centres in Germany and Austria from 1997 until today. A total of 357 patients with a thyroid gland in loco typico were identified and retrospectively grouped according to cessation (TCH, n = 24) or continuation (PCH, n = 333) of l-thyroxine (l-T4) treatment at 2 years of age. The receiver operating characteristic (ROC) analysis was performed to identify cutoffs predicting TCH by screening TSH concentrations and l-T4 dosages. Gestational ages, birth weights and prevalence of associated malformations were comparable in both groups. The cutoff screening TSH concentration was 73 mU/L. The cutoff daily l-T4 dosage at 1 year was 3.1 μg/kg (90% sensitivity, 63% specificity; 36 μg/day) and at 2 years of age 2.95 μg/kg (91% sensitivity, 59% specificity; 40 μg/day). At 2 years of age, specificity (71%) increased when both of these parameters were considered together. Conclusion: The decision to continue or cease l-T4 treatment at 2 years of age in CH patients diagnosed in neonatal screening may be based on their screening TSH concentrations and individual l-T4 dosages at 1 and 2 years of age. Thus, TCH and PCH may be distinguished; overtreatment avoided; and affected families reassured.What is Known:• The course of congenital primary hypothyroidism may be transient, causing potential overtreatment.• The dose ofl-thyroxine at 1 or 2 years of age may predict a transient course of primary congenital hypothyroidism.What is New:• TSH screening concentration andl-thyroxine dosages at 1 and 2 years of age represent reliable predictors for transient congenital primary hypothyroidism with higher sensitivity and specificity when considered together in order to select eligible patients who qualify for treatment withdrawal.
CRIS-Team Scopus Importer:2021-04-16
Keywords: Congenital primary hypothyroidism; Permanent congenital primary hypothyroidism; Prediction; Transient congenital primary hypothyroidism

Premature birth associated with a favorable course in gestational alloimmune liver disease (GALD): A case report - Mulzer, Linda-Marie; Reutter, Heiko Martin; Jüngert, Jörg M.; Knisely, A. S.; Schmid, Margit; Hörning, André; Morhart, Patrick (Frontiers in Pediatrics, 2023)
Gestational alloimmune liver disease (GALD) is a rare neonatal disorder with high mortality and morbidity. The patients come to caregivers' attention aged a few hours or days. The disease manifests as acute liver failure with or without siderosis. The differential diagnosis of neonatal acute liver failure (NALF) is broad, including mainly immunologic, infectious, metabolic and toxic disorders. The most common cause, however, is GALD followed by herpes simplex virus (HSV) infection. The best suited pathophysiological paradigm of GALD is that of a maternofetal alloimmune disorder. State of the art treatment combines intravenously administered immunoglobulin (IVIG) with exchange transfusion (ET). We report an infant born at 35 + 2 weeks' gestation in whom GALD had a favorable course, of interest because premature birth in our patient may have exerted protective aspects and lessened morbidity in that intrauterine exposure to maternal complement-fixing antibodies was shortened. The diagnosis of GALD was challenging and difficult. We suggest a modified diagnostic algorithm combining clinical findings with histopathologic findings in liver and lip mucosa and, if available, on abdominal magnetic resonance imaging-study focusing on the liver, spleen, and pancreas. This diagnostic workup must be followed by ET and subsequent administration of IVIG without delay.
CRIS-Team WoS Importer:2023-04-14

Prenatal Correction of X-Linked Hypohidrotic Ectodermal Dysplasia - Schneider, Holm; Faschingbauer, Florian; Schuepbach-Mallepell, Sonia; Koerber, Iris; Wohlfart, Sigrun; Dick, Angela; Wahlbuhl, Mandy; Kowalczyk-Quintas, Christine; Vigolo, Michele; Kirby, Neil; Tannert, Corinna; Rompel, Oliver; et al. (New England Journal of Medicine, 2018)
Genetic deficiency of ectodysplasin A (EDA) causes X-linked hypohidrotic ectodermal dysplasia (XLHED), in which the development of sweat glands is irreversibly impaired, an condition that can lead to life-threatening hyperthermia. We observed normal development of mouse fetuses with Eda mutations after they had been exposed in utero to a recombinant protein that includes the receptor-binding domain of EDA. We administered this protein intraamniotically to two affected human twins at gestational weeks 26 and 31 and to a single affected human fetus at gestational week 26; the infants, born in week 33 (twins) and week 39 (singleton), were able to sweat normally, and XLHED-related illness had not developed by 14 to 22 months of age. (Funded by Edimer Pharmaceuticals and others.).
EVALuna2:35486

Prenatal dexamethasone treatment for classic 21-hydroxylase deficiency in Europe - Nowotny, Hanna; Neumann, Uta; Tardy-Guidollet, Veronique; Faisal Ahmed, S.; Baronio, Federico; Battelino, Tadej; Bertherat, Jerome; Blankenstein, Oliver; Bonomi, Marco; Bouvattier, Claire; De la Perrière, Aude Brac; Brucker, Sara; et al. (European Journal of Endocrinology, 2022)
Objective: To assess the current medical practice in Europe regarding prenatal dexamethasone (Pdex) treatment of congenital adrenal hyperplasia (CAH) due to 21-hydroxylase defic iency. Design and methods: A questionnaire was designed and distributed, including 17 questions collecting quantitative and qualitative data. Thirty-six medical centres from 14 European countries responded and 30 out of 36 centres were reference centres of the European Reference Network on Rare Endocrine Conditions, EndoERN. Results: Pdex treatment is currently provided by 36% of the surveyed ce ntres. The treatment is initiated by different specialties, that is paediatricians, endocrinologists, gynaecologists or geneticists. Regarding the starting point of Pdex, 23% stated to initiate therapy at 4-5 weeks postconception (wpc), 31% at 6 wpc and 46 % as early as pregnancy is confirmed and before 7 wpc at the latest. A dose of 20 μg/kg/day is used. Dose distribution among the centres varies from once to thrice daily. Prenatal diagnostics for treated cases are conducted in 72% of the responding centres. Cases treated per country and year vary between 0.5 and 8.25. Registries for long-term follow-up are only available at 46% of the centres that are using Pdex treatment. National registries are only available in Sweden and France. Conclusions: This study reveals a high international variability and discrepancy in the use of Pdex treatment across Europe. It highlights the importance of a European cooperation initiative for a joint international prospective trial to establish evidence-based guidelines on prenatal diagnostics, treatment and follow-up of pregnancies at risk for CAH.
CRIS-Team Scopus Importer:2022-04-29

Prenatal diagnosis of HNF1B-associated renal cysts: Is there a need to differentiate intragenic variants from 17q12 microdeletion syndrome? - Vasileiou, Georgia; Hoyer, Juliane; Thiel, Christian; Schaefer, Jan Thomas; Zapke, Maren; Krumbiegel, Mandy; Kraus, Cornelia; Zweier, Markus; Uebe, Steffen; Ekici, Arif Bülent; Schneider, Michael; Wiesener, Michael; et al. (Prenatal Diagnosis, 2019)
Objective 17q12 microdeletions containing HNF1B and intragenic variants within this gene are associated with variable developmental, endocrine, and renal anomalies, often already noted prenatally as hyperechogenic/cystic kidneys. Here, we describe prenatal and postnatal phenotypes of seven individuals with HNF1B aberrations and compare their clinical and genetic data to those of previous studies. Methods Prenatal sequencing and postnatal chromosomal microarray analysis were performed in seven individuals with renal and/or neurodevelopmental phenotypes. We evaluated HNF1B-related clinical features from 82 studies and reclassified 192 reported intragenic HNF1B variants. Results In a prenatal case, we identified a novel in-frame deletion p.(Gly239del) within the HNF1B DNA-binding domain, a mutational hot spot as demonstrated by spatial clustering analysis and high computational prediction scores. The six postnatally diagnosed individuals harbored 17q12 microdeletions. Literature screening revealed variable reporting of HNF1B-associated clinical traits. Overall, both mutation groups showed a high phenotypic heterogeneity. The reclassification of all previously reported intragenic HNF1B variants provided an up-to-date overview of the mutational spectrum. Conclusions We highlight the value of prenatal HNF1B screening in renal developmental diseases. Standardized clinical reporting and systematic classification of HNF1B variants are necessary for a more accurate risk quantification of prenatal and postnatal clinical features, improving genetic counseling and prenatal decision making.
CRIS-Team WoS Importer:2019-11-08

Prenatal therapy in developmental disorders: drug targeting via intra-amniotic injection to treat X-linked hypohidrotic ectodermal dysplasia - Hermes, Katharina; Schneider, Pascal; Krieg, Peter; Anh Thu Dang,; Huttner, Kenneth; Schneider, Holm (Journal of Investigative Dermatology, 2014)
EVALuna2:18898

Prenatal treatment of X-linked hypohidrotic ectodermal dysplasia using recombinant ectodysplasin in a canine model - Margolis, Carol A.; Schneider, Pascal; Huttner, Kenneth; Kirby, Neil; Houser, Timothy P.; Wildman, Lee; Grove, Gary L.; Schneider, Holm; Casal, Margret L. (Journal of Pharmacology and Experimental Therapeutics, 2019)
X-linked hypohidrotic ectodermal dysplasia (XLHED) is caused by defects in the EDA gene that inactivate the function of ectodysplasin A1 (EDA1). This leads to abnormal development of eccrine glands, hair follicles, and teeth, and to frequent respiratory infections. Previous studies in the naturally occurring dog model demonstrated partial prevention of the XLHED phenotype by postnatal administration of recombinant EDA1. The results suggested that a single or two temporally spaced injections of EDI200 prenatally might improve the clinical outcome in the dog model. Fetuses received ultrasound-guided EDI200 intra-amniotically at gestational days 32 and 45, or 45 or 55 alone (of a 65-day pregnancy). Growth rates, lacrimation, hair growth, meibomian glands, sweating, dentition, and mucociliary clearance were compared in treated and untreated XLHED-affected dogs, and in heterozygous and wild-type control dogs. Improved phenotypic outcomes were noted in the earlier and more frequently treated animals. All animals treated prenatally showed positive responses compared with untreated dogs with XLHED, most notably in the transfer of moisture through paw pads, suggesting improved onset of sweating ability and restored meibomian gland development. These results exemplify the feasibility of ultrasound-guided intra-amniotic injections for the treatment of developmental disorders, with improved formation of specific EDA1-dependent structures in dogs with XLHED.
CRIS-Team Scopus Importer:2019-09-17

Preoperative assessment of the aortic arch in children younger than 1 year with congenital heart disease: utility of low-dose high-pitch dual-source computed tomography. A single-centre, retrospective analysis of 62 cases - Glöckler, Martin; Halbfass, Julia; Koch, Andreas; Dittrich, Sven; Achenbach, Stephan; Rueffer, Andre; Ihlenburg, Katharina Susanne; Cesnjevar, Robert; May, Matthias; Uder, Michael; Rompel, Oliver (European Journal of Cardio-Thoracic Surgery, 2014)
To evaluate the feasibility, image quality and impact of 3D imaging in low-dose high-pitch dual-source computed tomography (DSCT) to assess arbitrary anatomical malformations of the aortic arch in children <1 year of age with congenital heart disease (CHD).Between January 2010 and May 2013, DSCT was performed to assess the aortic arch anatomy in a total of 62 consecutive patients with CHD (aged 0-348 days). DSCT was used whenever conventional echocardiography was not sufficient to display the complex anatomy entirely. Image data acquisition was realized within a single cardiac cycle using prospective ECG triggering. 3D reconstruction for surgical planning was performed. Image quality was assessed retrospectively, using a 4-point scale from '1 = no artefacts' to '4 = uninterpretable'. The accuracy and impact of the 3D reconstructions was compared with intraoperative findings using a 5-point scale (from '1 = essential' to '5 = misleading'). Administered radiation exposure was evaluated.Imaging was successful in all patients, image quality was rated 1.34 on the 4-point scale and the impact of the 3D reconstructions for surgical planning was 2.05 on the 5-point scale. Mean dose-length product was 6.8 ± 2.6 mGy cm, and the effective dose was 0.45 ± 0.13 mSv (0.21-0.74).DSCT is a fast and appropriate imaging modality in the preoperative assessment of the aortic arch for surgical planning in CHD.
EVALuna2:11864

Prescription patterns of antiseizure drugs in tuberous sclerosis complex (TSC)-associated epilepsy: a multicenter cohort study from Germany and review of the literature - Strzelczyk, Adam; Grau, Janina; Bast, Thomas; Bertsche, Astrid; Bettendorf, Ulrich; Hahn, Andreas; Hartmann, Hans; Hertzberg, Christoph; Hornemann, Frauke; Immisch, Ilka; Jacobs, Julia; Klotz, Kerstin A.; et al. (Expert Review of Clinical Pharmacology, 2021)
Objective Seizures are a primary and early disease manifestation of Tuberous Sclerosis Complex (TSC). We aimed to describe the age-stratified patterns of antiseizure drug (ASD) treatments among children, adolescents, and adults with TSC in Germany. Additionally, we reviewed real-world and clinical study evidence regarding ASD utilization in patients with TSC. Methods We evaluated the pattern of routine ASD use and everolimus prescriptions based on a 2019 multicenter survey of 268 individuals with TSC-associated epilepsy. We contextualized the results with a structured review of real-world and clinical study evidence. Results TSC-associated epilepsy treatment comprises a wide variety of ASDs. In this German sample, the majority of patients were treated with polytherapy, and lamotrigine (34.7%), valproate (32.8%), oxcarbazepine (28.7%), vigabatrin (19.0%), and levetiracetam (17.9%) were identified as the most-commonly used ASDs. In addition, everolimus was used by 32.5% of patients. In adherence to current TSC guidelines, the disease-modifying ASD vigabatrin was widely used in children (58% below the age of 5 years), whereas treatment in adults did not necessarily reflect guideline preference for (partial) GABAergic ASDs. Conclusions The selection of ASDs for patients with TSC-associated epilepsy follows well-evaluated recommendations, including the guidelines regarding vigabatrin use in children. Several characteristics, such as the comparatively high frequency of valproate use and polytherapy, reflect the severity of TSC-associated epilepsy.
CRIS-Team WoS Importer:2021-06-11

Preterm small-for-gestational age children: Predictive role of gestational age for mental development at the age of 2 years - Nögel, Stephanie; Deiters, Ludger; Stemmler, Mark; Rascher, Wolfgang; Trollmann, Regina (Brain & Development, 2015)
AIM: The aim of the study was to compare the cognitive development of very low birth weight (VLBW) preterm SGA children and preterm AGA children at the age of 2 years. The hypothesis was that SGA children are at an additional risk for deficits in cognitive function. Additionally, the impact of neonatal risk factors and the parents' profession on the early cognitive development was analysed. METHODS: Cognitive function of 107 preterm infants with a gestational age of 24-35 weeks was assessed with the Mental Bayley Scales of Infant Development at the age of 2 years (mean±SEM). The results of SGA (n=38) and AGA (n=69) children were compared as well as neonatal risk factors and parental education. RESULTS: There was a linear regression between the Mental Bayley Scales result and gestational age for preterm infants with a gestational age of 24-32 weeks. SGA and AGA children did not differ significantly in their cognitive function at the age of 2 years. A strong association was found between the parents' profession and cognitive development. Among the neonatal risk factors, bronchopulmonary dysplasia was a strong predictor of mental development. INTERPRETATION: Cognitive development of two-year-old preterm children with a gestational age of 24-32 weeks was mainly related to their gestational age. Being born preterm and small for gestational age was not additionally associated with cognitive deficits at the age of 2 years. The parents' profession had a significant impact on the cognitive development. The role of the parents' profession on the early development of preterm infants should be elucidated in further studies. Copyright © 2014 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.
Keywords: Gestational age; Mental development; Parental profession; Preterm infants

Prevalence and prevention of severe complications of hypohidrotic ectodermal dysplasia in infancy - Blueschke, Gert; Nuesken, Kai-Dietrich; Schneider, Holm (Early Human Development, 2010)
Objective: To re-evaluate the mortality of hypohidrotic ectodermal dysplasia (HED) and the prevalence of hyperpyrexia and possible neurological sequelae in affected infants. Study design: A cross-sectional postal survey was conducted among parents of 100 children with ectodermal dysplasia who had been registered with the German-Swiss-Austrian patient support group at any time point within the past 10. years. Detailed questionnaires referring to the first year of life were evaluated statistically. Results: 63% of parents returned completed surveys, identifying 57% of children as patients with X-linked HED and 20% as patients with autosomal HED or HED of unknown origin. Of those two groups, 17 infants had been placed in an incubator after birth, where body temperature recording proved to be of utmost importance. In 94% of all HED patients, episodes of unexplained fever were observed during the first year of life. X-linked HED was associated with frequent airway infections. Febrile seizures occurred in 5.9% of infants with X-linked HED and in 17% of the other HED patients. Developmental retardation was reported for 15% and 25%, respectively. Prognosis depended on the type of genetic defect and the time point of diagnosis. Except for one all patients survived infancy. Early recognition of the disease was aided by vigilant neonatal care and consulting a dermatologist or geneticist. Adequate instruction of the parents and networking with patient support groups also reduced the risks associated with HED. Conclusions: Today, mortality of HED and the risk of hyperthermic brain damage are still increased, but lower than reported previously. © 2010 Elsevier Ltd.
CRIS-Team Scopus Importer:2020-07-01
Keywords: Ectodermal dysplasia; Febrile seizure; Hyperthermia; Sudden infant death

Prevalence of chronic drug use in pediatrics: Comprehensive overview based on German claims data - Scholle, Oliver; Neubert, Antje; Riedel, Oliver; Toni, Irmgard; Haug, Ulrike (PHARMACOEPIDEMIOLOGY AND DRUG SAFETY, 2020)
CRIS-Team WoS Importer:2020-11-13

Prevalence of metastases within the hypothalamic-pituitary area in patients with brain metastases - Janssen, Stefan; Mehta, Preena; Bartscht, Tobias; Schmid, Sebastian M.; Fahlbusch, Fabian; Rades, Dirk (Radiation Oncology, 2019)
Aim To quantify the prevalence of brain metastases involving the hypothalamic-pituitary (HT-P) area. Introduction Cognitive impairment and fatigue are common side effects of whole brain irradiation (WBI) comprising the quality of life (QoL) for survivors. While the former is related to radiation-induced hippocampal injury, the latter could be secondary to hormonal disbalance as a consequence of radiation of the HT-P area. Thus, sparing both regions from higher irradiation doses could reduce these sequelae. Methods T1 contrast medium enhanced magnetic resonance imaging (MRI) scans of 865 patients with brain metastases (4,280 metastases) were reviewed. HT-P area was individually contoured with a margin of 5 mm in order to evaluate the prevalence of brain metastases in this region. Results Involvement of the hypothalamic region was found in 26 patients (involvement rate of 3% for patients and 1% for metastases), involvement of the pituitary gland in 9 patients (1% for patients and < 1% for metastases). Binary logistical regression analysis revealed the presence of > 10 brain metastases as the only factor associated with hypothalamic involvement while no distinct factor was associated with an involvement of the pituitary gland. Conclusion The low prevalence of metastases within the HT-P area in patients with brain metastases calls for further studies examining whether sparing of this region might improve patients QoL.
CRIS-Team WoS Importer:2019-09-10

Prevalence of SARS-CoV-2 in Pregnant Women Assessed by RT-PCR in Franconia, Germany: First Results of the SCENARIO Study (SARS-CoV-2 prEvalence in pregNAncy and at biRth In FrancOnia) - Hein, Alexander; Kehl, Sven; Häberle, Lothar; Tiemann, Carsten; Peuker, Rebecca; Mereutanu, Denise; Stumpfe, Florian; Faschingbauer, Florian; Meyer-Schlinkmann, Kirstin; Koch, Martin C.; Kainer, Franz; Dammer, Ulf; et al. (Geburtshilfe und Frauenheilkunde, 2022)
Purpose Detection of SARS-CoV-2-infected pregnant women admitted to maternity units during a pandemic is crucial. In addition to the fact that pregnancy is a risk factor for severe COVID-19 and that medical surveillance has to be adjusted in infected women and their offspring, knowledge about infection status can provide the opportunity to protect other patients and healthcare workers against virus transmission. The aim of this prospective observational study was to determine the prevalence of SARS-CoV-2 infection among pregnant women in the hospital setting. Material and Methods All eligible pregnant women admitted to the nine participating hospitals in Franconia, Germany, from 2 June 2020 to 24 January 2021 were included. COVID-19-related symptoms, secondary diseases and pregnancy abnormalities were documented. SARS-CoV-2 RNA was detected by RT-PCR from nasopharyngeal swabs. The prevalence of acute SARS-CoV-2 infection was estimated by correcting the positive rate using the Rogan-Gladen method. The risk of infection for healthcare workers during delivery was estimated using a risk calculator. Results Of 2414 recruited pregnant women, six were newly diagnosed RT-PCR positive for SARS-CoV-2, which yielded a prevalence of SARS-CoV-2 infection of 0.26% (95% CI, 0.10-0.57%). Combining active room ventilation and wearing FFP2 masks showed an estimated reduction of risk of infection for healthcare workers in the delivery room to < 1%. Conclusions The prevalence of newly diagnosed SARS-CoV-2 infection during pregnancy in this study is low. Nevertheless, a systematic screening in maternity units during pandemic situations is important to adjust hygienic and medical management. An adequate hygienic setting can minimise the calculated infection risk for medical healthcare workers during patients' labour.
CRIS-Team Scopus Importer:2022-02-25
Keywords: COVID-19; infection; pregnancy; prevalence; SARS-CoV-2

Preventing maternal phenylketonuria (PKU) syndrome: important factors to achieve good metabolic control throughout pregnancy - Rohde, Carmen; Thiele, Alena Gerlinde; Baerwald, Christoph; Ascherl, Rudolf Georg; Lier, Dinah; Och, Ulrike; Heller, Christina; Jung, Alexandra; Schoenherr, Kathrin; Joerg-Streller, Monika; Luttat, Simone; Matzgen, Sabine; et al. (Orphanet Journal of Rare Diseases, 2021)
Background Insufficient metabolic control during pregnancy of mothers with phenylketonuria (PKU) leads to maternal PKU syndrome, a severe embryo-/fetopathy. Since maintaining or reintroducing the strict phenylalanine (Phe) limited diet in adults with PKU is challenging, we evaluated the most important dietary and psychosocial factors to gain and sustain good metabolic control in phenylketonuric women throughout pregnancy by a questionnaire survey with 38 questions concerning therapy feasibility. Among them, the key questions covered 5 essential items of PKU care as follows: General information about maternal PKU, PKU training, diet implementation, individual metabolic care, personal support. In addition, all participating PKU mothers were asked to estimate the quality of their personal metabolic control of the concluded pregnancies. 54 PKU mothers with 81 pregnancies were approached at 12 metabolic centers in Germany and Austria were included. According to metabolic control, pregnancies of PKU women were divided in two groups: group "ideal" (not more than 5% of all blood Phe concentrations during pregnancy > 360 mu mol/l; n = 23) and group "suboptimal" (all others; n = 51). Results The demand for support was equally distributed among groups, concerning both amount and content. Personal support by the direct social environment (partner, family and friends) ("suboptimal" 71% vs "ideal" 78%) as well as individual metabolic care by the specialized metabolic center (both groups around 60%) were rated as most important factors. The groups differed significantly with respect to the estimation of the quality of their metabolic situation (p < 0.001). Group "ideal" presented a 100% realistic self-assessment. In contrast, group "suboptimal" overestimated their metabolic control in 53% of the pregnancies. Offspring of group "suboptimal" showed clinical signs of maternal PKU-syndrome in 27%. Conclusion The development of training programs by specialized metabolic centers for females with PKU in child bearing age is crucial, especially since those mothers at risk of giving birth to a child with maternal PKU syndrome are not aware of their suboptimal metabolic control. Such programs should provide specific awareness training for the own metabolic situation and should include partners and families.
CRIS-Team WoS Importer:2021-12-03

Previous diabetic ketoacidosis as a risk factor for recurrence in a large prospective contemporary pediatric cohort: Results from the DPV initiative - Hammersen, Johanna; Tittel, Sascha R.; Warncke, Katharina; Fritsch, Maria; Placzek, Kerstin; Pacaud, Danièle; Karges, Beate; Wölfle, Joachim; Holl, Reinhard W. (Pediatric Diabetes, 2021)
Objective: To assess the role of previous episodes of diabetic ketoacidosis (DKA) and their time-lag as risk factors for recurring DKA in youth with type 1 diabetes (T1D). Research Design and Methods: In a population-based analysis, data from 29,325 children and adolescents with T1D and at least 5 years of continuous follow-up were retrieved from the “Diabetes Prospective Follow-up” (DPV) multi-center registry in March 2020. Statistical analyses included unadjusted comparisons, logistic and negative binomial regression models. Results: Among 29,325 patients with T1D, 86.0% (n = 25,219) reported no DKA, 9.7% (n = 2,833) one, and 4.3% (n = 1,273) more than one episode, corresponding to a DKA rate of 4.4 [95% CI: 4.3–4.6] per 100 patient-years. Female sex, migratory background, higher HbA1c values, higher daily insulin doses, a lower glucose monitoring frequency, and less CGM usage were associated with DKA. In patients with a previous episode, the DKA rate in the most recent year was significantly higher than in patients with no DKA (17.6 [15.9–19.5] vs. 2.8 [2.7–3.1] per 100 patient-years; p < 0.001). Multiple DKAs further increased the recurrence rate. The risk for DKA in the most recent year was higher in patients with an episode in the preceding year than in patients with no previous DKA (OR: 10.0 [95% CI: 8.6–11.8]), and remained significantly elevated 4 years after an episode (OR: 2.3 [1.6–3.1]; p < 0.001). Conclusions: Each episode of DKA is an independent risk factor for recurrence, even 4 years after an event, underlining the importance of a close follow-up after each episode.
CRIS-Team Scopus Importer:2021-03-05

Priapism at Diagnosis of Pediatric Chronic Myeloid Leukemia: Data Derived from a Large Cohort of Children and Teenagers and a Narrative Review on Priapism Management - Suttorp, Meinolf; Sembill, Stephanie; Kalwak, Krzysztof; Metzler, Markus; Millot, Frederic (Journal of Clinical Medicine, 2023)
Pediatric chronic myeloid leukemia (CML) is a very rare malignancy (age-related incidence 0.1/100,000) typically presenting with leucocyte counts >100,000/µL. However, clinical signs of leukostasis are observed at diagnosis in only approximately 10% of all cases and among these, priapism is infrequent. Here, we analyze data from pediatric CML registries on the occurrence of priapism heralding diagnosis of CML in 16/491 (3.2%) boys (median age 13.5 years, range 4–18) with pediatric CML. In the cohort investigated, duration of priapism resulting in a diagnosis of CML was not reported in 5 patients, and in the remaining 11 patients, occurred as stuttering priapism over 3 months (n = 1), over 6 weeks (n = 1), over 1–2 weeks (n = 2), over several days (n = 2), or 24 h (n = 1), while the remaining 4 boys reported continuous erection lasting over 11–12 h. All patients exhibited splenomegaly and massive leukocytosis (median WBC 470,000/µL, range 236,700–899,000). Interventions to treat priapism were unknown in 5 patients, and in the remaining cohort, comprised intravenous fluids ± heparin (n = 2), penile puncture (n = 5) ± injection of sympathomimetics (n = 4) ± intracavernous shunt operation (n = 1) paralleled by leukocyte-reductive measures. Management without penile puncture by leukapheresis or exchange transfusion was performed in 3 boys. In total, 7 out 15 (47%) long-term survivors (median age 20 years, range 19–25) responded to a questionnaire. All had maintained full erectile function; however, 5/7 had presented with stuttering priapism while in the remaining 2 patients priapism had lasted <12 h until intervention. At its extreme, low-flow priapism lasting for longer than 24 h may result in partial or total impotence by erectile dysfunction. This physical disability can exert a large psychological impact on patients’ lives. In a narrative review fashion, we analyzed the literature on priapism in boys with CML which is by categorization stuttering or persisting as mostly painful, ischemic (low-flow) priapism. Details on the pathophysiology are discussed on the background of the different blood rheology of hyperleukocytosis in acute and chronic leukemias. In addition to the data collected, instructive case vignettes demonstrate the diagnostic and treatment approaches and the outcome of boys presenting with priapism. An algorithm for management of priapism in a stepwise fashion is presented. All approaches must be performed in parallel with cytoreductive treatment of leukostasis in CML which comprises leukapheresis and exchange transfusions ± cytotoxic chemotherapy.
CRIS-Team Scopus Importer:2023-08-11
Keywords: chronic myeloid leukemia; exchange transfusion; hyperleukocytosis; leukapheresis; leukostasis; pediatric CML; pediatric CML registry; penile puncture; priapism

Primary Periphyseal Stress Injuries of the Fingers in Adolescent Climbers: A Critical Review - Jones, Gareth; Johnson, Rowena; Schöffl, Volker Rainer; Schöffl, Isabelle; Lutter, Chris; Johnson, Mark; Halsey, Tim (Current Sports Medicine Reports, 2022)
The worldwide rise in popularity of climbing and development of climbing as a competitive sport is reflected by its debut at the 2021 Summer Olympic Games in Tokyo. Digital primary periphyseal stress injuries in adolescent climbers may pose a significant risk to long-term skeletal health. The aim of this article is to critically review research on the diagnosis and management of primary periphyseal stress injuries of the fingers in adolescent climbers. We adopted a systematic approach to searching for relevant literature. Articles were identified after searches of the following electronic databases: Discover, Academic Search Complete, PubMed, Embase, SPORTDiscus, and ScienceDirect. Conclusive evidence suggests digital primary periphyseal stress injuries are a consequence of repetitive microtrauma. Pain reported by adolescent climbers on the dorsal aspect of the proximal interphalangeal joint should be investigated promptly to avoid serious negative consequences. Clinicians should be aware of the efficacy of imaging techniques to inform a clinical diagnosis. A conservative management approach is preferred but in rare cases surgical intervention may be necessary. A diagnostic and therapeutic algorithm for digital primary periphyseal stress injuries is presented.
CRIS-Team WoS Importer:2023-01-13

Problems of drug therapy in pediatrics - Wimmer, Stefan; Rascher, Wolfgang (Kinderkrankenschwester, 2016)
EVALuna2:33998

Prognostic value of cta-derived left ventricular mass in neonates with congenital heart disease - Ellmann, Stephan; Nickel, Julie-Marie; Heiß, Rafael; El Amrani, Nouhayla; Wüst, Wolfgang; Rompel, Oliver; Rueffer, Andre; Cesnjevar, Robert; Dittrich, Sven; Uder, Michael; May, Matthias (Diagnostics, 2021)
For therapeutic decisions regarding uni-or biventricular surgical repair in congenital heart disease (CHD), left ventricular mass (LVM) is an important factor. The aim of this retrospective study was to determine the LVM of infants with CHD in thoracic computed tomography angiographies (CTAs) and to evaluate its usefulness as a prognostic parameter, with special attention paid to hypoplastic left heart (HLH) patients. Manual segmentation of the left ventricular endo-and epicardial volumes was performed in CTAs of 132 infants. LVMs were determined from these volumes and normalized to body surface area. LVMs of patients with different types of CHD were compared to each other using analyses of variances (ANOVA). An LVM cutoff for discrimination between uni-and biventricular repair was determined using receiver operating characteristics. Survival rates were calculated using Kaplan–Meier statistics. Patients with a clinical diagnosis of an HLH had significantly lower mean LVM (21.88 g/m2) compared to patients without applicable disease (50.22 g/m2; p < 0.0001) and compared to other CHDs, including persistent truncus arteriosus, left ventricular outflow tract obstruction, transposition of the great arteries, pulmonary artery stenosis or atresia, and double-outlet right ventricle (all, p < 0.05). The LVM cutoff for uni-vs. biventricular surgery was 33.9 g/m2 (sensitivity: 82.3%; specificity: 73.7%; PPV: 94.9%). In a subanalysis of HLH patients, a sensitivity of 50.0%, specificity of 100%, PPV of 100%, and NPV of 83.3% was determined. Patient survival was not significantly different between the surgical approaches or between patients with LVM above or below the cutoff. LVM can be measured in chest CTA of newborns with CHD and can be used as a prognostic factor.
CRIS-Team Scopus Importer:2021-07-30
Keywords: Cardiac computed tomography; Computed tomography angiography; Congenital heart disease; Heart imaging; Heart surgery; Hypoplastic left heart

Prognostic Value of Speckle Tracking Echocardiography-Derived Strain in Unmasking Risk for Arrhythmias in Children with Myocarditis - Rolfs, Nele; Huber, Cynthia; Opgen-Rhein, Bernd; Altmann, Isabell; Anderheiden, Felix; Hecht, Tobias; Fischer, Marcus; Wiegand, Gesa; Reineker, Katja; Voges, Inga; Kiski, Daniela; Frede, Wiebke; et al. (Biomedicines, 2024)
Background/Objectives: Risk assessment in pediatric myocarditis is challenging, particularly when left ventricular ejection fraction (LVEF) is preserved. This study aimed to evaluate LV myocardial deformation using speckle-tracking echocardiography (STE)-derived longitudinal +strain (LS) and assessed its diagnostic and prognostic value in children with myocarditis. Methods: Retrospective STE-derived layer-specific LV LS analysis was performed on echocardiograms from patients within the multicenter, prospective registry for pediatric myocarditis “MYKKE”. Age- and sex-adjusted logistic regression and ROC analysis identified predictors of cardiac arrhythmias (ventricular tachycardia, ventricular fibrillation, atrioventricular blockage III°) and major adverse cardiac events (MACE: need for mechanical circulatory support (MCS), cardiac transplantation, and/or cardiac death). Results: Echocardiograms from 175 patients (median age 15 years, IQR 7.9–16.5 years; 70% male) across 13 centers were included. Cardiac arrhythmias occurred in 36 patients (21%), and MACE in 28 patients (16%). Impaired LV LS strongly correlated with reduced LVEF (r > 0.8). Impaired layer-specific LV LS, reduced LVEF, LV dilatation, and increased BSA-indexed LV mass, were associated with the occurrence of MACE and cardiac arrhythmias. In patients with preserved LVEF, LV LS alone predicted cardiac arrhythmias (p < 0.001), with optimal cutoff values of −18.0% for endocardial LV LS (sensitivity 0.69, specificity 0.94) and –17.0% for midmyocardial LV LS (sensitivity 0.81, specificity 0.75). Conclusions: In pediatric myocarditis, STE-derived LV LS is not only a valuable tool for assessing systolic myocardial dysfunction and predicting MACE but also identifies patients at risk for cardiac arrhythmias, even in the context of preserved LVEF.
CRIS-Team Scopus Importer:2024-11-08
Keywords: arrhythmias; longitudinal strain; major adverse cardiac events; myocarditis; pediatrics; prediction; speckle tracking echocardiography

Progressive Kidney Failure by Angiotensinogen Inactivation in the Germline - Wopperer, Florian; Olinger, Eric; Wiesener, Antje; Broeker, Katharina A.E.; Knaup, Karl; Schaefer, Jan Thomas; Galiano, Matthias; Schneider, Karen; Schiffer, Mario; Büttner-Herold, Maike; Reis, André; Schmieder, Roland; et al. (Hypertension, 2024)
BACKGROUND: Autosomal recessive renal tubular dysgenesis is a rare, usually fatal inherited disorder of the REN (renin)angiotensin system. Herein, we report an adolescent individual experiencing an unknown chronic kidney disease and aim to provide novel insights into disease mechanisms. METHODS: Exome sequencing for a gene panel associated with renal disease was performed. The REN-angiotensin system was assessed by comprehensive biochemical analysis in blood. REN expression was determined in primary tubular cells by quantitative polymerase chain reaction and in situ hybridization on kidney biopsy samples. Allele frequencies of heterozygous and biallelic deleterious variants were determined by analysis of the Genomics England 100,000 Genomes Project. RESULTS: The patient was delivered prematurely after oligohydramnios was detected during pregnancy. Postnatally, he recovered from third-degree acute kidney injury but developed chronic kidney disease stage G3b over time. Exome sequencing revealed a previously reported pathogenic homozygous missense variant, p.(Arg375Gln), in the AGT (angiotensinogen) gene. Blood AGT concentrations were low, but plasma REN concentration and gene expression in kidney biopsy, vascular, and tubular cells revealed strong upregulation of REN. Angiotensin II and aldosterone in blood were not abnormally elevated. CONCLUSIONS: Renal tubular dysgenesis may present as chronic kidney disease with a variable phenotype, necessitating broad genetic analysis for diagnosis. Functional analysis of the renin-angiotensin system in a patient with AGT mutation revealed novel insights regarding compensatory upregulation of REN in vascular and tubular cells of the kidney and in plasma in response to depletion of AGT substrate as a source of Ang II (similarly observed with hepatic AGT silencing for the treatment of hypertension).
CRIS-Team Scopus Importer:2024-07-26
Keywords: angiotensinogen; exome; mass spectrometry; mutation; renin-angiotensin system

Prospective Newborn Screening for SCID in Germany: A First Analysis by the Pediatric Immunology Working Group (API) - Speckmann, Carsten; Nennstiel, Uta; Hoenig, Manfred; Albert, Michael H.; Ghosh, Sujal; Schuetz, Catharina; Brockow, Inken; Hoerster, Friederike; Niehues, Tim; Ehl, Stephan; Wahn, Volker; Borte, Stephan; et al. (Journal of Clinical Immunology, 2023)
Background: T-cell receptor excision circle (TREC)-based newborn screening (NBS) for severe combined immunodeficiencies (SCID) was introduced in Germany in August 2019. Methods: Children with abnormal TREC-NBS were referred to a newly established network of Combined Immunodeficiency (CID) Clinics and Centers. The Working Group for Pediatric Immunology (API) and German Society for Newborn Screening (DGNS) performed 6-monthly surveys to assess the TREC-NBS process after 2.5 years. Results: Among 1.9 million screened newborns, 88 patients with congenital T-cell lymphocytopenia were identified (25 SCID, 17 leaky SCID/Omenn syndrome (OS)/idiopathic T-cell lymphocytopenia, and 46 syndromic disorders). A genetic diagnosis was established in 88%. Twenty-six patients underwent hematopoietic stem cell transplantation (HSCT), 23/26 within 4 months of life. Of these, 25/26 (96%) were alive at last follow-up. Two patients presented with in utero onset OS and died after birth. Five patients with syndromic disorders underwent thymus transplantation. Eight syndromic patients deceased, all from non-immunological complications. TREC-NBS missed one patient, who later presented clinically, and one tracking failure occurred after an inconclusive screening result. Conclusion: The German TREC-NBS represents the largest European SCID screening at this point. The incidence of SCID/leaky SCID/OS in Germany is approximately 1:54,000, very similar to previous observations from North American and European regions and countries where TREC-NBS was implemented. The newly founded API-CID network facilitates tracking and treatment of identified patients. Short-term HSCT outcome was excellent, but NBS and transplant registries will remain essential to evaluate the long-term outcome and to compare results across the rising numbers of TREC-NBS programs across Europe.
CRIS-Team Scopus Importer:2023-05-19
Keywords: Hematopoietic stem cell transplantation; HSCT; NBS; Newborn screening; SCID; Severe combined immunodeficiency; T cell receptor excision circles; Thymus transplantation; TREC

Prospective observational study protocol to investigate long-term adverse effects of methylphenidate in children and adolescents with ADHD: the Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) study - Inglis, S. K.; Carucci, S.; Garas, P.; Haege, A.; Banaschewski, T.; Buitelaar, J. K.; Dittmann, R. W.; Falissard, B.; Hollis, Chris; Kovshoff, Hanna; Liddle, Elizabeth; Mccarthy, S.; et al. (BMJ Open, 2016)
INTRODUCTION: Methylphenidate is the most frequently used medication for the treatment of attention-deficit/hyperactivity disorder (ADHD) in Europe. Following concerns about its safety, the European Commission called for research into the long-term effects of methylphenidate on children and adolescents with ADHD. The Attention Deficit Hyperactivity Disorder Drugs Use Chronic Effects (ADDUCE) research programme was designed to address this call. At the heart of this programme is a 2-year longitudinal naturalistic pharmacovigilance study being conducted in 27 European sites. METHODS AND ANALYSIS: 3 cohorts of children and adolescents (aged 6-17) living in the UK, Germany, Italy and Hungary are being recruited:Group 1 (Medicated ADHD): 800 ADHD medication-naive children and adolescents with a clinical diagnosis of ADHD about to start methylphenidate treatment for the first time.Group 2 (Unmedicated ADHD): 400 children and adolescents with a clinical diagnosis of ADHD who have never been treated with ADHD medication and have no intention of beginning medication.Group 3 (Non-ADHD): 400 children and adolescents without ADHD who are siblings of individuals in either group 1 or 2.All participants will be assessed 5 times during their 2-year follow-up period for growth and development, psychiatric, neurological and cardiovascular health. The primary outcome measure will be the height velocity SD score. ETHICS AND DISSEMINATION: Ethical approval for the study has been granted by the East of Scotland Research Ethics Service. Following this approval, patient information leaflets and consent forms were translated as necessary and submissions made by lead sites in each of the other 3 countries to their own ethics committees. Following ethical approval in each country, local ethical permissions at each site were sought and obtained as needed. The study's website (http://www.adhd-adduce.org/page/view/2/Home) provides information for researchers, participants and the general public. TRIAL REGISTRATION NUMBER: NCT01470261.
EVALuna2:34017

Prospective, randomized, double-blind, placebo-controlled phase IIa clinical trial on the effects of an estrogen-progestin combination as add-on to inpatient psychotherapy in adult female patients suffering from anorexia nervosa - Paslakis, Georgios; Maas, Stefanie; Gebhardt, Bernd; Mayr, Andreas; Rauh, Manfred; Erim, Yesim (BMC Psychiatry, 2018)

Protocol for the Phase 2 EDELIFE Trial Investigating the Efficacy and Safety of Intra-Amniotic ER004 Administration to Male Subjects with X-Linked Hypohidrotic Ectodermal Dysplasia - Schneider, Holm; Hadj-Rabia, Smail; Faschingbauer, Florian; Bodemer, Christine; Grange, Dorothy K.; Norton, Mary E.; Cavalli, Riccardo; Tadini, Gianluca; Stepan, Holger; Clarke, Angus; Guillén-Navarro, Encarna; Maier-Wohlfart, Sigrun; et al. (Genes, 2023)
X-linked hypohidrotic ectodermal dysplasia (XLHED) is a rare genetic disorder characte-rised by abnormal development of the skin and its appendages, such as hair and sweat glands, the teeth, and mucous glands of the airways, resulting in serious, sometimes life-threatening complications like hyperthermia or recurrent respiratory infections. It is caused by pathogenic variants of the ectodysplasin A gene (EDA). Most affected males are hemizygous for EDA null mutations that lead to the absence or inactivity of the signalling protein ectodysplasin A1 (EDA1) and, thus, to the full-blown phenotype with inability to perspire and few if any teeth. There are currently no long-term treatment options for XLHED. ER004 represents a first-in-class protein replacement molecule designed for specific, high-affinity binding to the endogenous EDA1 receptor (EDAR). Its proposed mechanism of action is the replacement of missing EDA1 in yet unborn patients with XLHED. Once bound to EDAR, ER004 activates the EDA/NFκB signalling pathway, which triggers the transcription of genes involved in the normal development of multiple tissues. Following preclinical studies, named-patient use cases demonstrated significant potential of ER004 in affected males treated in utero during the late second and third trimesters of pregnancy. In order to confirm these results, we started the EDELIFE trial, a prospective, open-label, genotype-match controlled, multicentre clinical study to investigate the efficacy and safety of intra-amniotic ER004 administration as a prenatal treatment for male subjects with XLHED. This article summarises the rationale, the study protocol, ethical issues of the trial, and potential pitfalls.
CRIS-Team Scopus Importer:2023-02-24
Keywords: anhidrosis; clinical trial; ectodermal dysplasia; ectodysplasin A; fetal therapy; protein replacement; sweat glands

PTEN hamartoma tumor syndrome in childhood and adolescence-a comprehensive review and presentation of the German pediatric guideline. - Plamper, Michaela; Gohlke, Bettina; Wölfle, Joachim (Molecular and Cellular Pediatrics, 2022)
BACKGROUND: The PTEN hamartoma tumor syndrome (PHTS) encompasses several different syndromes, which are linked to an autosomal-dominant mutation of the tumor suppressor PTEN gene on chromosome 10. Loss of PTEN activity leads to an increased phosphorylation of different cell proteins, which may have an influence on growth, migration, and apoptosis. Excessive activity of the PI3K/AKT/mTOR pathway due to PTEN deficiency may lead to the development of benign and malignant tumors and overgrowth. Diagnosis of PHTS in childhood can be even more challenging than in adulthood because of a lack of well-defined diagnostic criteria. So far, there are no official recommendations for cancer surveillance in affected children and adolescents. MAIN BODY: All individuals with PHTS are at high risk for tumor development and thus might benefit from cancer surveillance strategies. In childhood, macrocephaly may be the only evident symptom, but developmental delay, behavioral problems, dermatological features (e.g., penile freckling), vascular anomalies, lipoma, or enlarged perivascular spaces in cerebral magnetic resonance imaging (cMRI) may help to establish the diagnosis. Regular psychomotor assessment and assistance in subjects with neurological impairment play an important role in the management of affected children. Already in early childhood, affected patients bear a high risk to develop thyroid pathologies. For that reason, monitoring of thyroid morphology and function should be established right after diagnosis. We present a detailed description of affected organ systems, tools for initiation of molecular diagnostic and screening recommendations for patients < 18 years of age. CONCLUSION: Affected families frequently experience a long way until the correct diagnosis for their child's peculiarity is made. Even after diagnosis, it is not easy to find a physician who is familiar with this rare group of diseases. Because of a still-limited database, it is not easy to establish evidence-based (cancer) surveillance recommendations. The presented screening recommendation should thus be revised regularly according to the current state of knowledge.
EVALuna2:519679

Pubertal Timing and Growth Dynamics in Children With Severe Primary IGF-1 Deficiency: Results From the European Increlex® Growth Forum Database Registry - Bang, Peter; Polak, Michel; Perrot, Valérie; Sert, Caroline; Shaikh, Haris; Wölfle, Joachim (Frontiers in Endocrinology, 2022)
Background: Puberty is delayed in untreated children and adolescents with severe primary IGF-1 deficiency (SPIGFD); to date, it has not been reported whether recombinant human insulin-like growth factor-1 mecasermin (rhIGF-1) treatment affects this. Pubertal growth outcomes were extracted from the European Increlex® Growth Forum Database (Eu-IGFD) Registry (NCT00903110). Methods: The Eu-IGFD Registry includes children and adolescents aged 2 to 18 years with growth failure associated with SPIGFD who are treated with rhIGF-1. Reported outcomes include: age at last registration of Tanner stage 1 and first registration of Tanner stage 2-5 (T2-T5; based on breast development for girls and genital development for boys, respectively); maximum height velocity during each Tanner stage; and pubertal peak height velocity (PPHV). Data cut-off was 13 May 2019. Results: This analysis included 213 patients (132 boys and 81 girls). Mean (SD) age at last registration of T1 and first registration of T5 was 13.0 (2.0) and 16.3 (1.6) years, respectively, in boys and 11.6 (1.8) and 14.7 (1.5) years, respectively, in girls. Among patients reaching the end of puberty (25 boys and 11 girls), mean (SD) height SDS increased from -3.7 (1.4) at baseline in the Eu-IGFD Registry to -2.6 (1.4) at T5 in boys and from -3.1 (1.1) to -2.3 (1.5) in girls. Maximum height velocity was observed during T2 in girls and T3 in boys. Median (range) PPHV was 8.0 (0.3–13.0) cm/year in boys and 6.8 (1.3–9.6) cm/year in girls and occurred most frequently during T2. Overall, the adverse events seen in this analysis were in line with the known safety profile of rhIGF-1. Conclusion: Children and adolescents treated with rhIGF-1 for SPIGFD with growth failure experienced an increase in height SDS in prepubertal years compared with baseline. Despite 1.5 years delay in pubertal start and a delayed and slightly lower PPHV, height SDS gain during puberty was maintained.
CRIS-Team Scopus Importer:2022-03-18
Keywords: Eu-IGFD Registry; growth retardation; mecasermin; puberty; severe primary insulin-like growth factor-1 deficiency

Pulmonary Dysfunction after Pediatric COVID-19 - Heiß, Rafael; Tan, Lina; Schmidt, Sandy; Regensburger, Adrian; Ewert, Franziska; Mammadova, Dilbar; Bühler, Adrian; Vogel-Claussen, Jens; Voskrebenzev, Andreas; Rauh, Manfred; Rompel, Oliver; Nagel, Armin Michael; et al. (Radiology, 2022)
Background Long COVID occurs in lower frequency in children and adolescents than in adults. Morphologic and free-breathing phase-resolved functional low-field MRI may identify persistent pulmonary manifestations after SARS-CoV-2 infection. Purpose To characterize both morphologic and functional changes of lung parenchyma on low-field MRI in children and adolescents with post COVID-19 compared with healthy controls. Materials and Methods Between August and December 2021, a cross-sectional, prospective clinical trial using low-field MRI was performed in children and adolescents from a single academic medical center. The primary outcome was the frequency of morphologic changes on MRI. Secondary outcomes included MRI-derived functional proton ventilation and perfusion parameters. Clinical symptoms, the duration from positive RT-PCR test and serological parameters were compared with imaging results. Nonparametric tests for pairwise and corrected tests for groupwise comparisons were applied to assess differences in healthy controls, recovered participants and with long COVID. Results A total of 54 participants post COVID-19 infection (mean age, 11 years ±3 [SD], 56 males) and 9 healthy controls (mean age, 10 years ±3 [SD], 70 males) were included: 29 (54%) in the COVID-19 group had recovered from infection and 25 (46%) were classified as having long COVID on the day of enrollment. Morphologic abnormality was identified in one recovered participant. Both ventilated and perfused lung parenchyma (V/Q match) was reduced from 81±6.1% in healthy controls to 62±19% (P =.006) in the recovered group and 60±20% (P=.003) in the long COVID group. V/Q match was lower in post COVID patients with infection less than 180 days (63±20%, P=.03), 180 to 360 days (63±18%, P=0.03) and 360 days ago (41±12%, P<.001) as compared with the never-infected healthy controls (81±6.1%). Conclusion Low-field MRI showed persistent pulmonary dysfunction in both children and adolescents recovered from COVID-19 and with long COVI

Pulmonary Hypertension in Adults with Congenital Heart Disease: Real-World Data from the International COMPERA-CHD Registry - Kaemmerer, Harald; Gorenflo, Matthias; Huscher, Dorte; Pittrow, David; Apitz, Christian; Baumgartner, Helmut; Berger, Felix; Bruch, Leonhard; Brunnemer, Eva; Budts, Werner; Claussen, Martin; Coghlan, Gerry; et al. (Journal of Clinical Medicine, 2020)
Introduction: Pulmonary hypertension (PH) is a common complication in patients with congenital heart disease (CHD), aggravating the natural, post-operative, or post-interventional course of the underlying anomaly. The various CHDs differ substantially in characteristics, functionality, and clinical outcomes among each other and compared with other diseases with pulmonary hypertension. Objective: To describe current management strategies and outcomes for adults with PH in relation to different types of CHD based on real-world data. Methods and results: COMPERA (Comparative, Prospective Registry of Newly Initiated Therapies for Pulmonary Hypertension) is a prospective, international PH registry comprising, at the time of data analysis, >8200 patients with various forms of PH. Here, we analyzed a subgroup of 680 patients with PH due to CHD, who were included between 2007 and 2018 in 49 specialized centers for PH and/or CHD located in 11 European countries. At enrollment, the patients' median age was 44 years (67% female), and patients had either pre-tricuspid shunts, post-tricuspid shunts, complex CHD, congenital left heart or aortic disease, or miscellaneous other types of CHD. Upon inclusion, targeted therapies for pulmonary arterial hypertension (PAH) included endothelin receptor antagonists, PDE-5 inhibitors, prostacyclin analogues, and soluble guanylate cyclase stimulators. Eighty patients with Eisenmenger syndrome were treatment-naive. While at inclusion the primary PAH treatment for the cohort was monotherapy (70% of patients), with 30% of the patients on combination therapy, after a median observation time of 45.3 months, the number of patients on combination therapy had increased significantly, to 50%. The use of oral anticoagulants or antiplatelets was dependent on the underlying diagnosis or comorbidities. In the entire COMPERA-CHD cohort, after follow-up and receiving targeted PAH therapy (n = 511), 91 patients died over the course of a 5-year follow up. The 5-year Kaplan-Meier survival estimate for CHD associated PH was significantly better than that for idiopathic PAH (76% vs. 54%; p < 0.001). Within the CHD associated PH group, survival estimates differed particularly depending on the underlying diagnosis and treatment status. Conclusions: In COMPERA-CHD, the overall survival of patients with CHD associated PH was dependent on the underlying diagnosis and treatment status, but was significantly better as than that for idiopathic PAH. Nevertheless, overall survival of patients with PAH due to CHD was still markedly reduced compared with survival of patients with other types of CHD, despite an increasing number of patients on PAH-targeted combination therapy.
CRIS-Team WoS Importer:2020-06-26

Pulmonary valve prostheses: patient's lifetime procedure load and durability. Evaluation of the German National Register for Congenital Heart Defects - Boethig, Dietmar; Avsar, Murat; Bauer, Ulrike M. M.; Sarikouch, Samir; Beerbaum, Philipp; Berger, Felix; Cesnjevar, Robert; Daehnert, Ingo; Dittrich, Sven; Ewert, Peter; Haverich, Axel; Hoerer, Juergen; et al. (Interactive Cardiovascular and Thoracic Surgery, 2022)
OBJECTIVES: We evaluated 4384 procedures performed between 1957 and 2018, collected in the National Register for Congenital Heart Defects, conducted on 997 patients with 1823 pulmonary valve replacements (PVRs), including 226 implanted via catheter [transcatheter valve (TCV)]. Main study targets are as follows: TCV benefit, valve type durability, decade-wise treatment changes and procedure frequencies over the lifetime of a PVR patient. METHODS: We studied TCV impact on surgical valve replacement (via Kaplan-Meier); pulmonary valve type-specific performance (Kaplan-Meier and Cox regressions with age group as stratification or ordinary variable); procedure interval changes over the decades (Kaplan-Meier); procedure load, i.e. frequency of any procedure/surgical PVR/interventional or surgical PVR by patient age (multistate analyses). RESULTS: TCV performance was equivalent to surgical PVRs and extended durability significantly. Homografts were most durable; Contegras lasted comparably less in older; and Hancock devices lasted less in younger patients. Matrix P-valves showed poorer performance. Age group stratification improves the precision of valve-specific explantation hazard estimations. The current median interval between procedures is 2.6 years; it became significantly shorter in most age groups below 40 years. At 30 years, 80% of patients had undergone ≥3 procedures, 20% ≥3 surgical PVRs and 42% ≥3 surgical or interventional PVRs. CONCLUSIONS: TCVs doubled freedom from explantation of conventional valves. Homografts' age group-specific explantation hazard ratio was lowest; Matrix P's hazard ratio was highest. Age-stratified Cox regressions improve the precision of prosthesis durability evaluations. The median time between procedures for PVR patients shortened significantly to 2.6 years. At 30 years, 42% had ≥3 PVRs.
CRIS-Team Scopus Importer:2022-03-18
Keywords: Congenital heart disease; Long-term follow-up; Procedure load; Pulmonary valve prosthesis; Transcatheter pulmonary valve replacement

Pupillometry in the follow-up of patients undergoing EVT - prediction of space-occupying hemispheric infarction - Kossel, Clara-Sophie; Kobus, Franca; Borutta, Matthias; Kärtner, Maximilian; Kuramatsu, Joji; Engelhorn, Tobias; Schwab, Stefan; Köhn, Julia (Journal of Neurology, 2023)
Background: Despite benefits of endovascular treatment (EVT) for large vessel occlusion (LVO) ischemic stroke, space-occupying brain edema (BE) represents a detrimental complication. In critical-care settings, CT-imaging is needed for monitoring these patients. Yet, bed-side techniques with the potential to predict whether patients develop BE or not would facilitate a time- and cost-efficient patient care. We assessed clinical significance of automated pupillometry in the follow-up of patients undergoing EVT. Methods: From 10/2018 to 10/2021, neurocritical-care-unit patients were retrospectively enrolled after EVT of anterior circulation LVO. We monitored parameters of pupillary reactivity [light-reflex-latency (Lat), constriction- and redilation-velocities (CV, DV), percentage-change-of-apertures (per-change); NeurOptics-pupilometer®] up to every hour on day 1–3 of ICU stay. BE was defined as midline shift ≥ 5 mm on follow-up imaging 3–5 days after EVT. We calculated mean values of intra-individual differences between successive pairs of parameters (mean-deltas), determined best discriminative cut-off values for BE development (ROC-analyses), and evaluated prognostic performance of pupillometry for BE development (sensitivity/specificity/positive-/negative-predictive-values). Results: 3241 pupillary assessments of 122 patients [67 women, 73 years (61.0–85.0)] were included. 13/122 patients developed BE. Patients with BE had significantly lower CVs, DVs, and smaller per-changes than patients without BE. On day 1 after EVT mean-deltas of CV, DV, and per-changes were significantly lower in patients with than without BE. Positive-predictive-values of calculated thresholds to discriminate both groups were considerably low, yet, we found high negative-predictive-values for CV, DV, per-changes, and mean-deltas (max.: 98.4%). Conclusion: Our data suggest associations between noninvasively detected changes in pupillary reactivity and BE early after LVO-EVT. Pupillometry may identify patients who are unlikely to develop BE and may not need repetitive follow-up-imaging or rescue-therapy.
CRIS-Team Scopus Importer:2023-06-30
Keywords: Automated pupillometry; Endovascular treatment; Ischemic stroke; Large vessel occlusion; Pupillary reactivity

Qualitätssicherungsrichtlinie Früh- und Reifgeborene des Gemeinsamen Bundesausschusses als Qualitätsrisiko? Analyse zu Erfüllungsgrad und Konsequenzen in der Versorgung weiterer intensivpflichtiger Patienten sowie drohender Frühgeburten am Beispiel eines regionalen Verbund-Perinatalzentrums - Kleeberg, Markus; Beckmann, Matthias; Fusch, Christoph; Hanf, Volker; Kainer, Franz; Klinge, Jens; Koehler, Wolfgang; Morhart, Patrick; Schroth, Michael Andreas (Zeitschrift für Geburtshilfe und Neonatologie, 2020)
Background The quality guideline for care delivery to preterm and mature infants (QFR-RL) places high demands on perinatal centers. In this analysis, the degree of fulfillment was determined. Additionally, care delivery to further patient groups and sufficient nursing staff capacity for caredelivery to imminent preterm infants (FG) were evaluated. Methods A network of 4 perinatal centers (level 1) with about 10,000 births per year supplied the data on the ratio of 1:1/1:2-care infants,patients per nurse, and nursing staff capacity. This data was statistically evaluated by center, shift, and week day over a period of 5 months for compliance with QFR-RL and DGPM recommendations. Furthermore, imminent preterm infants were recorded and compared with available nursing staff capacity. Results In total, the QFR-RL was fulfilled in 88% of shifts (n=1,584). Only one center reached the required 95. The degree of fulfillment and the number of staff nurses declined from late to night shifts (p<0.001). The ratio of 1:1-care infants was significantly higher when demands were not fulfilled (p<0.001). Only 14.1 of imminent preterm infants could have been attended in accordance with the QFR-RL. Conclusion 1:1 care as well as lower nurse staffing in late and night shifts lead to non-fulfillment of requirements and poorer care delivery to other intensive care patients. This was also reflected in the lower degree of fulfillment of DGPM recommendations. Sufficient nursing staff capacity was rare with the consequence that it was almost impossible to deliver care to imminent preterm infants per the guideline.
CRIS-Team Scopus Importer:2020-11-06
Keywords: 1:1-Care; preterm infants care; quality guideline of care delivery of preterm and mature infants; quality of care; staffing ratio

Quality and clinical supply considerations of Paediatric Investigation Plans for IV preparations-A case study with the FP7 CloSed project - Hanning, Sara M.; Gul, Mine Orlu; Winslade, Jackie; Baarslag, Manuel A.; Neubert, Antje; Tuleu, Catherine (International Journal of Pharmaceutics, 2016)
A Paediatric Investigation Plan (PIP) is a development plan that aims to ensure that sufficient data are obtained through studies in paediatrics to support the generation of marketing authorisation of medicines for children. This paper highlights some practical considerations and challenges with respect to PIP submissions and paediatric clinical trials during the pharmaceutical development phase, using the FP7-funded Clonidine for Sedation of Paediatric Patients in the Intensive Care Unit (CloSed) project as a case study. Examples discussed include challenges and considerations regarding formulation development, blinding and randomisation, product labelling and shipment and clinical trial requirements versus requirements for marketing authorisation. A significant quantity of information is required for PIP submissions and it is hoped that future applicants may benefit from an insight into some critical considerations and challenges faced in the CloSed project.
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Quality of life of short-statured children born small for gestational age or idiopathic growth hormone deficiency within one year of growth hormone treatment - Quitmann, Julia; Bloemeke, Janika; Silva, Neuza; Bullinger, Monika; Witt, Stefanie; Akkurt, Ilker; Dunstheimer, Desirée; Vogel, Christian; Böttcher, Volker; Krahl, Ursula Kuhnle; Bettendorf, Markus; Schönau, Eckhard; et al. (Frontiers in Pediatrics, 2019)
Aside from clinical endpoints like height gain, health-related quality of life has also become an important outcome indicator in the medical field. However, the data on short stature and health-related quality of life is inconsistent. Therefore, we examined changes in health-related quality of life in German children with idiopathic growth hormone deficiency or children born small for gestational age before and after 12 months of human growth hormone treatment. Children with idiopathic short stature without treatment served as a comparison group. At baseline, health-related quality of life data of 154 patients with idiopathic growth hormone deficiency (n = 65), born small for gestational age (n = 58) and idiopathic short stature (n = 31) and one parent each was collected. Of these, 130 completed health-related quality of life assessments after 1-year of human growth hormone treatment. Outcome measures included the Quality of Life in Short Stature Youth questionnaire, as well as clinical and sociodemographic data. Our results showed that the physical, social, and emotional health-related quality of life of children treated with human growth hormone significantly increased, while untreated patients with idiopathic short stature reported a decrease in these domains. Along with this, a statistically significant increase in height in the treated group can be observed, while the slight increase in the untreated group was not significant. In conclusion, the results showed that human growth hormone treatment may have a positive effect not only on height but also in improving patient-reported health-related quality of life of children with idiopathic growth hormone deficiency and children born small for gestational age.
CRIS-Team Scopus Importer:2019-05-02
Keywords: Growth hormone treatment; Health-related quality of life; IGHD; ISS; QoLISSY; Short stature

Quality of life of young adults after a growth hormone therapy with childhood onset - Quitmann, J. H.; Rohenkohl, A. C.; Kammerer, U.; Schöfl, Christof; Bullinger, M.; Dörr, Helmuth-Günther (Deutsche Medizinische Wochenschrift, 2014)
Little is known about the health-related quality of life of young adults with childhood onset idiopathic growth hormone deficiency or neurosecretory dysfunction of growth hormone secretion, who have been treated with recombinant human growth hormone (GH).Patients were diagnosed and treated with human growth hormone at the University Children´s Hospital in Erlangen (n=85). The data of both groups were merged for analysis, because no difference between idiopathic growth hormone deficiency and neurosecretory dysfunction of growth hormone secretion in auxological. Data were found. Health-related quality of life was cross- sectionally assessed after the end of growth hormone therapy with the Short Form-36 Health Survey and the Nottingham Health Profiles for which population based norm data are available.At the time of the survey, the patients (53 m, 32 f) were 23.5 ± 4.6 years old. At start of GH therapy, age was 10.5 ± 2.8 and at the end 16.3 ± 1,4 years. At start, height SDS was -3.20 ± 1.06. GH dose was 0,026 ± 0,012 mg/kg/d (daily s. c.-injections). The increase in height SDS after the end of GH therapy was 1.69 ± 1.22. Compared to the reference population, patients reported significantly lower scores on the scales energy level, vitality, social functioning, indicating a greater social isolation, a stronger emotional reaction, an increased loss of mobility and a worse psychological state.Young adults report specific impairments after completion of GH therapy.
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Quality of Pediatric Palliative Care Crisis Intervention - A Retrospective Survey - Berkmueller, Magdalena; Gravou-Apostolatou, Chara; Rascher, Wolfgang (Klinische Pädiatrie, 2021)
Zusammenfassung
CRIS-Team WoS Importer:2021-10-01

Quality of Survival and Growth in Children and Young Adults in the PNET4 European Controlled Trial of Hyperfractionated Versus Conventional Radiation Therapy for Standard-Risk Medulloblastoma - Kennedy, Colin; Bull, Kim; Chevignard, Mathilde; Culliford, David; Dörr, Helmuth-Günther; Doz, Francois; Kortmann, Rolf-Dieter; Lannering, Birgitta; Massimino, Maura; Navajas Gutierrez, Aurora; Rutkowski, Stefan; Spoudeas, Helen A.; et al. (International Journal of Radiation Oncology Biology Physics, 2014)
To compare quality of survival in "standard-risk" medulloblastoma after hyperfractionated radiation therapy of the central nervous system with that after standard radiation therapy, combined with a chemotherapy regimen common to both treatment arms, in the PNET4 randomised controlled trial.Participants in the PNET4 trial and their parents/caregivers in 7 participating anonymized countries completed standardized questionnaires in their own language on executive function, health status, behavior, health-related quality of life, and medical, educational, employment, and social information. Pre- and postoperative neurologic status and serial heights and weights were also recorded.Data were provided by 151 of 244 eligible survivors (62%) at a median age at assessment of 15.2 years and median interval from diagnosis of 5.8 years. Compared with standard radiation therapy, hyperfractionated radiation therapy was associated with lower (ie, better) z-scores for executive function in all participants (mean intergroup difference 0.48 SDs, 95% confidence interval 0.16-0.81, P=.004), but health status, behavioral difficulties, and health-related quality of life z-scores were similar in the 2 treatment arms. Data on hearing impairment were equivocal. Hyperfractionated radiation therapy was also associated with greater decrement in height z-scores (mean intergroup difference 0.43 SDs, 95% confidence interval 0.10-0.76, P=.011).Hyperfractionated radiation therapy was associated with better executive function and worse growth but without accompanying change in health status, behavior, or quality of life.
EVALuna2:18860

Quantification of translocation-specific ctDNA provides an integrating parameter for early assessment of treatment response and risk stratification in ewing sarcoma - Krumbholz, Manuela; Eiblwieser, Johanna; Ranft, Andreas; Zierk, Jakob; Schmidkonz, Christian; Stuetz, Adrian M.; Peneder, Peter; Tomazou, Eleni M.; Agaimy, Abbas; Bäuerle, Tobias; Hartmann, Wolfgang; Dirksen, Uta; et al. (Clinical Cancer Research, 2021)
Purpose: We evaluated the predictive and prognostic value of circulating tumor DNA (ctDNA) in patients with Ewing sarcoma (EWS) treated in the EWING2008 trial. Experimental Design: Plasma samples from 102 patients with EWS enrolled in the EWING2008 trial were obtained before and during induction chemotherapy. Genomic EWSR1 fusion sequence spanning primers and probes were used for highly specific and sensitive quantification of the levels of ctDNA by digital droplet PCR. ctDNA levels were correlated to established clinical risk factors and outcome parameters. Results: Pretreatment ctDNA copy numbers were correlated with event-free and overall survival. The reduction in ctDNA levels below the detection limit was observed in most cases after only two blocks of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE) induction chemotherapy. The persistence of ctDNA after two VIDE blocks was a strong predictor of poor outcomes. ctDNA levels correlated well with most established clinical risk factors; an inverse correlation was found only for the histologic response to induction therapy. ctDNA levels did not provide simple representations of tumor volume, but integrated information from various tumor characteristics represented an independent EWS tumor marker with predictive and prognostic value. Conclusions: ctDNA copy number in the plasma of patients with EWS is a quantifiable parameter for early risk stratification and can be used as a dynamic noninvasive biomarker for early prediction of treatment response and outcome of patients.
CRIS-Team Scopus Importer:2021-11-26

Radiotherapy for prostate cancer: DISCERN quality assessment of patient-oriented websites in 2018 - Janssen, S.; Fahlbusch, F. B.; Kaesmann, L.; Rades, D.; Vordermark, D. (BMC Urology, 2019)
Background: Prostate cancer is the most commonly diagnosed cancer in men. Radiotherapy represents one major treatment option in different therapeutic settings. As patients increasingly rely on internet-based medical information, we examined the quality of information on radiotherapy and prostate cancer in websites used by laypersons. Methods: An Internet search from a patients' perspective was carried out using different search engines (Google, Yahoo and Bing, search terms: "prostate cancer" and "radiotherapy"). The quality of search results was analyzed with regard to the DISCERN score, HON code certification, the JAMA criteria and the ALEXA traffic rank. Results: In general, websites were of good quality. The highest quality was found for websites operated by charity organizations. No significant differences in results obtained via the above-mentioned tools were seen for the examined search engines, but Google revealed the most stable search results in terms of temporal changes. Conclusion: Patients with prostate cancer can sufficiently inform themselves on general treatment options including radiotherapy on websites directed at laypersons. However, no simple strategy could identify high quality websites in general. For treating physicians, it is important to support patients in interpreting and ranking the vast quantity of information.
CRIS-Team Scopus Importer:2019-06-18
Keywords: Health-related information; Internet; Online information; Prostate cancer; Radiotherapy

Rare intronic mutation between Exon 62 and 63 (c.9225–285A>G) of the dystrophin gene associated with atypical BMD phenotype - Schüssler, S. C.; Gerhalter, T.; Abicht, A.; Müller-Felber, W.; Nagel, Armin Michael; Trollmann, Regina (Neuromuscular Disorders, 2020)
Dystrophinopathies are predominantly caused by deletions, duplications and point mutations in the coding regions of the dystrophin gene with less than 1% of all pathogenic mutations identified within intronic sequences. We describe a 17-year-old male with a Becker muscular dystrophy diagnosis and mental disability due to an intron mutation that led to aberrant splicing and formation of an additional exon. Histopathological analysis of muscle tissue revealed signs of muscular dystrophy and reduced signal for dystrophin, alpha-sarcoglycan, and alpha-dystroglycan. Multiplex ligation-dependent probe amplification screening and total sequencing of the dystrophin gene did not identify a mutation in the coding regions. However, next generation sequencing revealed an intron mutation between exons 62 and 63 of the dystrophin gene known for pseudoexon formation and disruption of the reading frame. We report a functional consequence of this mutation as an increased intracellular-weighted sodium signal (assessed by 23Na-magnetic resonance imaging) in leg muscles.
CRIS-Team Scopus Importer:2020-08-28
Keywords: 23Na-MRI; Aberrant splicing; Becker muscular dystrophy; Dystrophin; Intracellular-weighted sodium signal; Next generation sequencing

Rare malignant pediatric tumors registered in the German Childhood Cancer Registry 2001-2010 - Brecht, Ines B.; Bremensdorfer, Claudia; Schneider, Dominik T.; Fruehwald, Michael C.; Offenmüller, Sonja; Mertens, Rolf; Vorwerk, Peter; Koscielniak, Ewa; Bielack, Stefan S.; Benesch, Martin; Hero, Barbara; Graf, Norbert; et al. (Pediatric Blood & Cancer, 2014)
The German Childhood Cancer Registry (GCCR) annually registers approximately 2,000 children diagnosed with a malignant disease (completeness of registration >95%). While most pediatric cancer patients are diagnosed and treated according to standardized cooperative protocols of the German Society for Pediatric Oncology and Hematology (GPOH), patients with rare tumors are at risk of not being integrated in the network including trials and reference centers.A retrospective analysis of all rare extracranial solid tumors reported to the GCCR 2001-2010 (age <18 years) was undertaken using a combination of the International Classification of Childhood Cancer (ICCC-3) and the International Classification of Diseases-Oncology (ICD-O-3). Tumors accounting for <0.3% of all malignancies were defined as rare (approx. 6 cases/year and registered malignancy).According to this definition 1,189 rare extracranial solid tumors (18.2% of all malignant extracranial solid tumors) were registered, among these 232 patients (19.5% of rare tumor cases), were not included in preexisting GPOH studies/registries. Within 10 years, the number of registered non-GPOH-trial patients with a rare tumor increased.Though most of the GCCR-registered patients with rare malignant tumors are treated within GPOH trials, there is a considerable number of patients that have been diagnosed and treated outside the structures of the GPOH. These patients should be reported to the recently founded German Pediatric Rare Tumor Registry (STEP). Active data accrual and the development of appropriate structures will allow for better registration and improvement of medical care in these patients.
EVALuna2:18876

Rare pediatric tumors in Germany – not as rare as expected: a study based on data from the Bavarian Cancer Registry and the German Childhood Cancer Registry - Achajew, Aisana; Brecht, Ines B.; Radespiel-Troeger, Martin; Meyer, Martin; Metzler, Markus; Bremensdorfer, Claudia; Spix, Claudia; Erdmann, Friederike; Schneider, Dominik T.; Abele, Michael (European Journal of Pediatrics, 2022)
Very rare pediatric tumors (VRTs) pose a challenge for treating physicians as little is known about the best diagnostic assessment and therapeutic decision-making in these malignancies. A large proportion of these cancers occur in adolescence. Therefore, the established structures of pediatric oncology including cancer registration may partly be circumvented. This may lead to an underregistration in clinical cancer registries of yet unclear extent. The aim of this study is to increase the knowledge on the occurrence of VRTs in pediatric patients in Germany. Pseudonymized data of cases recorded in the Bavarian Cancer Registry (BCR) between 2002 and 2014 were retrieved. VRTs according to the definition of the European Cooperative Study Group for Pediatric Rare Tumors were identified using the ICD and ICD-O classification. The numbers of registered patients were compared to those reported to the German Childhood Cancer Registry (GCCR). 6.3% (n = 290) of all malignancies (n = 4615) in the age below 18 years were classified as VRTs. Median age at diagnosis was 15 years (range 0–17 years). The most common tumor types included malignant melanoma, skin carcinoma, and gonadal tumors. During the same period, 49 pediatric patients from Bavaria with matchable VRTs were reported to the GCCR, accounting for 17% of cases reported to the BCR. Conclusions: The frequency of VRTs in Germany is underestimated in the national GCCR. With this study, we present population-based data on the incidence of VRTs in Germany for the first time. In order to gain additional knowledge about these malignancies, registration of VRTs must be improved through enhanced data exchange between the GCCR, the public cancer registries, and the clinical Registry for Rare Pediatric Tumors (STEP).What is Known:• Rare pediatric tumors pose a challenge for treating physicians as limited knowledge is available on these malignancies for diagnostic and therapeutic decision-making.• Little is known about the frequency of these rare tumors in pediatric patients.What is New:• The frequency of rare pediatric tumors in Germany is distinctly underestimated in the German Childhood Cancer Registry.• We present population-based data on the incidence of these rare pediatric cancers for the first time.
CRIS-Team Scopus Importer:2022-06-17
Keywords: Bavaria; Cancer registry; Germany; Incidence; Pediatric cancers; Rare tumors

Rare Subsequent Primary Cancers in Pediatric Cancer Survivors - Mertens, Ann C.; Langer, Thorsten (Rare Tumors in Children and Adolescents, 2022)
Advances in cancer therapy during the past four decades have resulted in remarkable increases in survival for most cancers of childhood and adolescence. Data from the National Cancer Institute’s Surveillance, Epidemiology, and End Results (SEER) Program show that the overall 5-year survival rate for childhood cancer has increased from 45% in 1970 to over 80% in 2005 (Ries et al., Cancer incidence and survival among children and adolescents: United States SEER Program 1975–1995, National Cancer Institute, SEER Program. NIH Publication No. 99-4649, National Cancer Institute, Bethesda, 1999). It is estimated that 1 in every 640 young adults is now a survivor of childhood cancer and that at least 328,000 persons in the USA alone have survived cancer diagnosed before the age of 20 years (Mariotto and Rowland, Cancer Epidemiol Biomarkers Prev 18:1033–1040, 2009). Because of the relatively young age of these survivors, and their potential longevity, the delayed consequences of therapy may have a significant impact on their lives, and on society at large, over an extended period of time.
CRIS-Team Scopus Importer:2022-06-17
Keywords: Cancer survivor; Childhood cancer; Childhood cancer survivor; Standardize incidence ratio; Thyroid cancer

Rare Tumors in Children and Adolescents - the STEP Working Group & apos;s Evolution to a Prospective Registry - Hippert, Felicitas; Desing, Lena; Diez, Sonja; Witowski, Andrea; Bernbeck, Benedikt; Abele, Michael; Seitz, Christian; Erdmann, Friederike; Brecht, Ines; Schneider, Dominik T. (Klinische Pädiatrie, 2021)
Zusammenfassung
CRIS-Team WoS Importer:2021-12-03

Rare Variant of GM2 Gangliosidosis through Activator-Protein Deficiency - Brackmann, Florian; Kehrer, Christiane; Kustermann, Wibke; Boehringer, Judith; Kraegeloh-Mann, Ingeborg; Trollmann, Regina (Neuropediatrics, 2017)
GM2 gangliosidosis, AB variant, is a very rare form of GM2 gangliosidosis due to a deficiency of GM2 activator protein. We report on two patients with typical clinical features suggestive of GM2 gangliosidosis, but normal results for hexosaminidase A and hexosaminidase B as well as their corresponding genes. Genetic analysis of the gene encoding the activator protein, the GM2A gene, elucidated the cause of the disease, adding a novel mutation to the spectrum of GM2 AB variant. This report points out that in typical clinical constellations with normal enzyme results, genetic diagnostic for activator protein defects should be performed.
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Raster-Scanning Optoacoustic Mesoscopy for Gastrointestinal Imaging at High Resolution - Knieling, Ferdinand; Menezes, Jean Gonzales; Claussen, Jing; Schwarz, Mathias; Neufert, Clemens; Fahlbusch, Fabian B.; Rath, Timo; Thoma, Oana-Maria; Kramer, Viktoria; Menchicchi, Bianca; Kersten, Christina; Scheibe, Kristina; et al. (Gastroenterology, 2018)
EVALuna2:33792

Ratiometric luminescence 2D in vivo imaging and monitoring of mouse skin oxygenation - Hofmann, Julian; Meier, Robert J.; Mahnke, Alexander; Schatz, Valentin; Brackmann, Florian; Trollmann, Regina; Bogdan, Christian; Liebsch, Gregor; Wang, Xu Dong; Wolfbeis, Otto S.; Jantsch, Jonathan (Methods and Applications in Fluorescence, 2013)
Tissue oxygenation plays a critical role in the pathogenesis of various diseases, but non-invasive, robust and user-friendly methods for its measurement in vivo still need to be established. Here, we are presenting an in vivo oxygen-detection system that uses ratiometric luminescence imaging (RLI) as a readout scheme to determine the skin oxygen tension of mouse hind footpads via side-by-side comparison with more established techniques including luminescence-lifetime imaging using planar sensor films and the polarographic electrode as the gold standard. We also demonstrate that this technology allows the detection of changes in mouse skin tissue oxygenation induced by subjecting mice to systemic hypoxia. The data demonstrate oxygen imaging based on RLI to be a most useful tool for reliably and easily analyzing and monitoring skin tissue oxygenation in vivo. This technology will advance our understanding of local regulation of skin tissue oxygenation in various disease conditions.
CRIS-Team Scopus Importer:2024-02-26

Ratio of Urinary Proteins to Albumin Excretion Shifts Substantially during Progression of the Podocytopathy Alport Syndrome, and Spot Urine Is a Reliable Method to Detect These Pathologic Changes - Boeckhaus, Jan; Mohr, Lea; Dihazi, Hassan; Tönshoff, Burkhard; Weber, Lutz T.; Pape, Lars; Latta, Kay; Fehrenbach, Henry; Lange-Sperandio, Baerbel; Kettwig, Matthias; Staude, Hagen; König, Sabine; et al. (Cells, 2023)
The urinary albumin- and protein-to-creatinine ratios (UACR and UPCR, respectively) are key endpoints in most clinical trials assessing risk of progression of chronic kidney disease (CKD). For the first time, the current study compares the UACR versus the UPCR head-to-head at early stages of CKD, taking use of the hereditary podocytopathy Alport syndrome (AS) as a model disease for any CKD. Urine samples originated from the prospective randomized, controlled EARLY PRO-TECT Alport trial (NCT01485978). Urine samples from 47 children with confirmed diagnoses of AS at very early stages of CKD were divided according to the current stage of AS: stage 0 (UACR < 30 mg/g), stage 1 (30–300 mg/g) or stage 2 (>300 mg/g). The range of estimated glomerular filtration rate was 75–187.6 mL/min. The mean age was 10.4 ± 4.5 years. In children at stage 0, proteinuria in spot urine, confirmed in 24 h urine, was almost ten times higher than albuminuria (106.4 ± 42.2 vs. 12.5 ± 9.7; p < 0.05); it was “only” about three times higher in stage 1 (328.5 ± 210.1 vs. 132.3 ± 80.5; p < 0.05) and almost equal in stage 2 (1481.9 ± 983.4 vs. 1109.7 ± 873.6; p = 0.36). In 17 children, UACRs and UPCRs were measured simultaneously in 24 h urine and spot urine in the same study visit. Interestingly, the UACR (and UPCR) in 24 h urine vs. in spot urine varied by less than 10% (266.8 ± 426.4 vs. 291.2 ± 530.2). In conclusion, our study provides the first evidence that in patients with normal glomerular filtration rate (GFR) and low amounts of albuminuria, especially in children with podocytopathies such as AS, measuring the UACR and UPCR in spot urine is a reliable and convenient alternative to 24 h urine collection. Our study advocates both the UACR and the UPCR as relevant diagnostic biomarkers in future clinical trials in children with glomerular diseases because the UPCR seems to be a very significant parameter at very early stages of podocytopathies. The German Federal Ministry of Education and Research funded this trial (01KG1104).
CRIS-Team Scopus Importer:2023-05-26
Keywords: albuminuria; Alport syndrome; diagnostic marker; glomerulus; hereditary kidney diseases; mechanical stretch; podocytes; podocytopathies; proteinuria; renal fibrosis; type IV collagen

Reactivations of Latent Viral Infections Are Associated with an Increased Thr389 p70S6k Phosphorylation in Peripheral Lymphocytes of Renal Transplant Recipients - Cherneha, Maxim; Korth, Johannes; Kaulfuss, Meike; Trilling, Mirko; Widera, Marek; Rohn, Hana; Dolff, Sebastian; Babel, Nina; Hörning, André; Kribben, Andreas; Witzke, Oliver (Viruses, 2021)
Reactivations of BK polyoma virus (BKPyV) and human cytomegalovirus (HCMV) frequently cause life- and graft-threatening complications after renal transplantation. Both viruses are dependent on the mTOR pathway for replication. In this study we investigated the association of viral replication with mTOR activity in peripheral lymphocytes of renal transplant recipients. A flow-cytometry based assay for the measurement of Thr389 p70S6k phosphorylation, a surrogate marker of the mTOR pathway was established. Forty-eight adult renal transplant recipients were recruited to measure p70S6k activity in their peripheral blood mononuclear cells. This data set in conjunction with information concerning previous replication of BKPyV and HCMV was examined for correlations. Episodes of BKPyV replication were significantly associated with increased p70S6k phosphorylation in CD4+ T lymphocytes (p = 0.0002) and CD19+ B lymphocytes (p = 0.0073). HCMV infection of patients with a high-risk HCMV constellation of donor and recipient (D+/R-) was associated with increased p70S6k phosphorylation in CD19+ B lymphocytes (p = 0.0325). These associations were found to be independent of the trough levels of the immunosuppressive drugs. Conclusion: P70S6k phosphorylation in peripheral lymphocytes is associated with BKPyV reactivations and to a lesser extent with HCMV infections in renal transplant recipients.
CRIS-Team Scopus Importer:2021-04-16
Keywords: BK polyoma virus; human cytomegalovirus; p70 ribosomal S6 kinase; PyVAN; renal transplantation

Real-world data in children with achondroplasia after licensing of Vosoritide - Palm, Katja; Bechthold-Dalla Pozza, Susanne; Gausche, Ruth; Hoegler, Wolfgang; Hoyer-Kuhn, Heike; Huebner, Angela; Keller, Alexandra; Mirante, Alice; Mohnike, Klaus; Muschol, Nicole; Nader, Sean; Pfaeffle, Roland; et al. (HORMONE RESEARCH IN PAEDIATRICS, 2022)
CRIS-Team WoS Importer:2022-10-07

Rearrangement bursts generate canonical gene fusions in bone and soft tissue tumors - Anderson, Nathaniel D.; De Borja, Richard; Young, Matthew D.; Fuligni, Fabio; Rosic, Andrej; Roberts, Nicola D.; Hajjar, Simon; Layeghifard, Mehdi; Novokmet, Ana; Kowalski, Paul E.; Anaka, Matthew; Davidson, Scott; et al. (Science, 2018)
Sarcomas are cancers of the bone and soft tissue often defined by gene fusions. Ewing sarcoma involves fusions between EWSR1, a gene encoding an RNA binding protein, and E26 transformation-specific (ETS) transcription factors. We explored how and when EWSR1-ETS fusions arise by studying the whole genomes of Ewing sarcomas. In 52 of 124 (42%) of tumors, the fusion gene arises by a sudden burst of complex, loop-like rearrangements, a process called chromoplexy, rather than by simple reciprocal translocations. These loops always contained the disease-defining fusion at the center, but they disrupted multiple additional genes. The loops occurred preferentially in early replicating and transcriptionally active genomic regions. Similar loops forming canonical fusions were found in three other sarcoma types. Chromoplexy-generated fusions appear to be associated with an aggressive form of Ewing sarcoma. These loops arise early, giving rise to both primary and relapse Ewing sarcoma tumors, which can continue to evolve in parallel.
EVALuna2:35824

Recessive Mutations in CFAP74 Cause Primary Ciliary Dyskinesia with Normal Ciliary Ultrastructure - Biebach, Luisa; Cindrić, Sandra; Koenig, Julia; Aprea, Isabella; Dougherty, Gerard W.; Raidt, Johanna; Bracht, Diana; Ruppel, Renate; Schreiber, Jens; Hjeij, Rim; Olbrich, Heike; Omran, Heymut (American journal of respiratory cell and molecular biology, 2022)
CRIS-Team Scopus Importer:2022-09-16

Recombinant Human Growth Hormone Activates Neuroprotective Growth Factors in Hypoxic Brain Injury in Neonatal Mice - Jung, Susan; Terörde, Klara; Dörr, Helmuth-Günther; Trollmann, Regina (Endocrinology, 2021)
Perinatal hypoxia severely disrupts cerebral metabolic and maturational programs beyond apoptotic cell death. Antiapoptotic treatments such as erythropoietin are suggested to improve outcomes in hypoxic brain injury; however, the results are controversial. We analyzed the neuroprotective effects of recombinant human growth hormone (rhGH) on regenerative mechanisms in the hypoxic developing mouse brain in comparison to controls. Using an established model of neonatal acute hypoxia (8% O2, 6 hours), P7 mice were treated intraperitoneally with rhGH (4000 µg/kg) 0, 12, and 24 hours after hypoxic exposure. After a regeneration period of 48 hours, expression of hypoxia-inducible neurotrophic factors (erythropoietin [EPO], vascular endothelial growth factor A [VEGF-A], insulin-like growth factors 1 and 2 [IGF-1/-2], IGF binding proteins) and proinflammatory markers was analyzed. In vitro experiments were performed using primary mouse cortical neurons (E14, DIV6). rhGH increased neuronal gene expression of EPO, IGF-1, and VEGF (P < .05) in vitro and diminished apoptosis of hypoxic neurons in a dose-dependent manner. In the developing brain, rhGH treatment led to a notable reduction of apoptosis in the subventricular zone and hippocampus (P < .05), abolished hypoxia-induced downregulation of IGF-1/IGF-2 expression (P < .05), and led to a significant accumulation of endogenous EPO protein and anti-inflammatory effects through modulation of interleukin-1β and tumor necrosis factor α signaling as well as upregulation of cerebral phosphorylated extracellularly regulated kinase 1/2 levels (ERK1/2). Indicating stabilizing effects on the blood-brain barrier (BBB), rhGH significantly modified cerebrovascular occludin expression. Thus, we conclude that rhGH mediates neuroprotective effects by the activation of endogenous neurotrophic growth factors and BBB stabilization. In addition, the modification of ERK1/2 pathways is involved in neuroprotective actions of rhGH. The present study adds further evidence that pharmacologic activation of neurotrophic growth factors may be a promising target for neonatal neuroprotection.
CRIS-Team Scopus Importer:2021-03-05
Keywords: apoptosis; BBB; IGF binding proteins; IGF-1; IGF-2; interleukin-1β; neuroprotection; occludin; pERK 1/2; TNF-α; VEGF

Recommendations of the AGG (Working Group for Obstetrics, Department of Maternal Diseases) on How to Treat Thyroid Function Disorders in Pregnancy. - Hamza, Amr; Schlembach, Dietmar; Schild, Ralf Lothar; Groten, Tanja; Wölfle, Joachim; Battefeld, Wilgard; Kehl, Sven; Schneider, Michael (Geburtshilfe und Frauenheilkunde, 2023)
Objective These recommendations from the AGG (Committee for Obstetrics, Department of Maternal Diseases) on how to treat thyroid function disorder during pregnancy aim to improve the diagnosis and management of thyroid anomalies during pregnancy. Methods Based on the current literature, the task force members have developed the following recommendations and statements. These recommendations were adopted after a consensus by the members of the working group. Recommendations The following manuscript gives an insight into physiological and pathophysiological thyroid changes during pregnancy, recommendations for clinical and subclinical hypo- and hyperthyroidism, as well as fetal and neonatal diagnostic and management strategies.
EVALuna2:548561

Recurrent Somatic PDGFRB Mutations in Sporadic Infantile/Solitary Adult Myofibromas But Not in Angioleiomyomas and Myopericytomas - Agaimy, Abbas; Bieg, Matthias; Michal, Michael; Geddert, Helene; Maerkl, Bruno; Seitz, Jan; Moskalev, Evgeny; Schlesner, Matthias; Metzler, Markus; Hartmann, Arndt; Wiemann, Stefan; Michal, Michal; et al. (American Journal of Surgical Pathology, 2017)
Infantile myofibroma (MF) is an uncommon benign myofibroblastic tumor of infancy and childhood. Solitary adult MF shares similar features with infantile MF. The lesions occur in 3 clinicopathologic settings: solitary, multicentric, and generalized and can be either sporadic or familial. Traditionally, infantile MF has been included in the spectrum of infantile hemangiopericytoma. The recent World Health Organization classification listed MF, angioleiomyoma, and myopericytoma under the general heading of perivascular tumors in the sense of a morphologic spectrum of perivascular myoid cell neoplasms. Although activating germline PDGFRB mutations have recently been linked to familial infantile MF, the molecular pathogenesis of sporadic infantile and adult solitary MF remained unclear. In this study, we analyzed 25 solitary MFs without evidence of familial disease (9 infantile and 16 adult MFs) to address the question whether somatic PDGFRB mutations might be responsible for the sporadic form of the disease. Given the presumed histogenetic link of MF to myopericytoma and angioleiomyoma, we additionally analyzed a control group of 6 myopericytomas and 9 angioleiomyomas for PDGFRB mutations. We detected PDGFRB mutations in 6/8 (75%) analyzable infantile and in 11/16 (69%) adult MFs but in none of the angioleiomyomas or myopericytomas. In 2 infantile MFs, additional sequencing of the germline confirmed the somatic nature of PDGFRB mutations. To our knowledge, this is the first study reporting apparently somatic recurrent PDGFRB mutations as molecular driver events in the majority of sporadic infantile and adult solitary MFs. Our results suggest molecular distinctness of MF as compared with angioleiomyoma/myopericytoma. Investigation of more cases including those with atypical and worrisome features, as well as other mimickers in the heterogenous morphologic spectrum of MF, is mandatory for validating the potential diagnostic value of PDGFRB mutation testing as a possible surrogate in difficult-to-classify lesions.
EVALuna2:6839

Red blood cell omega-3 fatty acids and the risk of ventricular arrhythmias in patients with heart failure - Wilhelm, Matthias; Tobias, Rueth; Asskali, Fatima; Kraehner, Robert; Kuly, Simone; Klinghammer, Lutz; Böhles, Hans Josef; Daniel, Werner (American Heart Journal, 2008)

Redirecting T cells to ewing's sarcoma family of tumors by a chimeric NKG2D receptor expressed by lentiviral transduction or mRNA transfection - Lehner, Manfred; Goetz, Gabriel; Proff, Julia; Schaft, Niels; Dörrie, Jan; Full, Florian; Enßer, Armin; Muller, Yves; Cerwenka, Adelheid; Abken, Hinrich; Parolini, Ornella; Ambros, Peter F.; et al. (PLoS ONE, 2012)
We explored the possibility to target Ewing's sarcoma family of tumors (ESFT) by redirecting T cells. To this aim, we considered NKG2D-ligands (NKG2D-Ls) as possible target antigens. Detailed analysis of the expression of MICA, MICB, ULBP-1, -2, and -3 in fourteen ESFT cell lines revealed consistent expression of at least one NKG2D-L. Thus, for redirecting T cells, we fused a CD3ζ/CD28-derived signaling domain to the ectodomain of NKG2D, however, opposite transmembrane orientation of this signaling domain and NKG2D required inverse orientation fusion of either of them. We hypothesized that the particularly located C-terminus of the NKG2D ectodomain should allow reengineering of the membrane anchoring from a native N-terminal to an artificial C-terminal linkage. Indeed, the resulting chimeric NKG2D receptor (chNKG2D) was functional and efficiently mediated ESFT cell death triggered by activated T cells. Notably, ESFT cells with even low NKG2D-L expression were killed by CD8 pos and also CD4 pos cells. Both, mRNA transfection and lentiviral transduction resulted in high level surface expression of chNKG2D. However, upon target-cell recognition receptor surface levels were maintained by tranfected RNA only during the first couple of hours after transfection. Later, target-cell contact resulted in strong and irreversible receptor down-modulation, whereas lentivirally mediated expression of chNKG2D remained constant under these conditions. Together, our study defines NKG2D-Ls as targets for a CAR-mediated T cell based immunotherapy of ESFT. A comparison of two different methods of gene transfer reveals strong differences in the susceptibility to ligand-induced receptor down-modulation with possible implications for the applicability of RNA transfection. © 2012 Lehner et al.
CRIS-Team Scopus Importer:2021-10-01

Reduced Perinatal Leptin Availability May Contribute to Adverse Metabolic Programming in a Rat Model of Uteroplacental Insufficiency - Nuesken, Eva; Wohlfarth, Maria; Lippach, Gregor; Rauh, Manfred; Schneider, Holm; Doetsch, Joerg; Nuesken, Kai-Dietrich (Endocrinology, 2016)
Leptin availability in perinatal life critically affects metabolic programming. We tested the hypothesis that uteroplacental insufficiency and intrauterine stress affect perinatal leptin availability in rat offspring. Pregnant rats underwent bilateral uterine vessel ligation (LIG; n = 14), sham operation (SOP; n = 12), or no operation (controls, n = 14). Fetal livers (n = 180), placentas (n = 180), and maternal blood were obtained 4 hours (gestational day [E] 19), 24 hours (E20), and 72 hours (E22) after surgery. In the offspring, we took blood samples on E22 (n = 44), postnatal day (P) 1 (n = 29), P2 (n = 16), P7 (n = 30), and P12 (n = 30). Circulating leptin (ELISA) was significantly reduced in LIG (E22, P1, P2) and SOP offspring (E22). Postnatal leptin surge was delayed in LIG but was accelerated in SOP offspring. Placental leptin gene expression (quantitative RT-PCR) was reduced in LIG (E19, E20, E22) and SOP (E20, E22). Hepatic leptin receptor (Lepr-a, mediating leptin degradation) gene expression was increased in LIG fetuses (E20, E22) only. Surprisingly, hypoxia-inducible factors (Hif; Western blot) were unaltered in placentas and were reduced in the livers of LIG (Hif1a, E20; Hif2a, E19, E22) and SOP (Hif2a, E19) fetuses. Gene expression of prolyl hydroxylase 3, a factor expressed under hypoxic conditions contributing to Hif degradation, was increased in livers of LIG (E19, E20, E22) and SOP (E19) fetuses and in placentas of LIG and SOP (E19). In summary, reduced placental leptin production, increased fetal leptin degradation, and persistent perinatal hypoleptinemia are present in intrauterine growth restriction offspring, especially after uteroplacental insufficiency, and may contribute to perinatal programming of leptin resistance and adiposity in later life.
EVALuna2:33880

Reduction of Tissue Na+ Accumulation After Renal Transplantation - Dahlmann, Anke; Linz, Peter; Zucker, Isabelle; Haag, Viktor; Jantsch, Jonathan; Dienemann, Thomas; Nagel, Armin Michael; Neubert, Patrick; Rosenhauer, Daniela; Rauh, Manfred; Horn, Stephan; Müller, Dominik N.; et al. (Kidney International Reports, 2021)
Introduction: Chronic kidney disease (CKD) engenders salt-sensitive hypertension. Whether or not tissue Nathorn accumulation is increased in CKD patients remains uncertain. How tissue Nathorn is affected after renal transplantation has not been assessed.
CRIS-Team WoS Importer:2021-10-01

Reference Interval Estimation from Mixed Distributions using Truncation Points and the Kolmogorov-Smirnov Distance (kosmic) - Zierk, Jakob; Arzideh, Farhad; Kapsner, Lorenz; Prokosch, Hans-Ulrich; Metzler, Markus; Rauh, Manfred (Scientific Reports, 2020)
Appropriate reference intervals are essential when using laboratory test results to guide medical decisions. Conventional approaches for the establishment of reference intervals rely on large samples from healthy and homogenous reference populations. However, this approach is associated with substantial financial and logistic challenges, subject to ethical restrictions in children, and limited in older individuals due to the high prevalence of chronic morbidities and medication. We implemented an indirect method for reference interval estimation, which uses mixed physiological and abnormal test results from clinical information systems, to overcome these restrictions. The algorithm minimizes the difference between an estimated parametrical distribution and a truncated part of the observed distribution, specifically, the Kolmogorov-Smirnov-distance between a hypothetical Gaussian distribution and the observed distribution of test results after Box-Cox-transformation. Simulations of common laboratory tests with increasing proportions of abnormal test results show reliable reference interval estimations even in challenging simulation scenarios, when <20% test results are abnormal. Additionally, reference intervals generated using samples from a university hospital’s laboratory information system, with a gradually increasing proportion of abnormal test results remained stable, even if samples from units with a substantial prevalence of pathologies were included. A high-performance open-source C++ implementation is available at https://gitlab.miracum.org/kosmic.
CRIS-Team Scopus Importer:2020-02-14

Reference Intervals of Serum TSH from Mixed Distributions Using Truncation Points and the Kolmogorov-Smirnov Distance - Ahmed, Sibtain; Zierk, Jakob; Khan, Aysha H.; Jafri, Lena; Majid, Hafsa; Ghani, Farooq; Siddiqui, Imran (Clinical Laboratory, 2022)
Background: Serum TSH reference intervals (RIs) are methodology, population, and age specific. However, the ethical and practical challenges restrict the establishment of pediatric RIs using conventional approaches and advocates the use of indirect data mining-based algorithms. This study was carried out to estimate the reference interval of neonatal serum TSH in Pakistani population using an indirect approach. Methods: A data mining of serum TSH results of neonates (<= 1 month of age) from 2013 -2018 was done. Two sub-groups on the basis of age from birth to 5 days and 6 -30 days were assessed. The German study group's pre -vali-dated indirect algorithm 'KOSMIC' was utilized for the statistical analysis. Results: A total of non-duplicate 82,299 neonatal serum TSH tests were retrieved over a period of 6 years, includ-ing 88% (n = 70,788) aged 0 -5 days and 12% (n = 11,511) ranging from 6 days to 1 month. The estimated RIs for the first age partition was 0.7 (90% CI 0.6 -0.8) to 15.5 (90% CI 12.9 -16.2) and for the second group 0.7 (90% CI 0.5 -0.9) to 7.8 (90% CI 6.1 -9.9) mu IU/mL. Conclusions: This study revealed age related trends in serum TSH. The study advocates the need for population specific RIs owing to the significant variations noted on comparison with previously published literature. Precise RIs become vital particularly when serum TSH is undertaken as a confirmatory test for presumptive positive re-sults on newborn screening for congenital hypothyroidism. (Clin. Lab. 2022
CRIS-Team WoS Importer:2022-08-12

refineR: A Novel Algorithm for Reference Interval Estimation from Real-World Data - Ammer, Tatjana; Schuetzenmeister, Andre; Prokosch, Hans-Ulrich; Rauh, Manfred; Rank, Christopher M.; Zierk, Jakob (Scientific Reports, 2021)
Reference intervals are essential for the interpretation of laboratory test results in medicine. We propose a novel indirect approach to estimate reference intervals from real-world data as an alternative to direct methods, which require samples from healthy individuals. The presented refineR algorithm separates the non-pathological distribution from the pathological distribution of observed test results using an inverse approach and identifies the model that best explains the non-pathological distribution. To evaluate its performance, we simulated test results from six common laboratory analytes with a varying location and fraction of pathological test results. Estimated reference intervals were compared to the ground truth, an alternative indirect method (kosmic), and the direct method (N = 120 and N = 400 samples). Overall, refineR achieved the lowest mean percentage error of all methods (2.77%). Analyzing the amount of reference intervals within ± 1 total error deviation from the ground truth, refineR (82.5%) was inferior to the direct method with N = 400 samples (90.1%), but outperformed kosmic (70.8%) and the direct method with N = 120 (67.4%). Additionally, reference intervals estimated from pediatric data were comparable to published direct method studies. In conclusion, the refineR algorithm enables precise estimation of reference intervals from real-world data and represents a viable complement to the direct method.
CRIS-Team Scopus Importer:2021-08-27

Regulated on Activation, Normal T cell Expressed and Secreted (RANTES) drives the resolution of allergic asthma - Li, Nina; Mirzakhani, Hoomann; Kiefer, Alexander; Kölle, Julia; Vuorinen, Tytti; Rauh, Manfred; Yang, Zuqin; Krammer, Susanne; Xepapadaki, Paraskevi; Lewandowska-Polak, Anna; Lukkarinen, Heikki; Zhang, Nan; et al. (iScience, 2021)
RANTES is implicated in allergic asthma and in T cell-dependent clearance of infection. RANTES receptor family comprises CCR1, CCR3, and CCR5, which are G-protein-coupled receptors consisting of seven transmembrane helices. Infections with respiratory viruses like Rhinovirus cause induction of RANTES production by epithelial cells. Here, we studied the role of RANTES in the peripheral blood mononuclear cells in cohorts of children with and without asthma and validated and extended this study to the airways of adults with and without asthma. We further translated these studies to a murine model of asthma induced by house dust mite allergen in wild-type RANTES and CCR5-deficient mice. Here we show an unpredicted therapeutic role of RANTES in the resolution of allergen-induced asthma by orchestrating the transition of effector GATA-3+CD4+ T cells into immune-regulatory-type T cells and inflammatory eosinophils into resident eosinophils as well as increased IL-10 production in the lung.
CRIS-Team WoS Importer:2021-11-19

RELATION BETWEEN NOISE ANNOYANCE, STRESS HORMONES AND THE RENAL HEMODYNAMIC - Bosch, Agnes; Kannenkeril, Dennis; Rauh, Manfred; Ott, Christian; Striepe, Kristina; Jung, Susanne; Kolwelter, Julie; Schmieder, Roland (JOURNAL OF HYPERTENSION, 2021)
CRIS-Team WoS Importer:2021-07-30

Relationship between age at initiation of cysteamine treatment, adherence with therapy, and glomerular kidney function in infantile nephropathic cystinosis - Nießl, Christina; Boulesteix, Anne Laure; Oh, Jun; Palm, Katja; Schlingmann, Peter; Wygoda, Simone; Haffner, Dieter; Wühl, Elke; Tönshoff, Burkhard; Buescher, Anja; Billing, Heiko; Hoppe, Bernd; et al. (Molecular Genetics and Metabolism, 2022)
Infantile nephropathic cystinosis, due to impaired transport of cystine out of lysosomes, occurs with an incidence of 1 in 100–200,000 live births. It is characterized by renal Fanconi syndrome in the first year of life and glomerular dysfunction progression to end-stage kidney disease by approximately 10 years of age. Treatment with oral cysteamine therapy helps preserve glomerular function, but affected individuals eventually require kidney replacement therapy. This is because glomerular damage had already occurred by the time a child is diagnosed with cystinosis, typically in the second year of life. We performed a retrospective multicenter study to investigate the impact of initiating cysteamine treatment within the first 2 months of life in some infants and comparing two different levels of adherence in patients diagnosed at the typical age. We collected 3983 data points from 55 patients born between 1997 and 2020; 52 patients with 1592 data points could be further evaluated. These data were first analyzed by dividing the patient cohort into three groups: (i) standard treatment start with good adherence, (ii) standard treatment start with less good adherence, and (iii) early treatment start. At every age, mean estimated glomerular filtration rate (eGFR) was higher in early-treated patients than in later-treated patients. Second, a generalized additive mixed model (GAMM) was applied showing that patients with initiation of treatment before 2 months of age are expected to have a 34 ml/min/1.73 m2 higher eGFR than patients with later treatment start while controlling for adherence and patients' age. These data strongly suggest that oral cysteamine treatment initiated within 2 months of birth preserves kidney function in infantile nephropathic cystinosis and provide evidence of the utility of newborn screening for this disease.
CRIS-Team Scopus Importer:2022-07-22
Keywords: Cysteamine; Cystinosis; Glomerular function

Relevance of glomerular c4d deposition in pediatric patients with henoch-schönlein purpura compared to IgA nephritis - Benz, Kerstin; Ferrazzi, Fulvia; Galiano, Matthias; Sauerstein, Katja; Vonbrunn, Eva; Daniel, Christoph; Büttner-Herold, Maike; Amann, Kerstin Ute (Journal of Nephropathology, 2021)
Introduction: IgA nephropathy (IgAN) is the most common primary glomerulonephritis (GN) in western countries and Henoch-Schönlein purpura nephritis (HSPN) is the most common form of vasculitis in childhood. Renal biopsy findings in both nephropathies are often similar and are characterized by mesangioproliferative GN with mesangial or mesangiocapillary IgA and C3c deposits. Objectives: The aim of this study was to investigate the significance of glomerular C4d-deposition as a discriminating factor between pediatric HSPN and IgAN. Patients and Methods: We retrospectively analyzed patient records and renal biopsies from 53 pediatric patients from one single center with a median age of 10.5 years (range 2.3-18 years). Twenty-two patients suffered from IgAN and 31 from HSPN. Work-up of all renal biopsies was performed using standard protocols including immunohistochemistry for C4d. Results: Pediatric IgAN patients presented significantly more often with gross hematuria, higher serum creatinine, lower glomerular filtration rate, lower serum C3 and proteinuria and on histology less endocapillary hypercellularity compared to HSPN patients. However, the rate of glomerular C4d-positivity was not different between IgAN (36%) and HSPN (42%). Comparing all cases with positive versus negative glomerular C4d-staining, pediatric patients with glomerular C4d-positivity showed significantly lesser gross hematuria and received significantly more often cyclophosphamide. This was in line with a tendency towards more proteinuria, hypertension and renal insufficiency at last follow-up in C4d-positive compared to C4d-negative patients. Conclusion: In conclusion, in our monocentric study glomerular C4d does not differ between pediatric HSPN and IgAN, but was associated with a tendency to a more severe course of the disease that needs to be confirmed in larger multicentric studies.
CRIS-Team Scopus Importer:2021-01-22
Keywords: C4d staining; Glomerulonephritis; Henoch-Schönlein purpura; IgA nephritis; IgA vasculitis; Pediatric nephrology

Reliability of prenatal detection of X-linked hypohidrotic ectodermal dysplasia by tooth germ sonography - Hammersen, Johanna; Wohlfart, Sigrun; Goecke, Tamme W.; Köninger, Angela; Stepan, Holger; Gallinat, Ralph; Morris, Susan; Bücher, Katharina; Clarke, Angus; Wünsche, Stephanie; Beckmann, Matthias; Schneider, Holm; et al. (Prenatal Diagnosis, 2019)
Objective: In X-linked hypohidrotic ectodermal dysplasia (XLHED), dysfunction of ectodysplasin A1 (EDA1) due to EDA mutations results in malformation of hair, teeth, and sweat glands. Hypohidrosis, which can cause life-threatening hyperthermia, is amenable to intrauterine therapy with recombinant EDA1. This study aimed at evaluating tooth germ sonography as a noninvasive means to identify affected fetuses in pregnant carrier women. Methods: Sonography, performed at 10 study sites between gestational weeks 18 and 28, led to the diagnosis of XLHED if fewer than six tooth germs were detected in mandible or maxilla. The assessment was verified postnatally by EDA sequencing and/or clinical findings. Estimated fetal weights and postnatal weight gain of boys with XLHED were assessed using appropriate growth charts. Results: In 19 of 38 sonographic examinations (23 male and 13 female fetuses), XLHED was detected prenatally. The prenatal diagnosis proved to be correct in 37 cases; one affected male fetus was missed. Specificity and positive predictive value were both 100%. Tooth counts obtained by clinical examination corresponded well with findings on panoramic radiographs. We observed no weight deficits of subjects with XLHED in utero but occasionally during infancy. Conclusion: Tooth germ sonography is highly specific and reliable in detecting XLHED prenatally.
CRIS-Team Scopus Importer:2019-08-27

Renal adaptation in pre-obesity patients with hypertension - Bosch, Agnes; Rauh, Manfred; Striepe, Kristina; Schiffer, Mario; Schmieder, Roland; Kannenkeril, Dennis (Journal of Hypertension, 2024)
Background and hypothesis: Obesity aggravates the risk to develop chronic kidney disease in hypertensive patients. Whether pre-obesity already impairs renal function, renal perfusion and intraglomerular hemodynamics in hypertensive patients is unknown. Methods: Renal hemodynamic profiles were measured using steady state input clearance (infusion of para-amino-hippuric acid and inulin) in 36 patients with primary arterial hypertension stage 1-2 without antihypertensive medication. Intraglomerular pressure (IGP) and resistances of the afferent (RA) and efferent (RE) arterioles were calculated. The study population was divided into two groups based on median of waist circumference (WC) (96 cm) (pre-obesity and non-obesity group1) and median of body mass index (BMI) (26.5 kg/m2) (pre-obesity and non-obesity group2), respectively. Results: All patients were males, non-smoking, aged 36 ± 10 years, with an office blood pressure of 145 ± 8.6/89 ± 11.8 mmHg. None of the patients had cardiovascular disease. Patients from the pre-obese group 1 showed lower glomerular filtration rate (GFR), lower renal plasma flow (RPF) and lower IGP compared to the non-obese group1. Renal vascular resistance (RVR) and RA were higher in the pre-obese group1 compared to the non-obese group1. Similar differences in the hemodynamic profile were found for patients in the pre-obesity group2 compared to the non-obesity group2. Conclusion: The renal hemodynamic profile in hypertensive patients with pre-obesity, irrespective whether defined by WC or BMI, was characterized by a reduced GFR and RPF and by an increased RVR preferentially at the preglomerular site. Our results suggest that hypofiltration is the first phase of renal adaptation in pre-obesity hypertension.
CRIS-Team Scopus Importer:2024-09-20
Keywords: body mass index; clearance analysis; pre-obesity; renal hemodynamic; waist circumference

Renal Chemerin Expression is Induced in Models of Hypertensive Nephropathy and Glomerulonephritis and Correlates with Markers of Inflammation and Fibrosis - Mocker, Alexander; Hilgers, Karl Friedrich; Cordasic, Nada; Wachtveitl, Rainer; Menendez-Castro, Carlos; Wölfle, Joachim; Hartner, Andrea; Fahlbusch, Fabian (International Journal of Molecular Sciences, 2019)
Chemerin and its receptor, chemokine-like receptor 1 (CmklR1), are associated with chemotaxis, inflammation, and endothelial function, especially in metabolic syndrome, coronary heart disease, and hypertension. In humans, circulating chemerin levels and renal function show an inverse relation. So far, little is known about the potential role of chemerin in hypertensive nephropathy and renal inflammation. Therefore, we determined systemic and renal chemerin levels in 2-kidney-1-clip (2k1c) hypertensive and Thy1.1 nephritic rats, respectively, to explore the correlation between chemerin and markers of renal inflammation and fibrosis. Immunohistochemistry revealed a model-specific induction of chemerin expression at the corresponding site of renal damage (tubular vs. glomerular). In both models, renal expression of chemerin (RT-PCR, Western blot) was increased and correlated positively with markers of inflammation and fibrosis. In contrast, circulating chemerin levels remained unchanged. Taken together, these findings demonstrate that renal chemerin expression is associated with processes of inflammation and fibrosis-related to renal damage. However, its use as circulating biomarker of renal inflammation seems to be limited in our rat models.
CRIS-Team Scopus Importer:2019-12-24
Keywords: 2-kidney-1-clip; 2k1c; chemerin; CmklR1; renal fibrosis; renal inflammation; renal injury; renovascular hypertension; Thy1.1 nephritis

Renal transplantation: Opportunities and risks for medical refugees - Mammadova, Dilbar; Hirsch, K.; Schwaiger, Brigitte; Wullich, Bernd; Rascher, Wolfgang (Urologe, 2018)
BACKGROUND: Families with children and adolescents with end-stage renal disease came to Germany from the former Eastern Bloc countries before the wave of refugees in 2015, in order to enable their children to survive with adequate kidney replacement therapy and in the best case a kidney transplant. METHODS: In a case study, medical records of 4 childen and adolescents were retrospectively analyzed. These patients who fled to Germany for the treatment of terminal renal failure applied for asylum and were successfully transplanted after the usual waiting period. RESULTS: Four of the eight children and adolescents who came to Erlangen for treatment of terminal renal failure between 2003 and 2013 received a functioning kidney transplant (deceased donor kidney) after dialysis therapy was difficult due to lack of compliance to drug and dietary recommendations such as fluid restriction. Since children and adolescents are treated with chronic dialysis only with the aim of kidney transplantation, a living donation was discussed but was not possible for medical reasons. 3 recipients are symptom-free with a functional graft. DISCUSSION: The case study demonstrates that children and adolescents fleeing to Germany due to their end stage renal disease are better integrated after kidney transplantation, have better chances of obtaining a good education and can be expected to live independently with their own income in the future.
EVALuna2:35726

Renin Uptake by the Endothelium Mediates Vascular Angiotensin Formation - Hilgers, Karl Friedrich; Veelken, Roland; Müller, Dominik N.; Kohler, Hans; Hartner, Andrea; Botki, Suzanne R.; Stumpf, Christian; Schmieder, Roland; Gomez, Ariel (Hypertension, 2001)
We investigated the role of the vascular endothelium in the local production of angiotensin. Angiotensin release from isolated rat hindquarters perfused with an artificial medium was measured by high-performance liquid chromatography and radioimmunoassay. Perfused hindquarters with endothelium released angiotensin I spontaneously, indicating ongoing renin-angiotensinogen reaction. Endothelium denudation (by a detergent, validated by electron microscopy and by the absence of a vasodilator response to acetylcholine) reduced angiotensin I release by >90%, whereas bilateral nephrectomy 24 hours before perfusion abolished the release completely. Infusion of renin into perfused hindquarters induced sustained local angiotensin I release in the presence of an intact endothelium but not after endothelium denudation. The conversion of angiotensin I to angiotensin II was abrogated by endothelium denudation, whereas the disappearance of angiotensin II was unchanged. Endothelium denudation diminished the pressor response to angiotensin II but abolished the response to renin and angiotensin I. Expression of renin messenger RNA, investigated by reverse-transcription polymerase chain reaction using 4 different primer combinations, was not detected in up to 5 μg vascular RNA, whereas a renin signal was readily detected with 5 ng kidney RNA. The effects of endothelium destruction on Ang I formation support the notion that the endothelium mediates vascular angiotensin formation by taking up reni
Keywords: renin; angiotensin; angiotensinogen; mRNA; vessels; perfusion; endothelium

Repair of common arterial trunk: palliation and delayed correction as a viable alternative strategy in selected patients - Cuomo, Michela; Purbojo, Ariawan; Blumauer, Robert; Schober, Martin; Wällisch, Wolfgang; Dittrich, Sven; Cesnjevar, Robert (European Journal of Cardio-Thoracic Surgery, 2021)
OBJECTIVES Primary repair of common arterial trunk (CAT) is burdened by high mortality rates, especially in the presence of multiple risk factors. Timing, possible palliative methods, optimal management of associated cardiac lesions and handling of a poor preoperative state are still under discussion. METHODS We retrospectively analysed all patients who underwent surgery for CAT in our institution between 2008 and November 2020. We included 22 patients, 11 of whom received primary correction (PC) and 11 of whom underwent initial palliation by partial repair, leaving the ventricular septal defect open and connecting the right ventricle to the pulmonary arteries with a small valveless right ventricle-to-pulmonary artery conduit. A delayed correction (DC) was performed after 11.5 ± 3.6 months. RESULTS The overall operative mortality was 4.5%; 1 patient (affected by severe truncal valve stenosis and presenting in a poor state preoperatively) in the DC group died after palliation. The incidence of postoperative pulmonary hypertensive crisis was significantly higher in the PC group (P = 0.027). No patient from either group required postoperative extracorporeal support. Survival rates after 6 years differed slightly (PC group, 90%; DC group, 70%; log-rank = 0.270). CONCLUSIONS PC of CAT remains an optimal surgical approach for patients with an expected low mortality. However, our data support palliation and DC as a suitable alternative strategy, especially in the presence of significant risk factors like interrupted aortic arch, poor preoperative condition or complex surgical anatomy.
CRIS-Team WoS Importer:2022-05-13
Keywords: Common arterial trunk; Palliation; Sano-Shunt; Outcomes; Patient-tailored therapy; Congenital cardiac surgery

Repeated CXCR4 Blockade by Plerixafor Attenuates Transplant Vasculopathy in Murine Aortic Allografts - Theil, Frank; Kuckhahn, Annika; Hörning, André; Völkl, Simon; Knab, Katharina; Fritz, Niklas; Gräbner, Cindy; Ramsperger-Gleixner, Martina; Weyand, Michael; Heim, Christian (Journal of Immunology, 2024)
Plerixafor, a hematopoietic stem cell mobilization agent, increases the peripheral blood content of effector and regulatory T cells and may have beneficial effects on cardiac allograft vasculopathy. The aim of the current study was to evaluate its effects in a murine aortic allograft model using different application procedures. Allogeneic donor aorta grafts (n 5 8/group) from C57BL/6 mice(H2b) were abdominally transplanted into CBA mice (H2k). Plerixafor application was performed either continuously for 14 d using abdominally implanted osmotic pumps (1 mg/kg/d) or i.p. with a single dose (1 and 5 mg/kg) on day 0 or pulsed injections of 1 mg/kg on days 0, 7, 14, and 21. Cell distribution was monitored by FACS. Aortic grafts were evaluated for neointima development by Elastica-van-Gieson on day 30. Immunofluorescence and intragraft gene expression analysis were performed. On day 14, significantly fewer hematopoietic stem cells were found in the bone marrow of all plerixafor-treated mice. In the pulsed application group, significantly more hematopoietic stem cells were found in the peripheral blood on day 14 (0.045 ± 0.002%; p < 0.01 [pulsed]; versus 0.0068 ± 0.002% [control]) and also more regulatory T cells. PCR revealed lower inflammatory cytokines. The luminal occlusion was significantly reduced in the pulsed treated group (33.65 ± 8.84 versus 53.13 ± 12.41) going along with decreased neointimal CD4+ T cell and plasmacytoid dendritic cell infiltration, as well as less smooth muscle cell proliferation. The application of plerixafor attenuates chronic rejection in aortic allografts via immunomodulatory effects. Injection of repeated low-dose plerixafor is the most effective application form in the aortic transplant model.
CRIS-Team Scopus Importer:2024-11-22

Repeated Use of Prescription Drugs in Pediatrics: Comprehensive Overview Based on German Claims Data - Scholle, Oliver; Neubert, Antje; Riedel, Oliver; Toni, Irmgard; Haug, Ulrike (Frontiers in Pharmacology, 2021)
Background: Investigating drug utilization in large and unselected samples of children and adolescents is an important component of public health monitoring. Most existing studies in this field focused on any drug use (i.e., >= 1 prescription of a certain drug) although chronic drug use may be more relevant. This study aimed to provide a comprehensive overview of prevalence and types of prescription drugs used repeatedly in children and adolescents in Germany in 2016. Methods: We used the German Pharmacoepidemiological Research Database (GePaRD)-a claims database covering similar to 20% of the German population. We included children and adolescents aged 0-17 years and assessed repeated use of prescription drugs (>= 3 prescriptions in 2016) on two levels: therapeutic subgroups (ATC 2nd level) and chemical substances (ATC 5th level). Analyses were stratified by sex and age groups (<2, 2-5, 6-12, and 13-17 years). Results: Overall, 2.5 million children and adolescents were included. In the age groups below 13 years, the prevalence rates of repeated use of prescription drugs (ATC 2nd level) were higher in boys than in girls (113-152 vs. 83-130 per 1,000 person-years), whereas in the age group 13-17 years, they were twice as high in girls than in boys (236 vs. 118 per 1,000 person-years). In boys and girls aged below six years, systemic antibiotics, topical ocular antibiotics, and drugs for constipation were among the most common drugs used repeatedly. For higher ages, methylphenidate, levothyroxine, and combined hormonal contraceptives, were among the most common drugs used repeatedly. Conclusions: Overall, about one in ten children in Germany repeatedly used prescription drugs. This proportion as well as the type of drugs used repeatedly markedly varied by sex and age. For certain drugs, our findings raise concerns regarding appropriateness of prescribing that should be addressed in future studies.
CRIS-Team WoS Importer:2021-08-13

Report from the HarmoSter study: Different LC-MS/MS androstenedione, DHEAS and testosterone methods compare well; however, unifying calibration is a double-edged sword - Fanelli, Flaminia; Peitzsch, Mirko; Bruce, Stephen; Cantù, Marco; Temchenko, Anastasia; Mezzullo, Marco; Lindner, Johanna M.; Hawley, James M.; Ackermans, Mariette T.; Van Den Ouweland, Jody; Köppl, Daniel; Nardi, Elena; et al. (Clinical Chemistry and Laboratory Medicine, 2024)
Current LC-MS/MS applications for circulating androgen measurements are technically diverse. Previously, variable results have been reported for testosterone. Data are scarce for androstenedione and absent for DHEAS. We assessed the agreement of androstenedione, DHEAS and testosterone LC-MS/MS measurements among nine European centers and explored benefits of calibration system unification. Androgens were measured twice by laboratory-specific procedures in 78 patient samples and in EQA materials. Results were obtained by in-house and external calibration. Intra- and inter-laboratory performances were valued. Intra-laboratory CVs ranged between 4.2-13.2 » % for androstenedione, 1.6-10.8 » % for DHEAS, and 4.3-8.7 » % and 2.6-7.1 » % for female and male testosterone, respectively. Bias and trueness in EQA materials were within ±20 » %. Median inter-laboratory CV with in-house vs. external calibration were 12.0 vs. 9.6 » % for androstenedione (p<0.001), 7.2 vs. 4.9 » % for DHEAS (p<0.001), 6.4 vs. 7.6 » % for female testosterone (p<0.001) and 6.8 and 7.4 » % for male testosterone (p=0.111). Median bias vs. all laboratory median with in-house and external calibration were -13.3 to 20.5 » % and -4.9 to 18.7 » % for androstenedione, -10.9 to 4.8 » % and -3.4 to 3.5 » % for DHEAS, -2.7 to 6.5 % and -11.3 to 6.6 » % for testosterone in females, and -7.0 to 8.5 » % and -7.5 to 11.8 » % for testosterone in males, respectively. Methods showed high intra-laboratory precision but variable bias and trueness. Inter-laboratory agreement was remarkably good. Calibration system unification improved agreement in androstenedione and DHEAS, but not in testosterone measurements. Multiple components, such as commutability of calibrators and EQA materials and internal standard choices, likely contribute to inter-laboratory variability.
CRIS-Team Scopus Importer:2024-01-26
Keywords: androstenedione; dehydroepiandrosterone-sulfate; harmonization; inter-laboratory performance; liquid chromatography-tandem mass spectrometry; testosterone

Report from the HarmoSter study: impact of calibration on comparability of LC-MS/MS measurement of circulating cortisol, 17OH-progesterone and aldosterone - Fanelli, Flaminia; Cantu, Marco; Temchenko, Anastasia; Mezzullo, Marco; Lindner, Johanna M.; Peitzsch, Mirko; Hawley, James M.; Bruce, Stephen; Binz, Pierre-Alain; Ackermans, Mariette T.; Heijboer, Annemieke C.; Van Den Ouweland, Jody; et al. (Clinical Chemistry and Laboratory Medicine, 2022)
Objectives Liquid chromatography-tandem mass spectrometry (LC-MS/MS) is recommended for measuring circulating steroids. However, assays display technical heterogeneity. So far, reproducibility of corticosteroid LC-MS/MS measurements has received scant attention. The aim of the study was to compare LC-MS/MS measurements of cortisol, 17OH-progesterone and aldosterone from nine European centers and assess performance according to external quality assessment (EQA) materials and calibration. Methods Seventy-eight patient samples, EQA materials and two commercial calibration sets were measured twice by laboratory-specific procedures. Results were obtained by in-house (CAL1) and external calibrations (CAL2 and CAL3). We evaluated intra and inter-laboratory imprecision, correlation and agreement in patient samples, and trueness, bias and commutability in EQA materials. Results Using CAL1, intra-laboratory CVs ranged between 2.8-7.4%, 4.4-18.0% and 5.2-22.2%, for cortisol, 17OH-progesterone and aldosterone, respectively. Trueness and bias in EQA materials were mostly acceptable, however, inappropriate commutability and target value assignment were highlighted in some cases. CAL2 showed suboptimal accuracy. Median inter-laboratory CVs for cortisol, 17OH-progesterone and aldosterone were 4.9, 11.8 and 13.8% with CAL1 and 3.6, 10.3 and 8.6% with CAL3 (all p<0.001), respectively. Using CAL1, median bias vs. all laboratory-medians ranged from -6.6 to 6.9%, -17.2 to 7.8% and -12.0 to 16.8% for cortisol, 17OH-progesterone and aldosterone, respectively. Regression lines significantly deviated from the best fit for most laboratories. Using CAL3 improved cortisol and 17OH-progesterone between-method bias and correlation. Conclusions Intra-laboratory imprecision and performance with EQA materials were variable. Inter-laboratory performance was mostly within specifications. Although residual variability persists, adopting common traceable calibrators and RMP-determined EQA materials is beneficial for standardization of LC-MS/MS steroid measurements.
CRIS-Team WoS Importer:2022-03-04

Report from the HarmoSter study: inter-laboratory comparison of LC-MS/MS measurements of corticosterone, 11-deoxycortisol and cortisone - Fanelli, Flaminia; Bruce, Stephen; Cantu, Marco; Temchenko, Anastasia; Mezzullo, Marco; Lindner, Johanna M.; Peitzsch, Mirko; Binz, Pierre-Alain; Ackermans, Mariette T.; Heijboer, Annemieke C.; Van Den Ouweland, Jody; Koeppl, Daniel; et al. (Clinical Chemistry and Laboratory Medicine, 2022)
Objectives Liquid chromatography-tandem mass spectrometry (LC-MS/MS) panels that include glucocorticoid-related steroids are increasingly used to characterize and diagnose adrenal cortical diseases. Limited information is currently available about reproducibility of these measurements among laboratories. The aim of the study was to compare LC-MS/MS measurements of corticosterone, 11-deoxycortisol and cortisone at eight European centers and assess the performance after unification of calibration. Methods Seventy-eight patient samples and commercial calibrators were measured twice by laboratory-specific procedures. Results were obtained according to in-house and external calibration. We evaluated intra-laboratory and inter-laboratory imprecision, regression and agreement against performance specifications derived from 11-deoxycortisol biological variation. Results Intra-laboratory CVs ranged between 3.3 and 7.7%, 3.3 and 11.8% and 2.7 and 12.8% for corticosterone, 11-deoxycortisol and cortisone, with 1, 4 and 3 laboratories often exceeding the maximum allowable imprecision (MAI), respectively. Median inter-laboratory CVs were 10.0, 10.7 and 6.2%, with 38.5, 50.7 and 2.6% cases exceeding the MAI for corticosterone, 11-deoxycortisol and cortisone, respectively. Median laboratory bias vs. all laboratory-medians ranged from -5.6 to 12.3% for corticosterone, -14.6 to 12.4% for 11-deoxycortisol and -4.0 to 6.5% for cortisone, with few cases exceeding the total allowable error. Modest deviations were found in regression equations among most laboratories. External calibration did not improve 11-deoxycortisol and worsened corticosterone and cortisone inter-laboratory comparability. Conclusions Method imprecision was variable. Inter-laboratory performance was reasonably good. However, cases with imprecision and total error above the acceptable limits were apparent for corticosterone and 11-deoxycortisol. Variability did not depend on calibration but apparently on imprecision, accuracy and specificity of individual methods. Tools for improving selectivity and accuracy are required to improve harmonization.
CRIS-Team WoS Importer:2022-11-11

Reproductive decision-making by women with X-linked hypohidrotic ectodermal dysplasia - Leo, B.; Schneider, Holm; Hammersen, J. (Journal of the European Academy of Dermatology and Venereology, 2022)
Background: In X-linked hypohidrotic ectodermal dysplasia (XLHED), ectodysplasin A1 (EDA1) deficiency results in malformation of hair, teeth and sweat glands. Lack of sweating which can cause life-threatening hyperthermia is amenable to intrauterine therapy with recombinant EDA1. Objectives: This study aimed at evaluating reproductive decision-making by women with XLHED and at clarifying the potential impact of a prenatal treatment option. Methods: In a retrospective cross-sectional analysis, a 75-item questionnaire filled in by 50 women with XLHED (age 19–49 years) was assessed. Results: Sixteen women (32%) prevented pregnancies because of the risk to pass on XLHED; 15 considered assisted reproduction for the same reason. Twelve women had a history of miscarriage, stillbirth or abortion, and three women reported on previous abortion of affected fetuses. When imagining to be pregnant, all except one showed interest in prenatal diagnosis of XLHED and in the possibility of treatment before birth. In 13 out of 50 women (26%), XLHED if detected prenatally would have impact on the continuation of pregnancy. Among 35 mothers of at least one affected child, XLHED had rarely been diagnosed during the first pregnancy (17%) but regularly during subsequent pregnancies (77%). Becoming aware of the condition before birth had caused a moral conflict for 50% of these women. Subjects with an affected child less frequently considered assisted reproduction to prevent XLHED (P < 0.05). In 69% of the women who reported an effect of XLHED on family planning, a prenatal treatment option for this disease would influence their decision-making. Conclusions: Many pregnant XLHED carriers who seek prenatal diagnosis experience moral conflicts. A prenatal treatment option would have strong impact on reproductive decisions, underlining the importance of adequate professional counselling.
CRIS-Team Scopus Importer:2022-06-17

Resection of dominant fusiform gyrus is associated with decline of naming function when temporal lobe epilepsy manifests after the age of five: A voxel-based lesion-symptom mapping study - Reindl, Caroline; Allgäuer, Andrea; Kleiser, Benedict; Onugoren, Müjgan Dogan; Lang, Johannes; Welte, Tamara; Stritzelberger, Jenny; Winder, Klemens; Schwarz, Michael; Gollwitzer, Stephanie; Trollmann, Regina; Rösch, Julie; et al. (NeuroImage: Clinical, 2022)
Objective: To determine patients’ characteristics and regions in the temporal lobe where resections lead to a decline in picture naming. Methods: 311 patients with left hemispheric dominance for language were included who underwent epilepsy surgery at the Epilepsy Center of Erlangen and whose picture naming scores (Boston Naming Test, BNT) were available preoperatively and 6-months postoperatively. Surgical lesions were mapped to an averaged template based on preoperative and postoperative MRI using voxel-based lesion-symptom mapping (VBLSM). Postoperative brain shifts were corrected. The relationship between lesioned brain areas and the presence of a postoperative naming decline was examined voxel-wise while controlling for effects of overall lesion size at first in the total cohort and then restricted to temporal lobe resections. Results: In VBLSM in the total sample, a decline in BNT score was significantly related to left temporal surgery. When only considering patients with left temporal lobe resections (n = 121), 40 (33.1%) significantly worsened in BNT postoperatively. VBLSM including all patients with left temporal resections generated no significant results within the temporal lobe. However, naming decline of patients with epilepsy onset after 5 years of age was significantly associated with resections in the left inferior temporal (extent of BNT decline range: 10.8− 14.4%) and fusiform gyrus (decline range: 12.1−18.4%). Significance: Resections in the posterior part of the dominant fusiform and inferior temporal gyrus was associated with a risk of deterioration in naming performance at six months after surgery in patients with epilepsy onset after 5 years of age but not with earlier epilepsy onset.
CRIS-Team Scopus Importer:2022-08-19
Keywords: Basal temporal language area; Epilepsy surgery; Gyrus fusiformis; Lesion localization; Naming; Neuropsychological outcome

Re-sequencing of candidate genes FOXF1, HSPA6, HAAO, and KYNU in 522 individuals with VATER/VACTERL, VACTER/VACTERL-like association, and isolated anorectal malformation - Thiem, Corina E.; Stegmann, Jil D.; Hilger, Alina C.; Waffenschmidt, Lea; Bendixen, Charlotte; Köllges, Ricarda; Schmiedeke, Eberhard; Schäfer, Frank Mattias; Lacher, Martin; Kosch, Ferdinand; Grasshoff-Derr, Sabine; Kabs, Carmen; et al. (Birth Defects Research, 2022)
Background: The acronym VATER/VACTERL association describes the combination of at least three component features (CFs): vertebral defects (V), anorectal malformations (ARM) (A), cardiac defects (C), tracheoesophageal fistula with or without esophageal atresia (TE), renal malformations (R), and limb defects (L). Individuals presenting two CFs have been termed VATER/VACTERL-like. Recently, FOXF1, HSPA6, HAAO, KYNU, TRAP1, and ZIC3 have been proposed as candidate genes for VATER/VACTERL, VATER/VACTERL-like, and ARM. Re-sequencing studies identified disease-causing variants in TRAP1 and ZIC3, the contribution of other genes was not independently investigated. One affected variant carrier in FOXF1 was previously identified. Here we re-sequenced FOXF1, HSPA6, HAAO, and KYNU in 522 affected individuals. Methods: Using molecular inversion probe (MIP) technology, re-sequencing was performed in 63 individuals with VATER/VACTERL association, 313 with VATER/VACTERL-like association, and 146 with ARM. All individuals were of European ethnicity. Variant filtering considered variants with a minor allele frequency (MAF) ≤0.01 for putative recessive disease-genes HSPA6, HAAO, and KYNU. For the putative dominant disease-gene FOXF1 we considered variants with a MAF ≤0.0001. In silico prediction tools were used for further prioritization. Results: Only two variants in FOXF1 in two independently affected individuals [c.443G>T, p.(Cys148Phe); c.850T>C, p.(Tyr284His)] passed our filter criteria. One individual presented with ARM, the second presented with TE and C comprising atrial and ventricular septal defects. Sanger sequencing confirmed both variants but also their inheritance from the healthy mother. Conclusion: Our analysis suggests that FOXF1, HSPA6, HAAO and KYNU do not play a major role in the formation of VACTER/VACTERL phenotypes or ARM.
CRIS-Team Scopus Importer:2022-04-15
Keywords: anorectal malformation; birth defects; candidate gene; penetrance; variants

Resistance to antibacterial therapy in pediatric febrile urinary tract infections—a single-center analysis - Raupach, Thomas; Held, Jürgen; Prokosch, Hans-Ulrich; Rascher, Wolfgang; Zierk, Jakob (Journal of Pediatric Urology, 2019)
Background: Febrile urinary tract infections (UTIs) are common serious bacterial infections in childhood and require early diagnosis and antibacterial therapy. However, considerable uncertainty exists regarding the optimal antibacterial agent for primary treatment of pediatric UTIs. Additionally, patterns of susceptibility and resistance change over time and microbiological in vitro resistance is not necessarily associated with treatment failure. Here, we analyzed uropathogens, their resistance patterns, and response to antibacterial treatment in children with acute pyelonephritis. Methods: We used billing codes (international classification of diseases) to identify all inpatients aged 0–18 years with febrile UTIs in a German university tertiary care center from 2009 until 2018. Microbial results were retrieved from the laboratory information system for all children, and treatment regimen and treatment response were analyzed in a subgroup of children. Results: We identified 907 children with acute pyelonephritis; in 590 cases (65%) an uropathogen was detected. Escherichia coli (60.8%), Enterococcus faecalis (13.2%), Klebsiella pneumoniae (7.0%), Proteus spp. (5.2%), and Pseudomonas aeruginosa (4.2%) were the most common pathogens. 353 of 436 E. coli isolates (81.0%) were susceptible or intermediate to aminopenicillin/β-lactamase-inhibitor (BLI) combinations. We examined 52 cases where E. coli was resistant to initial therapy with aminopenicillin/BLI combinations: Therapy was changed in 35 cases (67%) and left unchanged in 17 cases (33%), and we found no significant differences in C-reactive protein and leucocyte count in blood and urine between both groups after 3 days. Conclusions: We present the spectrum of uropathogens and susceptibility test results in pediatric UTIs in a tertiary care center. Our findings suggest a satisfactory response to first-line therapy with aminopenicillin/BLI combinations.
CRIS-Team Scopus Importer:2019-12-03
Keywords: Antibiotic susceptibility/resistance; Escherichia coli; Febrile urinary tract infections; Pediatrics

Respiratory infections regulated blood cells IFN-β-PD-L1 pathway in pediatric asthma - Kölle, Julia; Haag, Patricia; Vuorinen, Tytti; Kiefer, Alexander; Rauh, Manfred; Zimmermann, Theodor; Papadopoulos, Nikolaos G.; Finotto, Susetta (Immunity, Inflammation and Disease, 2020)
Background: Respiratory infections, in general, and rhinovirus infection specifically are the main reason for asthma exacerbation in children and programmed cell death protein 1 ligand (PD-L1) expression inhibits T cell responses. Objective: Could the interferon (IFN) type I expression in peripheral blood mononuclear cells (PBMCs) improve disease exacerbation in pediatric asthma?. Results: Here we found increased level of PD-L1 messenger RNA (mRNA) in total blood cells isolated from preschool children with virus-induced asthma, with lower percentage of forced expiratory volume in 1 second and with high serum levels of the C-reactive-protein. Conclusions and Clinical Relevance: These data indicate that, in the presence of infection in the airways of preschool children, worse asthma is associated with induced PD-L1 mRNA expression in blood cells. Further, type I IFN, IFN-β, a cytokine that is involved in the clearance of infections, was found to be associated with a better lung function in asthmatic children. These data suggest that improving peripheral blood IFN type I expression in PBMCs in pediatric asthma could improve disease exacerbation due to suppressing PD-L1 expression in blood cells.
CRIS-Team Scopus Importer:2020-05-22
Keywords: human rhinovirus; IFNβ; PD-L1; pediatric asthma

Response monitoring of infant acute myeloid leukemia treatment by quantification of the tumor specific MLL-FNBP1 fusion gene - Krumbholz, Manuela; Jung, Ronny; Bradtke, Jutta; Reinhardt, Dirk; Stachel, Daniel; Metzler, Markus (Leukemia & Lymphoma, 2015)
EVALuna2:18906

Results from an international multicenter trial evaluating the ease-of-use of and preference for a newly developed disposable injection pen for the treatment of growth hormone deficiency in treatment-naïve children and adults - Pleil, Andreas M.; Darendeliler, Feyza; Dörr, Helmuth-Günther; Hutchinson, Katherine; Wollmann, Hartmut A. (Medical Devices : Evidence and Research, 2014)
Previous research has reported that ease of use of and preference for a delivery device are associated with greater patient compliance - an important factor in achieving optimal therapeutic results. The objective of this study was to assess the ease-of-use of a new disposable pen (GoQuick(®), Pfizer, Inc.) versus the current reusable pen (GENOTROPIN Pen(®), Pfizer, Inc.) to inject a daily dose of recombinant DNA origin human growth hormone, Genotropin(®) (somatropin) in standard practice. In this randomized, crossover, multicenter, multinational, open-label study, ease-of-use of and preference for the two pens were assessed in three treatment-naïve populations: 1) parents of very young children; 2) parent-child dyads; and 3) adults via use of a validated self-report Injection Pen Assessment Questionnaire (IPAQ) after 2 months of at-home-use experience. The primary endpoint was the proportion of participants who reported the new disposable pen to be no different from or easier to use than the current reusable pen. Safety was also assessed and reported according to local legal requirements. Of the 120 screened patients, 119 were included in the ease-of-use analysis and all were included in the safety analyses. In all, 67.2% found the new somatropin disposable pen to be no different from or easier to use than the reusable pen (95% confidence interval: 58.8-75.7). Most adverse events were mild or moderate. No deaths or device- or treatment-related serious adverse events were reported. These results suggest that improvements made to the reusable somatropin pen are tangible and recognizable to treatment-naïve patients and their caregivers, child-caregiver dyads, and adults, and may positively impact continued compliance with therapy.ClinicalTrials.gov identifier: NCT01112865.
EVALuna2:18887

Results of a multicenter, randomized trial examining a new transition model for post-kidney transplant adolescents - Kreuzer, Martin; Prüfe, Jenny; Dierks, Marie Luise; Müther, Silvia; Bethe, Dirk; Büscher, Anja; Heindl-Rusai, Krisztina; Hollenbach, Sabine; Hoppe, Bernd; John-Kroegel, Ulrike; Kanzelmeyer, Nele Kirsten; Klaus, Günter; et al. (Scientific Reports, 2025)
Allograft loss after pediatric kidney transplantation (KTx) is highest in adolescents and young adults. Non-adherence and Health Care Transition (HCT) are important factors, but others also contribute. In the TransNephro study patients were randomized 1:1. The intervention group was included in the Berlin Transition Program (BTP) and incorporated a central case manager, a communication app, and joined transition rounds for one year before and one year after transfer. Primary endpoint was the coefficient of variation (CoV) of the trough level of the calcineurin inhibitor as a surrogate marker for medication adherence associated with graft loss. Least square (LS) mean differences and corresponding 95% confidence intervals (CIs) were estimated using an analysis of covariance (ANCOVA) model. We assessed 220 patients for eligibility. 49 patients were randomized to the intervention group and 53 to the control group. We analyzed 84 patients in the modified intention-to-treat analysis (38 intervention, 46 controls) and 60 in the per protocol analysis (25 intervention, 35 controls). We found no difference in CoV. We saw low numbers of graft-related events and observed no differences with respect to quality of life. BTP did not improve adherence and other outcome parameters. Non-adherent patients may have decided not to participate, whilst adherence of participants was already good at study start. It is therefore achallenge to design future multicenter trials on HCT that include multiple interventions. Trial registration: ISRCTN22988897, 24/04/2014, https://doi.org/10.1186/ISRCTN22988897.
CRIS-Team Scopus Importer:2025-05-02

Reversing the Inflammatory Process—25 Years of Tumor Necrosis Factor-α Inhibitors - Muth, Katharina N.; Rech, Jürgen; Losch, Florian O.; Hörning, André (Journal of Clinical Medicine, 2023)
Immune-mediated inflammatory diseases, such as rheumatoid arthritis, psoriatic arthritis, peripheral and/or axial spondyloarthritis, Crohn’s disease, and ulcerative colitis, are characterized by molecular and cellular changes in the immune system. Due to the systemic nature of these diseases, organs such as the liver or cardiovascular system are often affected by the inflammatory process. Tumor necrosis factor-α inhibitor therapy reduces the activation of pro-inflammatory signaling cascades, mitigates the chronic inflammatory process by restoring cellular balance, and alleviates clinical consequences, such as pain and tissue damage.
CRIS-Team Scopus Importer:2023-09-01
Keywords: cytokines; immune-mediated inflammatory diseases; inflammation; liver; rheumatoid arthritis; tumor necrosis factor alpha-inhibitors

Rezidivierende E.-coli-Meningitis in der Neonatalperiode - Dierl, Alexander; Hanslik, Gregor (Monatsschrift Kinderheilkunde, 2023)
Background: Due to heterogeneous data, case studies with a small study population and different clinical constellations, a generally valid statement about the duration of antibacterial treatment in cases of neonatal meningitis is difficult. Single case reports could be helpful to optimize the antibacterial treatment strategy. Objective: This study illustrates our experience in the treatment of a female preterm infant with recurrent episodes of meningitis in the neonatal period after initial Escherichia coli sepsis. Possible risk factors and suggestions for improvement of the treatment strategy as well as different diagnostic options to exclude anatomical or immunological risk factors are demonstrated. Material and methods: Case report of a female preterm infant of 35 + 3 weeks gestational age with 3 episodes of E. coli meningitis. Results: In this case an administration period of 6 weeks was necessary for successful infection treatment. No anatomical aberrations or immunodeficiencies were present as risk factors for the three episodes of E. coli meningitis with sepsis. Using magnetic resonance imaging (MRI) and positron emission tomography computed tomography (PET-CT) as well as repeated imaging with ultrasonography, the diagnosis could also be presented in cross-sectional imaging. Conclusion: The optimal duration of treatment of neonatal meningitis still needs to be selected based on the patient-related risk factors as well as the results of the microbial examination. In our case, the causative pathogen (E. coli) was identified as a significant risk factor for recurrent meningitis and the need for prolonged antibacterial treatment.
CRIS-Team Scopus Importer:2023-11-24
Keywords: Cerebrospinal fluid; Neonate; Pleocytosis; Preterm; Sepsis

RHABDOID TUMOR PREDISPOSITION SYNDROME (RTPS) - FINDING EVIDENCE BY SYSTEMATIC ANALYSES - Nemes, Karolina; Bens, Susanne; Johann, Pascal D.; Steinbuegl, Mona; Gruhle, Miriam; Kachanov, Denis; Teleshova, Margarita; Hauser, Peter; Simon, Thorsten; Tippelt, Stephan; Eberl, Wolfgang; Woessmann, Wilhelm; et al. (NEURO-ONCOLOGY, 2022)
CRIS-Team WoS Importer:2022-09-02

Rhinovirus inhibits IL-17A and the downstream immune responses in allergic asthma - Graser, Anna; Ekici, Arif Bülent; Sopel, Nina; Melichar, V. O.; Zimmermann, Theodor; Papadopoulos, N. G.; Taka, S.; Ferrazzi, Fulvia; Vuorinen, T.; Finotto, Susetta (Mucosal Immunology, 2016)
The proinflammatory cytokine interleukin-17A (IL-17A) is known to mediate antimicrobial activity, but its role during rhinovirus (RV) infections and in asthma needs further investigation. Therefore, we addressed the role of IL-17A during allergic asthma and antiviral immune response in human and murine immunocompetent cells. In this study we found that asthmatic children with a RV infection in their upper airways have upregulated mRNA levels of the antiviral cytokine interferon type I (IFN)-? and the transcription factor T-box 21 (TBX21) and reduced levels of IL-17A protein in their peripheral blood mononuclear cells (PBMCs). We also found that IL-17A inhibited RV1b replication in infected human lung epithelial cells A549. Furthermore, by using gene array analysis we discovered that targeted deletion of Il17a in murine lung CD4(+) T cells impaired Oas1g mRNA downstream of Ifn?, independently from RV infection. Additionally, in PBMCs of children with a RV infection in their nasalpharyngeal fluid OAS1 gene expression was found downregulated. Finally RV1b inhibited IL-17A production in lung CD4(+) T cells in a setting of experimental asthma. These results indicate that the RV1b inhibits IL-17A in T helper type 17 cells and IL-17A clears RV1b infection in epithelial cells. In both cases IL-17A contributes to fend off RV1b infection by inducing genes downstream of interferon type I pathway.
EVALuna2:9312

Rhinovirus species/genotypes and interferon-λ: subtypes, receptor and polymorphisms - missing pieces of the puzzle of childhood asthma? - Bergauer, Annika; Sopel, Nina; Kro, Bettina; Vuorinen, Tytti; Xepapadaki, Paraskevi; Weiss, Scott T.; Blau, Ashley; Sharma, Himanshu; Kraus, Cornelia; Springel, Rebekka; Rauh, Manfred; Mittler, Susanne; et al. (European Respiratory Journal, 2017)
EVALuna2:25986

RIbench: A Proposed Benchmark for the Standardized Evaluation of Indirect Methods for Reference Interval Estimation - Ammer, Tatjana; Schuetzenmeister, Andre; Prokosch, Hans-Ulrich; Zierk, Jakob; Rank, Christopher M.; Rauh, Manfred (Clinical Chemistry, 2022)
Background Indirect methods leverage real-world data for the estimation of reference intervals. These constitute an active field of research, and several methods have been developed recently. So far, no standardized tool for evaluation and comparison of indirect methods exists. Methods We provide RIbench, a benchmarking suite for quantitative evaluation of any existing or novel indirect method. The benchmark contains simulated test sets for 10 biomarkers mimicking routine measurements of a mixed distribution of non-pathological (reference) values and pathological values. The non-pathological distributions represent 4 common distribution types: normal, skewed, heavily skewed, and skewed-and-shifted. To identify strengths and weaknesses of indirect methods, test sets have varying sample sizes and pathological distributions differ in location, extent of overlap, and fraction. For performance evaluation, we use an overall benchmark score and sub-scores derived from absolute z-score deviations between estimated and true reference limits. We illustrate the application of RIbench by evaluating and comparing the Hoffmann method and 4 modern indirect methods -TML (Truncated-Maximum-Likelihood), kosmic, TMC (Truncated-Minimum-Chi-Square), and refineR- against one another and against a nonparametric direct method (n = 120). Results For the modern indirect methods, pathological fraction and sample size had a strong influence on the results: With a pathological fraction up to 20% and a minimum sample size of 5000, most methods achieved results comparable or superior to the direct method. Conclusions We present RIbench, an open-source R-package, for the systematic evaluation of existing and novel indirect methods. RIbench can serve as a tool for enhancement of indirect methods, improving the estimation of reference intervals.
CRIS-Team WoS Importer:2022-11-04

Risk Factor Analysis for Long-Term Graft Survival Following Pediatric Kidney Transplantation: The Importance of Pretransplantation Time on Dialysis and Donor/Recipient Age Difference - Marcou, Marios; Galiano, Matthias; Tzschoppe, Anja; Sauerstein, Katja; Wach, Sven; Taubert, Helge; Wullich, Bernd; Hirsch-Koch, Karin; Apel, Hendrik (Journal of Clinical Medicine, 2023)
Recognizing risk factors that may negatively affect long-term graft survival following pediatric kidney transplantation is a key element in the decision-making process during organ allocation. We retrospectively reassessed all cases of pediatric kidney transplantation performed in our center in the last 20 years with the aim of determining baseline characteristics that could be identified as prognostic risk factors for long-term graft survival. Between 2001 and 2020, a total of 91 kidney transplantations in children under the age of 18 years were undertaken in our center. Early graft failure was observed in six of the 91 patients (7%). The median follow-up of the remaining 85 children was 100 months, and the overall kidney graft survival rates at 5, 10, 15 and 20 years were 85.2%, 71.4%, 46.0% and 30.6%, respectively. Small children with a body surface area of <1 m2 were significantly associated with better long-term graft survival outcomes, while adolescents aged more than twelve years showed poorer graft survival rates than younger children. Body surface area of the recipient of ≥1 m2, pretransplantation duration of the recipient on dialysis ≥18 months, hemodialysis prior to transplantation and donor/recipient age difference of ≥25 years were significantly associated with poorer long-term graft survival.
CRIS-Team Scopus Importer:2023-12-08
Keywords: age difference; children; graft survival; kidney transplantation; renal dialysis

Risk factors for chylothorax and persistent serous effusions after congenital heart surgery - Raatz, Anna; Schöber, Martin; Zant, Robert; Cesnjevar, Robert; Rüffer, André; Purbojo, Ariawan; Dittrich, Sven; Alkassar, Muhannad (European Journal of Cardio-Thoracic Surgery, 2019)
OBJECTIVES: This study evaluated the various risk factors for chylothorax and persistent serous effusions (>7 days) after congenital heart surgery and developed equations to calculate the probability of their occurrence. METHODS: We performed a retrospective review of different medical databases at the University Hospital of Erlangen between January 2014 and December 2016. Full model regression analysis was used to identify risk factors, and prediction algorithms were set up to calculate probabilities. Discriminative power of the models was checked with the help of C-statistics. RESULTS: Of 745 operations on 667 patients, 68 chylothoraxes (9.1%) and 125 persistent pleural effusions (16.8%) were diagnosed. Lowest temperature [P = 0.043; odds ratio (OR) 0.899], trisomy 21 (P = 0.001; OR 5.548), a higher vasoactive inotropic score on the day of surgery (P = 0.001; OR 1.070) and use of an assist device (P = 0.001; OR 5.779) were significantly associated with chylothorax. Risk factors for persistent serous effusions were a given or possible involvement of the aortic arch during the operation (P = 0.000; OR 3.982 and 2.905), univentricular hearts (P = 0.019; OR 2.644), a higher number of previous heart operations (P = 0.014; OR 1.436), a higher vasoactive inotropic score 72 h after surgery (P = 0.019; OR 1.091), a higher central venous pressure directly after surgery (P = 0.046; OR 1.076) and an aortic cross-clamp time >86 min (P = 0.023; OR 2.223), as well as use of an assist device (P = 0.002; OR 10.281). The prediction models for both types of effusions proved to have excellent discriminative power. CONCLUSIONS: Persistent serous effusion is associated with a higher vasoactive inotropic score 72 h after surgery, an aortic cross-clamp time >86 min and elevated central venous pressure directly after surgery, which, in combination, potentially indicate cardiac stress. The developed logistic algorithm helps to estimate future likelihood.
CRIS-Team Scopus Importer:2019-11-29
Keywords: Cardiac insufficiency; Cardiac surgery; Chylothorax; Congenital heart disease; Persistent effusions; Risk factor

Risk Factors for Early Dialysis Dependency in Autosomal Recessive Polycystic Kidney Disease. - Burgmaier, Kathrin; Kunzmann, Kevin; Ariceta, Gema; Bergmann, Carsten; Buescher, Anja Katrin; Burgmaier, Mathias; Dursun, Ismail; Duzova, Ali; Eid, Loai; Erger, Florian; Feldkoetter, Markus; Galiano, Matthias; et al. (Journal of Pediatrics, 2018)
OBJECTIVE: To identify prenatal, perinatal, and postnatal risk factors for dialysis within the first year of life in children with autosomal recessive polycystic kidney disease (ARPKD) as a basis for parental counseling after prenatal and perinatal diagnosis. STUDY DESIGN: A dataset comprising 385 patients from the ARegPKD international registry study was analyzed for potential risk markers for dialysis during the first year of life. RESULTS: Thirty-six out of 385 children (9.4%) commenced dialysis in the first year of life. According to multivariable Cox regression analysis, the presence of oligohydramnios or anhydramnios, prenatal kidney enlargement, a low Apgar score, and the need for postnatal breathing support were independently associated with an increased hazard ratio for requiring dialysis within the first year of life. The increased risk associated with Apgar score and perinatal assisted breathing was time-dependent and vanished after 5 and 8 months of life, respectively. The predicted probabilities for early dialysis varied from 1.5% (95% CI, 0.5%-4.1%) for patients with ARPKD with no prenatal sonographic abnormalities to 32.3% (95% CI, 22.2%-44.5%) in cases of documented oligohydramnios or anhydramnios, renal cysts, and enlarged kidneys. CONCLUSIONS: This study, which identified risk factors associated with onset of dialysis in ARPKD in the first year of life, may be helpful in prenatal parental counseling in cases of suspected ARPKD.
EVALuna2:203368
Keywords: PKHD1; renal replacement therapy; oligohydramnios; ciliopathy

Risk factors for mixed chimerism in children with hemophagocytic lymphohistiocytosis after reduced toxicity conditioning - Wustrau, Katharina; Greil, Johann; Sykora, Karl-Walter; Albert, Michael H.; Burkhardt, Birgit; Lang, Peter; Meisel, Roland; Woessmann, Wilhelm; Beier, Rita; Schulz, Ansgar; Bader, Peter; Chada, Martin; et al. (Pediatric Blood & Cancer, 2020)
Background Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined. Procedure Patients with primary HLH transplanted 2009-2016 after treosulfan- or melphalan-based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if < 25% donor chimerism occurred and/or if secondary cell therapy was administered. Donor type, graft source, type of alkylating agent, type of serotherapy, and remission status were analyzed as potential risk factors in a multivariable logistic regression model. Results Among 60 patients, engraftment was achieved in 95%, and the five-year estimated overall survival rate was 75%. Prevalence of any recipient chimerism was 48%. Substantial recipient chimerism was recorded in 32% of patients. Secondary post-HSCT cell therapy was administered in 30% of patients. A human leukocyte antigen (HLA)-mismatched donor (< 10/10) was the only significant risk factor for the occurrence of substantial recipient chimerism (P = 0.01; odds ratio, 5.8; CI 95%, 1.5-26.3). Conclusion The use of an HLA-matched donor is the most important factor to avoid substantial recipient chimerism following treosulfan -or melphalan-based conditioning in primary HLH.
CRIS-Team WoS Importer:2020-07-17

Risk of behavioral disturbances in pediatric patients with epilepsy and mild to moderate cognitive impairment: A cross-sectional study - Schader, Carla; Schmidlechner, Tristan; Cornell, Sonia; Gerstl, Lucia; Trollmann, Regina; Borggraefe, Ingo (Epileptic Disorders, 2024)
Objective: The aim of the study was to assess whether children and adolescents with epilepsy are at higher risk of behavioral disturbances when they have concomitant cognitive disturbances. Methods: Behavioral scores were generated using the Child Behavior Checklist (CBCL). Cognitive evaluation was applied by using different age appropriate versions of the Wechsler Intelligence Scale. CBCL scores (total, externalizing, internalizing) were compared between patients with and without intellectual disability (IQ score < 70 and ≥70, respectively). Results: 144 (10.2 mean age, 6.0–17.9 range) patients were recruited for the study. Patients with mild to moderate intellectual disability (full-scale intelligence quotient (FSIQ) < 70) were not at higher risk of behavioral disturbances (total CBCL score ≥ 63) than patients without cognitive impairment. The mean total CBCL score was 62.0 ± 10.6 (range 42.0–83.5, 95% CI 57.9–62.0) and 59.3 ± 10.3 (range 38.0–80.0, CI 57.4–61.2) for patients with FSIQ < 70 and ≥70, respectively. There was no correlation between FSIQ and total CBCL scores. These findings were true for all IQ subcategories. Significance: Behavioral disturbances among children and adolescents with epilepsy occur despite the presence or absence of intellectual dysfunction with respect to full-scale IQ.
CRIS-Team Scopus Importer:2024-07-19
Keywords: behavior; cognition; epilepsy; neuropsychology; risk

RNA expression profiles and regulatory networks in human right ventricular hypertrophy due to high pressure load - Chouvarine, Philippe; Photiadis, Joachim; Cesnjevar, Robert; Scheewe, Jens; Bauer, Ulrike M. M.; Pickardt, Thomas; Kramer, Hans-Heiner; Dittrich, Sven; Berger, Felix; Hansmann, Georg (iScience, 2021)
Right ventricular hypertrophy (RVH) occurs in high pressure afterload, e.g., tetralogy of Fallot/pulmonary stenosis (TOF/PS). Such RVH is associated with alterations in energy metabolism, neurohormonal and epigenetic dysregulation (e.g., microRNA), and fetal gene reprogramming in animal models. However, comprehensive expression profiling of competing endogenous RNA in human RVH has not been performed. Here, we unravel several previously unknown circular, long non-coding, and microRNAs, predicted to regulate expression of genes specific to human RVH in the non-failing heart (TOF/PS). These genes are significantly overrepresented in pathways related to regulation of glucose and lipid metabolism (SIK1, FABP4), cell surface interactions (THBS2, FN1), apoptosis (PIK3IP1, SIK1), extracellular matrix composition (CTGF, IGF1), and other biological events. This is the first unbiased RNA sequencing study of human compensated RVH encompassing coding and noncoding RNA expression and predicted sponging of miRNAs by non-coding RNAs. These findings advance our understanding of adaptive RVH and highlight future therapeutic targets.
CRIS-Team WoS Importer:2021-04-16

RNA sequencing reveals induction of specific renal inflammatory pathways in a rat model of malignant hypertension - Menendez-Castro, Carlos; Cordasic, Nada; Fahlbusch, Fabian; Ekici, Arif Bülent; Kirchner, Philipp; Daniel, Christoph; Amann, Kerstin Ute; Velkeen, Roland; Wölfle, Joachim; Schiffer, Mario; Hartner, Andrea; Hilgers, Karl Friedrich (Journal of Molecular Medicine, 2021)
Abstract: In malignant hypertension, far more severe kidney injury occurs than in the “benign” form of the disease. The role of high blood pressure and the renin–angiotensin–aldosterone system is well recognized, but the pathogenesis of the renal injury of malignant hypertension (MH) remains incompletely understood. Using the rat model of two-kidney, one-clip renovascular hypertension in which some but not all animals develop MH, we performed a transcriptomic analysis of gene expression by RNA sequencing to identify transcriptional changes in the kidney cortex specific for MH. Differential gene expression was assessed in three groups: MH, non-malignant hypertension (NMH), and normotensive, sham-operated controls. To distinguish MH from NMH, we considered two factors: weight loss and typical renovascular lesions. Mean blood pressure measured intraarterially was elevated in MH (220 ± 6.5 mmHg) as well as in NMH (192 ± 6.4 mmHg), compared to controls (119 ± 1.7 mmHg, p < 0.05). Eight hundred eighty-six genes were exclusively regulated in MH only. Principal component analysis revealed a separated clustering of the three groups. The data pointed to an upregulation of many inflammatory mechanisms in MH including pathways which previously attracted relatively little attention in the setting of hypertensive kidney injury: Transcripts from all three complement activation pathways were upregulated in MH compared to NMH but not in NMH compared with controls; immunohistochemistry confirmed complement deposition in MH exclusively. The expression of chemokines attracting neutrophil granulocytes (CXCL6) and infiltration of myeloperoxidase-positive cells were increased only in MH rats. The data suggest that these pathways, especially complement deposition, may contribute to kidney injury under MH. Key messages: The most severe hypertension-induced kidney injury occurs in malignant hypertension.In a rat model of malignant hypertension, we assessed transcriptional responses in the kidney exposed to high blood pressure. A broad stimulation of inflammatory mechanisms was observed, but a few specific pathways were activated only in the malignant form of the disease, notably activation of the complement cascades.Complement inhibitors may alleviate the thrombotic microangiopathy of malignant hypertension even in the absence of primary complement abnormalities.
CRIS-Team Scopus Importer:2021-09-24
Keywords: Complement activation; Inflammation; Kidney injury; Malignant hypertension; RNA-Seq; Two-kidney one-clip renovascular hypertension (2K1C)

Role of nuclear factor of activated T cells 2 (NFATc2) in allergic asthma - Jakobi, Marielena; Kiefer, Alexander; Mirzakhani, Hooman; Rauh, Manfred; Zimmermann, Theodor; Xepapadaki, Paraskevi; Stanic, Barbara; Akdis, Mubeccel; Papadopoulos, Nikolaos G.; Raby, Benjamin A.; Neurath-Finotto, Susetta; Weiss, Scott T.; et al. (Immunity, Inflammation and Disease, 2020)
Background: We recently described increased NFATc1, IRF4, and NIP45 messenger RNA (mRNA) expression in peripheral blood mononuclear cells (PBMCs) of asthmatic children and adults with multiple allergies. Objective: NFATc2 has been described to associate with IRF4 to induce interleukin-4, and to be inhibited by T-bet. Here, we analyzed the role of NFATc2 in asthmatic children and adults. Methods: PBMCs were isolated from the blood of control of asthmatics subjects. Some PBMCs were analyzed untreated and some cultured with and without phytohemagglutinin. Then, RNA was extracted from the cells and cytokines were measured in the supernatants via enzyme-linked immunosorbent assay or multiplex analysis. RNA was then reverse-transcribed and NFATc1, NFATC2, IRF4, and T-bet mRNA were analyzed by real-time polymerase chain reaction. In addition, in peripheral blood cells, NFATc2 expression was analyzed, in a population of asthmatic children and adults from the Asthma BRIDGE study. Results: In addition to NFATc1 and NIP45, also NFATc2 was found upregulated in PBMCs and peripheral blood cells from asthmatic children and adults with allergic asthma. Moreover, NFATc1 directly correlated with lymphocytes number whereas NFATc2 correlated with peripheral eosinophilia in asthma. Conclusions: In addition to NFATc1 and NIP45, NFATc2 was found upregulated in asthma. Moreover, NFATc1 mRNA correlated with lymphocytes both in control and asthma, and NFATC1 and NFATc2 mRNA showed a direct correlation with eosinophils in controls but not in asthma, indicating that NFATc1 is associated with lymphocytes and not eosinophils in asthma. Clinical Significance: Targeting NFATc2 in T lymphocytes might ameliorate the allergic phenotype in asthmatic subjects.
CRIS-Team Scopus Importer:2020-10-30
Keywords: allergy processes; animals; eosinophils cells; human; T cells

Role of nuclear factor of activated T cells 2 (NFATc2) in allergic asthma - Jakobi, M.; Mirzakahni, H.; Kiefer, Alexander; Rauh, Manfred; Zimmermann, Theodor; Papadopoulos, N. G.; Raby, B. A.; Weiss, S. T.; Finotto, Susetta (ALLERGY, 2020)
CRIS-Team WoS Importer:2020-10-02

Role of TGF-β in anti-rhinovirus immune responses in asthmatic patients - Bielor, Carina; Sopel, Nina; Maier, Anja; Blau, Ashley; Sharma, Himanshu; Vuorinen, Tytti; Kross, Bettina; Mittler, Susanne; Graser, Anna; Mousset, Stephanie; Melichar, Volker O.; Kiefer, Alexander; et al. (Journal of Allergy and Clinical Immunology, 2017)
EVALuna2:32796

Routine Surveillance of SARS-CoV-2 Serostatus in Pediatrics Allows Monitoring of Humoral Response - Wachter, Felix; Knieling, Ferdinand; Raming, Roman; Simon, David; Wölfle, Joachim; Hörning, André; Neubert, Antje; Rauh, Manfred; Regensburger, Adrian (Microorganisms, 2023)
The occurrence of SARS-CoV-2 infections during the pandemic was mainly based on PCR testing of symptomatic patients. However, with new variants, vaccinations, and the changing of the clinical disease severity, knowledge about general immunity is elusive. For public health systems, timely knowledge of these conditions is essential, but it is particularly scarce for the pediatric population. Therefore, in this study, we wanted to investigate the spike and nucleocapsid seroprevalence in pediatric patients using routine residual blood tests collected during the pandemic. This prospective observational study was conducted over seven one-month periods. Herein, the latest four time periods (November 2021, January 2022, March 2022, and May 2022) are depicted. Each patient of a tertiary-care center in Germany was anonymized after collection of clinical diagnosis (ICD-10) and then routinely tested for the respective spike and nucleocapsid SARS-CoV-2 antibody titer. A total of 3235 blood samples from four time periods were included. Spike seroprevalence rose from 37.6% to 51.9% to 70.5% to 85.1% and nucleocapsid seroprevalence from 11.6% to 17.0% to 36.7% to 58.1% in May 2022. In detail, significant changes in seroprevalence between age groups but not between sex or diagnosis groups were found. Quantitative measures revealed rising spike and constant nucleocapsid antibody levels over the pandemic with a half-life of 102 days for spike and 45 days for nucleocapsid antibodies. Routine laboratory assessment of SARS-CoV-2 in residual blood specimens of pediatric hospitals enables monitoring of the seroprevalence and may allow inferences about general immunity in this cohort.
EVALuna2:547467
Keywords: COVID-19; pediatrics; seroprevalence; SARS-CoV-2; Omicron; surveillance

Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic defects in cytotoxicity - Groß, Miriam; Speckmann, Carsten; May, Annette; Gajardo-Carrasco, Tania; Wustrau, Katharina; Maier, Sarah Lena; Panning, Marcus; Huzly, Daniela; Agaimy, Abbas; Bryceson, Yenan T.; Choo, Sharon; Chow, C. W.; et al. (Journal of Allergy and Clinical Immunology, 2021)
Background: Rubella virus–induced granulomas have been described in patients with various inborn errors of immunity. Most defects impair T-cell immunity, suggesting a critical role of T cells in rubella elimination. However, the molecular mechanism of virus control remains elusive. Objective: This study sought to understand the defective effector mechanism allowing rubella vaccine virus persistence in granulomas. Methods: Starting from an index case with Griscelli syndrome type 2 and rubella skin granulomas, this study combined an international survey with a literature search to identify patients with cytotoxicity defects and granuloma. The investigators performed rubella virus immunohistochemistry and PCR and T-cell migration assays. Results: This study identified 21 patients with various genetically confirmed cytotoxicity defects, who presented with skin and visceral granulomas. Rubella virus was demonstrated in all 12 accessible biopsies. Granuloma onset was typically before 2 years of age and lesions persisted from months to years. Granulomas were particularly frequent in MUNC13-4 and RAB27A deficiency, where 50% of patients at risk were affected. Although these proteins have also been implicated in lymphocyte migration, 3-dimensional migration assays revealed no evidence of impaired migration of patient T cells. Notably, patients showed no evidence of reduced control of concomitantly given measles, mumps, or varicella live-attenuated vaccine or severe infections with other viruses. Conclusions: This study identified lymphocyte cytotoxicity as a key effector mechanism for control of rubella vaccine virus, without evidence for its need in control of live measles, mumps, or varicella vaccines. Rubella vaccine–induced granulomas are a novel phenotype with incomplete penetrance of genetic disorders of cytotoxicity.
CRIS-Team Scopus Importer:2021-07-02
Keywords: Cytotoxicity; granuloma; Griscelli syndrome type 2; hemophagocytic lymphohistiocytosis; live vaccine; primary immunodeficiency; rubella virus

RVAD implantation in a Fontan patient with protein-losing enteropathy as a bridge to transplant: Prêtre modification - Moosmann, Julia; Dittrich, Sven; Purbojo, Ariawan; Cesnjevar, Robert (Journal of Cardiac Surgery, 2020)
Fontan patients with protein-losing enteropathy (PLE) represent poor candidates for cardiac transplantation due to end-organ injury and severely impaired clinical condition. Ventricular assist device (VAD) therapy has evolved as a promising bridge to transplant strategy improving quality of life and survival on the waiting list. However, VAD therapy for the Fontan circulation remains challenging. For Fontan patients with preserved ventricular function implantation of a right ventricular assist device (RVAD) has been described by Prêtre et al as bridge to transplant. We present the second case of RVAD support in a Fontan patient with PLE.
CRIS-Team Scopus Importer:2020-06-30
Keywords: assist in Fontan; congenital heart disease; Fontan circulation; protein-losing enteropathy; right ventricular assist device

Safety and effectiveness of pediatric growth hormone therapy: Results from the full cohort in KIGS - Maghnie, Mohamad; Ranke, Michael B.; Geffner, Mitchell E.; Vlachopapadopoulou, Elpis; Dörr, Helmuth-Günther; Wikland, Kerstin Albertsson; Ibanez, Lourdes; Carlsson, Martin; Cutfield, Wayne; Rooman, Raoul; Gomez, Roy; Wajnrajch, Michael P.; et al. (HORMONE RESEARCH IN PAEDIATRICS, 2021)
CRIS-Team WoS Importer:2021-10-08

Safety and Efficacy of Pediatric Growth Hormone Therapy: Results From the Full KIGS Cohort - Maghnie, Mohamad; Ranke, Michael B.; Geffner, Mitchell E.; Vlachopapadopoulou, Elpis; Ibanez, Lourdes; Carlsson, Martin; Cutfield, Wayne; Rooman, Raoul; Gomez, Roy; Wajnrajch, Michael P.; Linglart, Agnes; Stawerska, Renata; et al. (Journal of Clinical Endocrinology and Metabolism, 2022)
Context The Kabi/Pfizer International Growth Database (KIGS) is a large, international database (1987-2012) of children treated with recombinant human growth hormone (rhGH) in real-world settings. Objective This work aimed to evaluate the safety and efficacy of rhGH from the full KIGS cohort. Methods Data were collected by investigators from children with growth disorders treated with rhGH (Genotropin [somatropin]; Pfizer). Safety was evaluated in all treated patients, and efficacy in those treated for 1 year or more. A subgroup included patients treated for 5 years or more (>= 2 years prepubertal) who had reached near-adult height (NAH). Main outcomes included adverse events (AEs), serious AEs (SAEs), and height growth. Results The full KIGS cohort (N = 83 803 [58% male]) was treated for idiopathic GH deficiency (IGHD; 46.9%), organic GHD (10.0%), small for gestational age (SGA; 9.5%), Turner syndrome (TS; 9.2%), idiopathic short stature (ISS; 8.2%), and others (16.2%). Median rhGH treatment duration was 2.7 years and observation 3.1 years. SAEs occurred in 3.7% of patients and death in 0.4%. The most common SAEs were recurrence of craniopharyngioma (n = 151), neoplasm (n = 99), and cancer (n = 91); and scoliosis (n = 91). Median first-year delta height-SD score (SDS) (Prader) in prepubertal patients was 0.66 (IGHD), 0.55 (ISS), 0.58 (TS), and 0.71 (SGA). Median gains in NAH-SDS were 1.79 (IGHD), 1.37 (ISS), and 1.34 (SGA) for boys, and 2.07 (IGHD), 1.62 (ISS), 1.07 (TS), and 1.57 (SGA) for girls. Conclusion Data from KIGS, the largest and longest running international database of rhGH-treated children, show that rhGH is safe and increases short-term height gain and adult height across GHD and non-GHD conditions.
CRIS-Team WoS Importer:2022-10-14

Safety and immunogenicity of Fc-EDA, a recombinant ectodysplasin A1 replacement protein, in human subjects - Körber, Iris; Klein, Ophir D.; Morhart, Patrick; Faschingbauer, Florian; Grange, Dorothy K.; Clarke, Angus; Bodemer, Christine; Maitz, Silvia; Huttner, Kenneth; Kirby, Neil; Durand, Caroline; Schneider, Holm (British Journal of Clinical Pharmacology, 2020)
In X-linked hypohidrotic ectodermal dysplasia, the most frequent ectodermal dysplasia, an inherited deficiency of the signalling protein ectodysplasin A1 (EDA1) impairs the development of the skin and its appendages, various eccrine glands, and dentition. The severe hypohidrosis common to X-linked hypohidrotic ectodermal dysplasia patients may lead to life-threatening hyperthermia, especially during hot weather or febrile illness. Fc-EDA, an EDA1 replacement protein known to prevent the disease in newborn animals, was tested in 2 clinical trials (human adults and neonates) and additionally administered under compassionate use to 3 infants in utero. The data support the safety of Fc-EDA and efficacy if applied prenatally. Anti-drug antibodies were detected after intravenous administration in adult males and nonpregnant females, but not in pregnant women when Fc-EDA was delivered intra-amniotically. Most importantly, there was no detectable immune response to the investigational drug in neonates treated by intravenous infusions and in infants who had received Fc-EDA in utero. In conclusion, the safety profile of this drug encourages further development of prenatal EDA1 replacement therapy.
CRIS-Team Scopus Importer:2020-05-02
Keywords: drug safety; ectodermal dysplasia; ectodysplasin A; immunogenicity; prenatal therapy; protein replacement

Safety of clonidine used for long-term sedation in paediatric intensive care: A systematic review - Eberl, Sonja; Ahne, Gabriele; Toni, Irmgard; Standing, Joseph; Neubert, Antje (British Journal of Clinical Pharmacology, 2020)
Aim: Although not approved, the alpha-adrenoceptor agonist clonidine is considered an option for long-term sedation protocols in paediatric intensive care. We reviewed adverse effects of clonidine occurring in this indication.
CRIS-Team WoS Importer:2021-01-15

Safety Profile of Oral Iron Chelator Deferiprone in Chinese Children with Transfusion-Dependent Thalassaemia - Botzenhardt, Sebastian; Sing, Chor W; Wong, Ian C K; Chan, Godfrey Chi-Fung; Wong, Lisa Y L; Felisi, Mariagrazia; Rascher, Wolfgang; Ceci, Adriana; Neubert, Antje (Current Drug Safety, 2016)
UNLABELLED: There is a lack of knowledge regarding the incidence of serious adverse drug reactions (ADR) to the oral iron chelator deferiprone in Chinese children with transfusion-dependent thalassaemia. In this retrospective population-based cohort study, paediatric thalassaemia patients in Hong Kong were screened for serious and medically important adverse events related to deferiprone therapy using diagnosis codes, laboratory data and hospital admissions. Potential ADRs were assessed by reviewing concomitant medications, diagnoses and laboratory data and evaluated using standardised causality assessment. Eighty-seven patients contributing 169.8 person-years were included. Thirty ADRs were identified in 21 patients. Most ADRs (56.0%) occurred in the first three months of therapy. Neutropenia occurred in 11 patients (12.6%; incidence rate 6.5 per 100 patient-years) and severe neutropenia (agranulocytosis) was observed in 5 patients (5.7%, incidence rate 2.9 per 100 patient-years). Other identified ADRs involve severe arthropathy, elevated liver enzymes and mild thrombocytopenia. In conclusion, the safety profile of DFP therapy in Chinese children suffering from transfusion-dependent thalassaemia is in line with previous studies of non-Chinese children. However, unlike previous studies, we observed a relatively high incidence of agranulocytosis and neutropenia in patients with simultaneous combined therapy. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy. Further prospective clinical and pharmacogenetic studies are required to better evaluate this important safety signal. KEY POINTS: • Half of the identified ADRs related to deferiprone therapy occurred during the first three months of treatment. • A relatively high incidence of agranulocytosis and neutropenia. Hence close monitoring for white blood cell counts is advised in Chinese children under combined iron chelation therapy.
EVALuna2:34001

Safety profiles of iron chelators in young patients with haemoglobinopathies - Botzenhardt, Sebastian; Li, Niya; Chan, Esther W.; Sing, Chor Wing; Wong, Ian C. K.; Neubert, Antje (European Journal of Haematology, 2017)
BACKGROUND: This review describes the safety of deferoxamine (DFO), deferiprone (DFP), deferasirox (DFX) and combined therapy in young patients less than 25 yr of age with haemoglobinopathies. METHODS: Searches in electronic literature databases were performed. Studies reporting adverse events associated with iron chelation therapy were included. Study and reporting quality was assessed using AHRQ Risk of Bias Assessment Tool and McMaster Quality Assessment Scale of Harms. Prospective clinical studies were pooled in a random-effects meta-analysis of proportions. RESULTS: Safety data of 2040 patients from 34 studies were included. Ninety-two case reports of 246 patients were identified. DFX (937 patients) and DFP (667 patients) possess the largest published safety evidence. Fewer studies on combination regimens are available. Increased transaminases were seen in all regimens (3.9-31.3%) and gastrointestinal disorders with DFP and DFX (3.7-18.4% and 5.8-18.8%, respectively). Therapy discontinuations due to adverse events were low (0-4.1%). Reporting quality was selective and poor in most of the studies. CONCLUSION: Iron chelation therapy is generally safe in young patients, and published data correspond to summary of product characteristics. Each iron chelation regimen has its specific safety risks. DFO seems not to be associated with serious adverse effects in recommended doses. In DFP and DFX, rare, but serious, adverse reactions can occur. Data on combined therapy are scarce, but it seems equally safe compared to monotherapy.
EVALuna2:34283

Sarcoma treatment in the era of molecular medicine - Grünewald, Thomas G.P.; Alonso, Marta; Avnet, Sofia; Banito, Ana; Burdach, Stefan; Cidre-Aranaz, Florencia; Di Pompo, Gemma; Distel, Martin; Dorado-Garcia, Heathcliff; Garcia-Castro, Javier; González-González, Laura; Grigoriadis, Agamemnon E.; et al. (Embo Molecular Medicine, 2020)
Sarcomas are heterogeneous and clinically challenging soft tissue and bone cancers. Although constituting only 1% of all human malignancies, sarcomas represent the second most common type of solid tumors in children and adolescents and comprise an important group of secondary malignancies. More than 100 histological subtypes have been characterized to date, and many more are being discovered due to molecular profiling. Owing to their mostly aggressive biological behavior, relative rarity, and occurrence at virtually every anatomical site, many sarcoma subtypes are in particular difficult-to-treat categories. Current multimodal treatment concepts combine surgery, polychemotherapy (with/without local hyperthermia), irradiation, immunotherapy, and/or targeted therapeutics. Recent scientific advancements have enabled a more precise molecular characterization of sarcoma subtypes and revealed novel therapeutic targets and prognostic/predictive biomarkers. This review aims at providing a comprehensive overview of the latest advances in the molecular biology of sarcomas and their effects on clinical oncology; it is meant for a broad readership ranging from novices to experts in the field of sarcoma.
CRIS-Team Scopus Importer:2020-10-23
Keywords: bone sarcoma; molecular diagnostics; molecular medicine; soft tissue sarcoma; targeted therapy

SARS-CoV-2-Infektion in der Schwangerschaft und Auftreten von angeborenen Fehlbildungen – Besteht ein Zusammenhang? Auswertung von 8032 Schwangerschaften aus dem CRONOS-Register - Hofbauer, Anna; Schneider, Holm; Kehl, Sven; Reutter, Heiko Martin; Pecks, Ulrich; Andresen, Kristin; Morhart, Patrick (Zeitschrift für Geburtshilfe und Neonatologie, 2024)
Background Based on single case reports, the COVID-19 Related Obstetric and Neonatal Outcome Study (CRONOS) registry, sponsored by the German Society for Perinatal Medicine (DGPM), investigated the likelihood that SARS-CoV-2 infections of the mother in (early) pregnancy cause embryopathies and/or fetopathies. Material/Methods The CRONOS registry enrolled a total of 8032 women with confirmed SARS-CoV-2 infection during pregnancy at more than 130 participating hospitals from April 2020 to February 2023. Both maternal and fetal data were documented and the anonymized multicenter data were analyzed. Results Of 7142 fully documented pregnancies (including postnatal data), 140 showed congenital malformations. 8.57% of the mothers had had a SARS-CoV-2-infection in the 1st trimester and 36.43% in the 2nd trimester. In 66 cases with congenital malformations (47.14%), the malformation was only detected after the diagnosis of a maternal SARS-CoV-2 infection. The overall prevalence of congenital malformations in this cohort was 1.96%, compared to a prevalence of 2.39% reported in the EUROCAT (European network of population-based registries for the epidemiological surveillance of congenital anomalies) pre-pandemic registry between 2017-2019. Discussion Our multicenter data argue against a link between maternal SARS-CoV-2 infection in early pregnancy and congenital malformation.
CRIS-Team Scopus Importer:2024-02-23
Keywords: Coronavirus; COVID-19; CRONOS-registry; embryopathy; fetopathy; malformations

Schilddrüsenfunktionsstörungen in der Schwangerschaft - Hamza, Amr; Schlembach, Dietmar; Schild, Ralf Lothar; Groten, Tanja; Wölfle, Joachim; Battefeld, Wilgard; Kehl, Sven; Schneider, Michael (gynäkologische praxis, 2024)
With the onset of pregnancy, TSH values fall then rise with ongoing gestation. A TSH screening should be performed in the first trimester under certain indications. Furthermore, the TPO-Ab status should be determined when the TSH levels exceeds 2.5 mU/l as it might lower threshold of a levothyroxine (LT4) substitution. Subclinical hypothyroidism is associated with an increased risk of miscarriage, preterm birth but not an increased risk of preeclampsia, fetal growth restriction or adverse neonatal neurocognitive outcomes and may not require a supplementation especially with negative TPO-Ab. However, the overt hypothyroidism requires LT4 administration. A manifest hyperthyroidism necessitates treatment adjustments before and with the onset pregnancy. Propylthiouracil is recommended in the first trimester and replaced by with thiamazole in the second trimester. A thorough birth plan with neonatological management should be planned. In cases of a fetal hyperthyroidism, a vertical treatment should be introduced in perinatal centres with a specialized experience. Regarding birth management, a detailed intra- and postnatal management plan, including a specialized paediatric care, is necessary. Fetal hyperthyroidism should be ruled out prenatally upon taking thyrostatic agents during the first trimester. Intrauterine therapies for fetal hyper- and hypothyroidism should only be carried out after careful consideration in centres with a therapeutic expertise. In complex cases, the birth should occur in a prenatal centre with paediatric personal that have the necessary expertise.
CRIS-Team Scopus Importer:2024-08-23
Keywords: hyperthyroidism; hypothyroidism; thyroid disease; TSH

Sclerosing epithelioid fibrosarcoma of the kidney: clinicopathologic and molecular study of a rare neoplasm at a novel location - Ohlmann, Carsten-Henning; Brecht, Ines B.; Junker, Kerstin; Van Der Zee, Jill A.; Nistor, Adriana; Bohle, Rainer M.; Stöckle, Michael; Metzler, Markus; Hartmann, Arndt; Agaimy, Abbas (Annals of Diagnostic Pathology, 2015)
Sclerosing epithelioid fibrosarcoma (SEF) is a rare fibrosarcoma variant with specific histomorphology and consistent translocation (EWSR1-CREB3L1/2). To date, 110 cases have been reported; only 15 originated within the abdomen. With only 2 cases reported parallel to our study and one case briefly mentioned in a previous series, primary renal SEF is exceptionally rare but might be underrecognized. We herein describe 2 cases affecting a 23-year-old woman and a 43-year-old man. Tumor size was 22 and 4.2 cm, respectively. Patient 1 developed skeletal and multiple pulmonary metastases. She died of disease 82 months later, despite aggressive multimodality therapy. Patient 2 has no evidence of recurrence or metastasis (8 months after surgery). Histologic examination showed similar appearance with monotonous bland medium-sized epithelioid cells with rounded slightly vesicular nuclei and clear cytoplasm imparting a carcinoma-like appearance set within a highly sclerotic hyaline fibrous stroma. The tumor cells were arranged in nests, single cell cords, trabeculae, or solid sheets with frequent entrapment of renal tubules and glomeruli. Immunohistochemistry showed strong expression of vimentin, bcl2, CD99, and MUC4, whereas cytokeratin and other markers were negative. Fluorescence in situ hybridization showed a translocation involving the EWSR1 gene locus in case 2. Molecular analysis in case 1 was not successful due to poor signal quality. To our knowledge, this is the second report documenting primary renal SEF. Awareness of this entity would help avoid misinterpretation as clear cell carcinoma, sclerosing perivascular epithelioid cell tumor, Xp.11 translocation carcinoma, and other more frequent neoplasms at this site.
EVALuna2:6701

Searching the web: a survey on the quality of advice on postnatal sequelae of intrauterine growth restriction and the implication of developmental origins of health and disease - Perzel, S.; Hübner, Hanna; Rascher, Wolfgang; Menendez-Castro, C.; Fahlbusch, F. B.; Hartner, Andrea (Journal of Developmental Origins of Health and Disease, 2017)
Intrauterine growth restriction (IUGR) and fetal growth restriction (FGR) are pregnancy complications associated with morbidity in later life. Despite a growing body of evidence from current research on developmental origins of health and disease (DOHaD), little information is currently provided to parents on long-term metabolic, cardiovascular and neurologic consequences. As parents strongly rely on internet-based health-related information, we examined the quality of information on IUGR/FGR sequelae and DOHaD in webpages used by laypersons. Simulating non-clinicians experience, we entered the terms 'IUGR consequences' and 'FGR consequences' into Google and Yahoo search engines. The quality of the top search-hits was analyzed with regard to the certification through the Health On the Net Foundation (HON), currentness of cited references, while reliability of information and DOHaD-related consequences were assessed via the DISCERN Plus score (DPS). Overall the citation status was not up-to-date and only a few websites were HON-certified. The results of our analysis showed a dichotomy between the growing body of evidence regarding IUGR/FGR-related sequelae and lack of current guidelines, leaving parents without clear directions. Furthermore, detailed information on the concept of DOHaD is not provided. These findings emphasize the responsibility of the individual physician for providing advice on IUGR/FGR-related sequelae, monitoring and follow-up.
EVALuna2:34005

Second International Conference on a classification of ectodermal dysplasias: development of a multiaxis model - Salinas, Carlos F.; Irvine, Alan D.; Itin, Peter H.; Di Giovanna, John J.; Schneider, Holm; Clarke, Angus J.; Mcgovern, Laura Sternesky; Fete, Mary (American Journal of Medical Genetics Part A, 2014)
Ectodermal dysplasias (EDs) comprise a large clinically and etiologically heterogeneous group of genetic disorders characterized by abnormalities in tissues derived from the embryonic ectoderm. Controversy exists over which syndromes should be classified as EDs and which should be excluded from the classification. The challenge will be to balance comprehensiveness within the classification with usability and accessibility so that the benefits truly serve the needs of researchers, health-care providers, and ultimately the individuals and families directly affected by EDs. The overarching goal of the Second International Conference was to develop a consensus on EDs classifications, with the ultimate goal of creating a system that integrates clinical and molecular knowledge, using an interactive Internet-based database that clinicians, researchers, and laymen can use. The Conference, brought together a group of experts from around the world, including a diverse health-care providers, researchers, patient advocate representatives, and administrators. The Conference was modeled after the 2008 conference, with plenary sessions, scientific updates, and small group discussions. Based on the present clinical knowledge, new molecular advances and both coupled with new bioinformatics developments, the participants agree to develop a multi-axis system approach for the classification of EDs. The multi-axis approach will include a clinical/phenotype axis, a gene-based axis, and a functional/pathways axis. The significance of the conference outcomes includes, a new classification approach that will foster a better understanding of EDs, open new fields of research and develop a nosologic approach that may have broad implications for classifying other hereditary conditions.
EVALuna2:18896

Seizure-induced neuronal apoptosis is related to dysregulation of the RNA-edited GluR2 subunit in the developing mouse brain - Jung, Susan; Ballheimer, Yili Elisabeth; Brackmann, Florian; Zoglauer, Daniel; Geppert, Carol-Immanuel; Hartmann, Arndt; Trollmann, Regina (Brain Research, 2020)
Ca2+-permeable AMPA receptors (AMPAR) which crucially modify maturational programs of the developing brain are involved in seizure-induced glutamate excitotoxicity and apoptosis. Regulatory effects on AMPAR subunit composition and RNA-editing in the developing brain and their significance as therapeutic targets are not well understood. Here, we analyzed acute effects of recurrent pilocarpine-induced neonatal seizures on age- and region-specific expression of AMPAR subunits and adenosine deaminases (ADAR) in the developing mouse brain (P10). After recurrent seizure activity and regeneration periods of 6–72 h cerebral mRNA levels of GluR (glutamate receptor subunit) 1, GluR2, GluR3, and GluR4 were unaffected compared to controls. However, ratio of GluR2 and GluR4 to pooled GluR1-4 mRNA concentration significantly decreased in seizure-exposed brains in comparison to controls. After a regeneration period of 24–72 h ADAR1 and ADAR2 mRNA expression was significantly lower in seizure-exposed brains than in those of controls. This was confirmed at the protein level in the hippocampal CA3 region. We observed a regionally increased apoptosis (TUNEL+ and CC3+ cells) in the hippocampus, parietal cortex and subventricular zone of seizure-exposed brains in comparison to controls. Together, present in vivo data demonstrate the maturational age-specific, functional role of RNA-edited GluR2 in seizure-induced excitotoxicity in the developing mouse brain. In response to recurrent seizure activity, we observed reduced expression of GluR2 and the GluR2 mRNA-editing enzymes ADAR1 and ADAR2 accompanied by increased apoptosis in a region-specific manner. Thus, AMPA receptor subtype-specific mRNA editing is assessed as a promising target of novel neuroprotective treatment strategies in consideration of age-related developmental mechanisms.
CRIS-Team Scopus Importer:2020-03-17
Keywords: ADAR; Adenosine deaminases; Apoptosis; Brain injury; Experimental seizure model; Neonatal brain; Neurodegeneration; Neuroprotection; Pilocarpine; RNA editing

Seizure management and prescription patterns of anticonvulsants in Dravet syndrome: A multicenter cohort study from Germany and review of literature - Schubert-Bast, Susanne; Wolff, Markus; Wiemer-Kruel, Adelheid; von Spiczak, Sarah; Trollmann, Regina; Reif, Philipp S.; Pritchard, Clive; Polster, Tilman; Neubauer, Bernd A.; Mayer, Thomas; Macdonald, Daniel; Kurlemann, Gerhard; et al. (Epilepsy & Behavior, 2019)
Objective: The aim of this study was to describe the treatment pattern of patients with Dravet syndrome (DS) in Germany with routine antiepileptic drugs (AEDs) and emergency medication, and to review the literature of real-world evidence on medicine utilization of patients with DS in Europe. Methods: Patient use of routine AEDs and emergency medications over 3–6 months was analyzed from a 2018 multicenter survey of 93 caregivers of patients with DS throughout Germany. Results were contextualized in a review of real-world evidence on medicine utilization of patients with DS in Europe. Results: The variety of medications and the most frequent combinations routinely used by patients with DS (AEDs and others) are described. Patients use a large number of pharmaceutical treatments to manage seizures. The five most commonly used AEDs were sodium valproate (66% of the patients; mean daily dose: 660 mg; 24.5 mg per kg bodyweight), bromide (44%; 1462 mg; 51.2 mg per kg), clobazam (41%; 10.4 mg; 0.32 mg per kg), stiripentol (35%; 797 mg; 27.6 mg per kg), and topiramate (24%; 107 mg; 3.5 mg per kg). Ninety percent had reported using emergency medications in the last 3 months;, with the most common medications being Buccolam (40%, an oromucosal form of midazolam) and diazepam (20%, mostly rectal application). No discernable relationships between current medication and age or seizure frequency were observed. Significance: This is the first comprehensive report of routine AEDs and emergency medication use in a large sample of patients with DS in Germany over a period of 3–6 months and shows that despite the most common AED combinations being in line with clinical guidelines/best practice, there is no discernable impact of best treatment on seizure frequency. We find a higher use of bromide in Germany compared with other real-world evidence in Europe.
CRIS-Team Scopus Importer:2019-07-16
Keywords: Antiepileptic drugs; Benzodiazepines; Epilepsy; Severe myoclonic epilepsy of infants

Selecting A Digitization Device for Bone Marrow Aspirate Smears - Kock, Farina; Pontones, Martina; Ghete, Tabita; Metzler, Markus; Höfener, Henning (Laboratory Investigation, 2025)
The digitization of histologic specimens has become increasingly common within the last years; however, digitization of cytologic slides has its own challenges and there is little guidance on the optimal use of digitization devices for cytopathology. For the morphologic analysis of cells in, for example, bone marrow aspirate smears, different studies have used a variety of scanner setups and there is no direct comparison between those. This makes it nontrivial to choose an optimal scanner setup. This work pragmatically analyzes different whole-slide image scanners but also cost-effective light microscope solutions and identifies important aspects for the digitization of cytopathological samples. We aimed to share our experience in selecting a digitization device for generating a bone marrow aspirate data set.
CRIS-Team Scopus Importer:2025-03-28
Keywords: bone marrow aspirate smear; cytology; digitization; light microscope; whole-slide image scanner

Self-medication in children under the aspect of medication safety Selbstmedikation bei Kindern unter dem Aspekt der Arzneimitteltherapiesicherheit - Neubert, Antje; Schulze, Christopher (Monatsschrift Kinderheilkunde, 2022)
Background: Self-medication, also known as over the counter (OTC) medication, is generally understood as the use of drugs that do not require a doctor’s prescription. It is very often used for colds or pain and fever; however, the OTC status does not mean, as is often assumed, that these drugs can be used completely uncritically. Especially in children and adolescents, serious side effects repeatedly occur. Objective: This article investigates which drugs are often used in self-medication and describes which problems can arise in association with different indications. Material and methods: The article is based on a search and analysis of the current literature. Results and discussion: The most commonly used OTC drugs are cough and cold medicines, medicines used to treat pain and fever and medicines used to treat nausea. Herbal preparations play an important role in self-medication for cold remedies; however, these multisubstance preparations are not always harmless and, especially with combination therapies, a doctor or pharmacist should always be consulted. In addition, the use of both herbal and synthetic preparations is based on very limited scientific evidence. Decongestant preparations for the nose and drugs against nausea (H1 antihistamines) have been and are repeatedly associated with serious adverse effects, especially in young children and should therefore be used strictly according to the license. Pain and fever can be treated very well with ibuprofen or paracetamol. Monotherapy should always be preferred for self-medication.
CRIS-Team Scopus Importer:2022-03-11
Keywords: Adverse effects; Nonprescription drugs; Over the counter drugs; Plant preparations; Synthetic drugs

Sensor Fusion for the Robust Detection of Facial Regions of Neonates Using Neural Networks - Gleichauf, Johanna; Hennemann, Lukas; Fahlbusch, Fabian; Hofmann, Oliver; Niebler, Christine; Koelpin, Alexander (Sensors, 2023)
The monitoring of vital signs and increasing patient comfort are cornerstones of modern neonatal intensive care. Commonly used monitoring methods are based on skin contact which can cause irritations and discomfort in preterm neonates. Therefore, non-contact approaches are the subject of current research aiming to resolve this dichotomy. Robust neonatal face detection is essential for the reliable detection of heart rate, respiratory rate and body temperature. While solutions for adult face detection are established, the unique neonatal proportions require a tailored approach. Additionally, sufficient open-source data of neonates on the NICU is lacking. We set out to train neural networks with the thermal-RGB-fusion data of neonates. We propose a novel indirect fusion approach including the sensor fusion of a thermal and RGB camera based on a 3D time-of-flight (ToF) camera. Unlike other approaches, this method is tailored for close distances encountered in neonatal incubators. Two neural networks were used with the fusion data and compared to RGB and thermal networks. For the class “head” we reached average precision values of 0.9958 (RetinaNet) and 0.9455 (YOLOv3) for the fusion data. Compared with the literature, similar precision was achieved, but we are the first to train a neural network with fusion data of neonates. The advantage of this approach is in calculating the detection area directly from the fusion image for the RGB and thermal modality. This increases data efficiency by 66%. Our results will facilitate the future development of non-contact monitoring to further improve the standard of care for preterm neonates.
CRIS-Team Scopus Importer:2023-06-30
Keywords: face detection; neonates; neural network; non-contact monitoring; sensor fusion

Serial T2-Weighted Thoracic and Abdominal Lymphatic Imaging in Fontan Patients—New Insights into Dynamics of Lymphatic Abnormalities after Total Cavopulmonary Connection - Moosmann, Julia; Schroeder, Christian; Rompel, Oliver; Purbojo, Ariawan; Dittrich, Sven (Journal of Cardiovascular Development and Disease, 2022)
Lymphatic congestion in single-ventricle patients has been associated with increased morbidity and poor outcomes. Little is known about the dynamics of lymphatic abnormalities over time, on their association with clinical presentation or response to catheter interventions. This retrospective, single-center study describes Fontan patients who underwent at least two magnetic resonance imaging (MRI) studies. T2-weighted lymphatic imaging was used to classify thoracic and abdominal (para-aortic and portal-venous) lymphatic abnormalities. The relationship between lymphatic congestion and hemodynamic changes after cardiac catheter interventions, clinical presentation and MRI data was analyzed. A total of 33 Fontan patients underwent at least two cardiac MRI studies. Twenty-two patients had two, eight had three and three had four lymphatic imaging studies (total of 80 MRIs studies). No significant changes in lymphatic classification between MRI 1 and 2 were observed for thoracic (p = 0.400), para-aortic (0.670) and portal-venous (p = 0.822) abnormalities. No significant correlation between lymphatic classification and hemodynamic changes after intervention or MRI parameters was found. This study illustrates thoracic and abdominal lymphatic abnormalities in serial T2-weighted imaging after Fontan. Fontan patients did not demonstrate significant changes in their lymphatic perfusion, despite clinical or hemodynamic changes. We assume that lymphatic congestion might develop after total cavopulmonary connection (TCPC) and remain relatively stable, despite further intervention targeting hemodynamic parameters.
CRIS-Team Scopus Importer:2022-06-10
Keywords: Fontan; lymphatic abnormalities; magnetic resonance imaging; T2-weighted imaging

Serious Adverse Drug Reactions to Antipsychotics in Minors with Multiple Disabilities: Preventability and Potential Cost Savings by Therapeutic Drug Monitoring - Fekete, Stefanie; Guentzel, Tim; Egberts, Karin; Geissler, Julia; Neubert, Antje; Gerlach, Manfred; Romanos, Marcel; Taurines, Regina (Pharmacopsychiatry, 2022)
Introduction Children and adolescents with multiple disabilities and mental disorders (CAMD) are frequently treated with antipsychotic drugs. However, CAMD are particularly susceptible to serious adverse drug reactions (sADRs). This retrospective study examined the frequency of sADRs to antipsychotics in CAMD. Further, the potential preventability of these sADRs through therapeutic drug monitoring (TDM) and the potential socio-economic benefits of TDM were explored.Methods Routine clinical data of all patients treated at a specialized psychiatric clinic for CAMD between January 2017 and December 2018 were retrospectively examined. Data on the occurrence of sADRs (definition according to the European Medicines Agency), their causality with antipsychotics, as well as their preventability (Schumock criteria) were extracted from patient files. The prolongation of the hospital stay due to sADRs was calculated, and the cost savings were estimated if TDM had been applied. The data were based on a subsample of the KiDSafe project, supported by the Innovation Fund of the Joint Federal Committee, grant number 01NVF16021.Results One hundred two CAMD who were administered at least one antipsychotic drug during inpatient treatment were identified. Of these patients, 22 (21.6%) sADRs with a possible causal relationship with the antipsychotic treatment were documented. Eleven sADRs (50%) could potentially have been prevented through TDM. Mitigating sADRs through TDM likely would have prevented prolonged hospital stays and thus conferred considerable savings for health insurance companies.Discussion The routine implementation of TDM is urgently recommended for antipsychotic treatment in CAMD to increase drug therapy safety.
CRIS-Team WoS Importer:2022-11-25

Serum (1→3)-β-D-glucan and galactomannan levels in patients with cystic fibrosis: a retrospective cohort study - Traeger, Johannes; Melichar, Volker Otto; Meyer, Renate; Rauh, Manfred; Bogdan, Christian; Held, Jürgen (BMC Pulmonary Medicine, 2018)
BACKGROUND: Aspergillus fumigatus is frequently encountered in sputum samples of patients with cystic fibrosis (CF), which traditionally has been interpreted as saprophytic airway colonization. However, this mere bystander role has been challenged by recent data. There is now evidence that Aspergillus fumigatus accelerates the decline of pulmonary function. (1→3)-β-D-glucan (BDG) and galactomannan (GM) are highly sensitive fungal biomarkers that are used to diagnose invasive fungal disease. However, their diagnostic value in CF patients is largely unknown. METHODS: We conducted a retrospective cohort study on 104 CF patients to determine whether serum BDG and GM levels correlate with parameters such as Aspergillus-positive sputum cultures and lung function. RESULTS: Aspergillus fumigatus was persistently detected in 22 of the 104 CF patients (21%). Mean serum BDG and GM levels in the Aspergillus-positive patients were significantly higher than in those without persistent Aspergillus detection (89 versus 40 pg/ml [p = 0.022] and 0.30 versus 0.15 ODI [p = 0.013], respectively). 27 and 7 patients had elevated BDG (≥ 60 pg/ml) or GM levels (> 0.5 ODI), respectivly. BDG and GM levels showed a significant correlation (p = 0.004). Patients with increased serum concentrations of BDG were more frequently Aspergillus-positive (40.7 versus 14.3%, p = 0.004) and had a significantly lower forced expiratory volume in one second (FEV1) than patients with a normal BDG (61.6 versus 77.1%, p = 0.007). In the multivariate analysis, BDG but not GM or the growth of A. fumigatus, proved to be an independent predictor for the FEV1. CONCLUSIONS: CF patients with persistent Aspergillus detection have elevated BDG and GM levels which ranged between healthy and invasively infected patients. Serum BDG may be superior to GM and fungal culture in predicting an impaired lung function in CF patients.
EVALuna2:35821

Severe bullous pemphigoid in a 4-month-old infant - Holtsche, Maike M.; van Beek, Nina; Vorobyev, Artem; Schmidt, Enno; Lauten, Melchior; Wagner, Nicola; Krickau, Tobias; Anemüller, Waltraud (Journal der Deutschen Dermatologischen Gesellschaft, 2024)
CRIS-Team Scopus Importer:2024-07-26

Severe heart failure and the need for mechanical circulatory support and heart transplantation in pediatric patients with myocarditis: Results from the prospective multicenter registry “MYKKE” - Schubert, Stephan; Opgen-Rhein, Bernd; Boehne, Martin; Weigelt, Annika; Wagner, Robert; Mueller, Goetz; Rentzsch, Axel; Zu Knyphausen, Edzard; Fischer, Marcus; Papakostas, Konstantin; Wiegand, Gesa; Ruf, Bettina; et al. (Pediatric Transplantation, 2019)
Myocarditis represents an important cause for acute heart failure. MYKKE, a prospective multicenter registry of pediatric patients with myocarditis, aims to gain knowledge on courses, diagnostics, and therapy of pediatric myocarditis. The role of mechanical circulatory support (MCS) in children with severe heart failure and myocarditis is unclear. The aim of this study was to determine characteristics and outcome of patients with severe heart failure requiring MCS and/or heart transplantation. The MYKKE cohort between September 2013 and 2016 was analyzed. A total of 195 patients were prospectively enrolled by 17 German hospitals. Twenty-eight patients (14%) received MCS (median 1.5 years), more frequently in the youngest age group (0-2 years) than in the older groups (P < 0.001; 2-12 and 13-18 years). In the MCS group, 50% received a VAD, 36% ECMO, and 14% both, with a survival rate of 79%. The weaning rate was 43% (12/28). Nine (32%) patients were transplanted, one had ongoing support, and six (21%) died. Histology was positive for myocarditis in 63% of the MCS group. Patients within the whole cohort with age <2 years and/or ejection fraction <30% had a significantly worse survival with high risk for MCS, transplantation, and death (P < 0.001). Myocarditis represents a life-threatening disease with an overall mortality of 4.6% in this cohort. The fulminant form more often affected the youngest, leading to significantly higher rate of MCS, transplantation, and mortality. MCS represents an important and life-saving therapeutic option in children with myocarditis with a weaning rate of 43%.
CRIS-Team Scopus Importer:2019-07-23
Keywords: MCS; myocarditis; pediatric; transplantation

Severe neurological outcomes after very early bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) - Burgmaier, Kathrin; Ariceta, Gema; Bald, Martin; Buescher, Anja Katrin; Burgmaier, Mathias; Erger, Florian; Gessner, Michaela; Gokce, Ibrahim; König, Jens; Kowalewska, Claudia; Massella, Laura; Mastrangelo, Antonio; et al. (Scientific Reports, 2020)
To test the association between bilateral nephrectomies in patients with autosomal recessive polycystic kidney disease (ARPKD) and long-term clinical outcome and to identify risk factors for severe outcomes, a dataset comprising 504 patients from the international registry study ARegPKD was analyzed for characteristics and complications of patients with very early (≤ 3 months; VEBNE) and early (4–15 months; EBNE) bilateral nephrectomies. Patients with very early dialysis (VED, onset ≤ 3 months) without bilateral nephrectomies and patients with total kidney volumes (TKV) comparable to VEBNE infants served as additional control groups. We identified 19 children with VEBNE, 9 with EBNE, 12 with VED and 11 in the TKV control group. VEBNE patients suffered more frequently from severe neurological complications in comparison to all control patients. Very early bilateral nephrectomies and documentation of severe hypotensive episodes were independent risk factors for severe neurological complications. Bilateral nephrectomies within the first 3 months of life are associated with a risk of severe neurological complications later in life. Our data support a very cautious indication of very early bilateral nephrectomies in ARPKD, especially in patients with residual kidney function, and emphasize the importance of avoiding severe hypotensive episodes in this at-risk cohort.
CRIS-Team Scopus Importer:2020-10-16

Severe T-System Remodeling in Pediatric Viral Myocarditis - Fiegle, Dominik; Schober, Martin; Dittrich, Sven; Cesnjevar, Robert; Klingel, Karin; Volk, Tilmann; Alkassar, Muhannad; Seidel, Thomas (Frontiers in Cardiovascular Medicine, 2021)
Chronic heart failure (HF) in adults causes remodeling of the cardiomyocyte transverse tubular system (t-system), which contributes to disease progression by impairing excitation-contraction (EC) coupling. However, it is unknown if t-system remodeling occurs in pediatric heart failure. This study investigated the t-system in pediatric viral myocarditis. The t-system and integrity of EC coupling junctions (co-localization of L-type Ca2+ channels with ryanodine receptors and junctophilin-2) were analyzed by 3D confocal microscopy in left-ventricular (LV) samples from 5 children with myocarditis (age 14 +/- 3 months), undergoing ventricular assist device (VAD) implantation, and 5 children with atrioventricular septum defect (AVSD, age 17 +/- 3 months), undergoing corrective surgery. LV ejection fraction (EF) was 58.4 +/- 2.3% in AVSD and 12.2 +/- 2.4% in acute myocarditis. Cardiomyocytes from myocarditis samples showed increased t-tubule distance (1.27 +/- 0.05 mu m, n = 34 cells) and dilation of t-tubules (volume-length ratio: 0.64 +/- 0.02 mu m(2)) when compared with AVSD (0.90 +/- 0.02 mu m, p < 0.001; 0.52 +/- 0.02 mu m(2), n = 61, p < 0.01). Intriguingly, 4 out of 5 myocarditis samples exhibited sheet-like t-tubules (t-sheets), a characteristic feature of adult chronic heart failure. The fraction of extracellular matrix was slightly higher in myocarditis (26.6 +/- 1.4%) than in AVSD samples (24.4 +/- 0.8%, p < 0.05). In one case of myocarditis, a second biopsy was taken and analyzed at VAD explantation after extensive cardiac recovery (EF from 7 to 56%) and clinical remission. When compared with pre-VAD, t-tubule distance and density were unchanged, as well as volume-length ratio (0.67 +/- 0.04 mu m(2) vs. 0.72 +/- 0.05 mu m(2), p = 0.5), reflecting extant t-sheets. However, junctophilin-2 cluster density was considerably higher (0.12 +/- 0.02 mu m(-3) vs. 0.05 +/- 0.01 mu m(-3), n = 9/10, p < 0.001), approaching values of AVSD (0.13 +/- 0.05 mu m(-3), n = 56), and the measure of intact EC coupling junctions showed a distinct increase (20.2 +/- 5.0% vs. 6.8 +/- 2.2%, p < 0.001). Severe t-system loss and remodeling to t-sheets can occur in acute HF in young children, resembling the structural changes of chronically failing adult hearts. T-system remodeling might contribute to cardiac dysfunction in viral myocarditis. Although t-system recovery remains elusive, recovery of EC coupling junctions may be possible and deserves further investigation.
CRIS-Team WoS Importer:2021-02-19

Sex chromosome DSD individuals with mosaic 45,X0 and aberrant Y chromosomes in 46,XY cells: distinct gender phenotypes and germ cell tumour risks§ - Vogt, Peter H.; Besikoglu, Banu; Bettendorf, Markus; Frank-Herrmann, Petra; Zimmer, Jutta; Bender, Urike; Knauer-Fischer, Sabine; Choukair, Daniela; Sinn, Peter; Dörr, Helmuth-Günther; Wölfle, Joachim; Heidemann, Peter H.; et al. (Systems Biology in Reproductive Medicine, 2022)
“Differences of Sexual Development (DSD),” individuals with rearranged Y chromosome breaks in their 46,XY cells are reported with male and female gender phenotypes and differences in germ cell tumour (GCT) risk. This raised the question of whether male or female gender and GCT risk depends on the site of the break and/or rearrangement of the individual´s Y chromosome. In this paper, we report molecular mapping of the breakpoint on the aberrant Y chromosome of 22 DSD individuals with a 45,X/46,XY karyotype reared with a different gender. Their Y chromosome breaks are found at different sites on the long and short Y arms. Our data indicate that gender rearing is, neither dependent on the site of Y breakage, nor on the amount of 45,X0 cells in the individuals' leukocytes. Most prominent are secondary rearrangements of the Y chromosome breaks forming di-centric Y-structures (“dic-Y”). Duplications of the short Y arm and the proximal part of the long Y arm are the results. A putative GCT risk has been analysed with immunohistochemical experiments on some dysgenetic gonadal tissue sections. With specific antibodies for OCT3/4 expression, we marked the pluripotent germ cell fraction being potential tumour precursor cells. With specific antibodies for DDX3Y, TSPY, and UTY we analyzed their putative Gonadoblastoma Y (GBY) tumour susceptibility function in the same specimen. We conclude GBY expression is only diagnostic for GCT development in the aberrant germ cells of these DSD individuals when strong OCT3/4 expression has marked their pluripotency.
CRIS-Team Scopus Importer:2022-05-27
Keywords: 45X/46XY mosaic DSD; di-centric Y chromosome; Germ cell tumour risk; OCT3/4 expression GBY expression

Sex differences in long-term kidney fibrosis following neonatal nephron loss during ongoing nephrogenesis - Menendez-Castro, Carlos; Cordasic, Nada; Fahlbusch, Fabian; Wölfle, Joachim; Hilgers, Karl Friedrich; Hartner, Andrea (Molecular and Cellular Pediatrics, 2023)
Background: Clinical studies suggest that female sex plays a protective role in the development and progression of kidney disease. Recent experimental studies indicate that in male rats early nephron loss under ongoing nephrogenesis is accompanied by severe long-term sequelae. In humans, nephron formation occurs mainly in the third trimester, ceasing with 36 weeks of gestation. Due to perinatal complications, preterm infants delivered during this vulnerable period may undergo acute nephron loss. In rats nephrogenesis persists until postnatal day 10, reflecting the situation of human preterms with persisting nephrogenesis. In our animal model of neonatal uninephrectomy, female and male rats were uninephrectomized at day 1 of life. Hypothesizing sex-dependent differences, long-term renal outcome was assessed after 1 year. Results: In both sexes, neonatal uninephrectomy was not followed by arterial hypertension at 1 year of age. Compensatory weight gain and glomerular hypertrophy of the remaining kidney occurred in uninephrectomized female and male animals. Selected markers of interstitial inflammation and fibrosis were regulated sex-dependently. The expression of monocyte chemoattractant protein-1 was increased in females, while tubulointerstitial infiltration by M1 macrophages was significantly higher in males after neonatal uninephrectomy. Neonatally uninephrectomized male rats had more glomerulosclerosis and podocyte damage compared to females, which was assessed by a semiquantitative score and desmin staining. RT-PCR revealed that after neonatal uninephrectomy in the remaining contralateral kidney of female rats the expression of candidate genes of renal development and function, i.e., wt-1, nephrin, synaptopodin, gdnf, and itga8 was higher than in males. Conclusions: Based on these observations we conclude that female sex is protective in the long-term response of the kidney to acute nephron loss under active nephrogenesis.
CRIS-Team Scopus Importer:2023-09-08
Keywords: Kidney fibrosis; Neonatal nephron loss; Neonatal uninephrectomy; Nephrogenesis; Sex differences

Sex differences in the development of vascular and renal lesions in mice with a simultaneous deficiency of Apoe and the integrin chain Itga8 - Marek, Ines; Canu, Maurizio; Cordasic, Nada; Rauh, Manfred; Volkert, Gudrun; Fahlbusch, Fabian B.; Rascher, Wolfgang; Hilgers, Karl Friedrich; Hartner, Andrea; Menendez-Castro, Carlos (Biology of Sex Differences, 2017)
BACKGROUND: Apoe-deficient (Apoe-/-) mice develop progressive atherosclerotic lesions with age but no severe renal pathology in the absence of additional challenges. We recently described accelerated atherosclerosis as well as marked renal injury in Apoe-/- mice deficient in the mesenchymal integrin chain Itga8 (Itga8-/-). Here, we used this Apoe-/-, Itga8-/- mouse model to investigate the sex differences in the development of atherosclerosis and concomitant renal injury. We hypothesized that aging female mice are protected from vascular and renal damage in this mouse model. METHODS: Apoe-/- mice were backcrossed with Itga8-/- mice. Mice were kept on a normal diet. At the age of 12 months, the aortae and kidneys of male and female Apoe-/-Itga8+/+ mice or Apoe-/-Itga8-/- mice were studied. En face preparations of the aorta were stained with Sudan IV (lipid deposition) or von Kossa (calcification). In kidney tissue, immunostaining for collagen IV, CD3, F4/80, and PCNA and real-time PCR analyses for Il6, Vegfa, Col1a1 (collagen I), and Ssp1 (secreted phosphoprotein 1, synonym osteopontin) as well as ER stress markers were performed. RESULTS: When compared to male mice, Apoe-/-Itga8+/+ female mice had a lower body weight, equal serum cholesterol levels, and lower triglyceride levels. However, female mice had increased aortic lipid deposition and more aortic calcifications than males. Male Apoe-/- mice with the additional deficiency of Itga8 developed increased serum urea, glomerulosclerosis, renal immune cell infiltration, and reduced glomerular cell proliferation. In females of the same genotype, these renal changes were less pronounced and were accompanied by lower expression of interleukin-6 and collagen I, while osteopontin expression was higher and markers of ER stress were not different. CONCLUSIONS: In this model of atherosclerosis, the female sex is a risk factor to develop more severe atherosclerotic lesions, even though serum fat levels are higher in males. In contrast, female mice are protected from renal damage, which is accompanied by attenuated inflammation and matrix deposition. Thus, sex affects vascular and renal injury in a differential manner.
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Sharing of decision-making for infective endocarditis surgery: a narrative review of clinical and ethical implications - Pollari, Francesco; Spadaccio, Cristiano; Cuomo, Michela; Chello, Massimo; Nenna, Antonio; Fischlein, Theodor; Nappi, Francesco (Annals of Translational Medicine, 2020)
Infective endocarditis (IE) is nowadays one of the most challenging disease in cardiac surgery because of its multifaceted clinical and anatomical presentation. Despite the many clinical and surgical advances achieved in the past 60 years, there is a lack of evidence regarding the ideal strategy. The present review aims to investigate and highlight two main novel concepts for the decision-making of the best substitute. Firstly, the concept of an "endocarditis team": a coordinated multidisciplinary effort in the diagnostic work-up, especially in conditions of high risk of embolization or clinical deterioration. A good "endocarditis team" has the role to overcome such problem, in order to ensure a prompt and balanced strategy. Secondly, which ethical considerations are required to drive the choice of valvular substitute. The choice of best valve substitute is a relevant issue of debate, not only with operative but also prognostic and accordingly ethical aftermaths. Many different solutions have been developed to substitute the infected valve. Among these: mechanical prosthesis (MP), biological stented prosthesis (BP), sutureless bioprosthesis and cryopreserved homografts (CHs). Patients need to be informed in detail about the technical issues pertaining the use of these valve substitute. We will discuss the evidences regarding the risk of recurrent infections or future potentially severe calcification of aortic homograft valve and wall (in other words, the failure of the homograft) and the difficulties in managing the reoperation.
CRIS-Team WoS Importer:2021-01-15

Shedding light on pediatric diseases: multispectral optoacoustic tomography at the doorway to clinical applications. - Regensburger, Adrian; Wagner, Alexandra; Claussen, Jing; Waldner, Maximilian; Knieling, Ferdinand (Molecular and Cellular Pediatrics, 2020)
Optoacoustic imaging (OAI), or photoacoustic imaging (PAI), has fundamentally influenced basic science by providing high-resolution visualization of biological mechanisms. With the introduction of multispectral optoacoustic tomography (MSOT), these technologies have now moved closer to clinical applications. MSOT utilizes short-pulsed near-infrared laser light to induce thermoelastic expansion in targeted tissues. This results in acoustic pressure waves, which are used to resolve specific endo- and exogenous chromophores. Especially in the pediatric population, this non-invasive imaging approach might hold fundamental advantages compared to conventional cross-sectional imaging modalities. As this technology allows the visualization of quantitative molecular tissue composition at high spatial resolution non-invasively in sufficient penetration depth, it paves the way to personalized medicine in pediatric diseases.
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Short and Long Term Outcome for Patients with Surgical Removal of Sacrococcygeal Teratoma in Newborns and Infancy - Ai, Maria; Schellerer, Vera; Besendörfer, Manuel (ONCOLOGY RESEARCH AND TREATMENT, 2020)
CRIS-Team WoS Importer:2020-03-20

Short Children with CHARGE Syndrome: Do They Benefit from Growth Hormone Therapy? - Dörr, Helmuth-Günther; Boguszewski, Margaret; Dahlgren, Jovanna; Dunger, David; Geffner, Mitchell E.; Hokken-Koelega, Anita C.; Lindberg, Anders; Polak, Michel; Rooman, Raoul (Hormone Research in Paediatrics, 2015)
The aim of this study was to evaluate the response to recombinant growth hormone (GH) treatment in short children with CHARGE syndrome.We identified 51 children (28 boys and 23 girls) in KIGS (Pfizer International Growth Database). The median chronological age was 7.6 years at the start of GH therapy and 13.2 years at the latest visit. Evaluation for GH deficiency (n = 33) was based on the following: peak GH level 7.3 ?g/l and IGF-I level -2.01 standard deviation score (SDS). Sixteen subjects (9 boys) were followed longitudinally for 2 years.Birth length (median SDS, -0.47) and weight (-0.97) were slightly reduced. At the start of GH therapy, height was -3.6 SDS, BMI -0.7 SDS, and the GH dose was 0.26 mg/kg/week. At the latest visit after 2.7 years of GH therapy, height had increased to -2.2 SDS and BMI to -0.5 SDS. In the longitudinal group, height increased from -3.72 SDS at the start of GH therapy to -2.92 SDS after 1 year to -2.37 SDS after 2 years of therapy (start - 2 years: p < 0.05), height velocity increased from -1.69 to 2.98 to 0.95 SDS, and BMI and GH dose (mg/kg/week) remained almost unchanged.Our data show a positive effect of conventional doses of GH on short-term growth velocity for the longitudinal as well as for the total group, without any safety issues.
EVALuna2:18915

Shortcut learning leads to sex bias in deep learning models for photoacoustic tomography - Knopp, Marcel; Bender, Christoph J.; Holzwarth, Niklas; Li, Yi; Kempf, Julius; Caranovic, Milenko; Knieling, Ferdinand; Lang, Werner; Rother, Ulrich; Seitel, Alexander; Maier-Hein, Lena; Dreher, Kris K. (International Journal of Computer Assisted Radiology and Surgery, 2025)
Purpose: Shortcut learning has been identified as a source of algorithmic unfairness in medical imaging artificial intelligence (AI), but its impact on photoacoustic tomography (PAT), particularly concerning sex bias, remains underexplored. This study investigates this issue using peripheral artery disease (PAD) diagnosis as a specific clinical application. Methods: To examine the potential for sex bias due to shortcut learning in convolutional neural network (CNNs) and assess how such biases might affect diagnostic predictions, we created training and test datasets with varying PAD prevalence between sexes. Using these datasets, we explored (1) whether CNNs can classify the sex from imaging data, (2) how sex-specific prevalence shifts impact PAD diagnosis performance and underdiagnosis disparity between sexes, and (3) how similarly CNNs encode sex and PAD features. Results: Our study with 147 individuals demonstrates that CNNs can classify the sex from calf muscle PAT images, achieving an AUROC of 0.75. For PAD diagnosis, models trained on data with imbalanced sex-specific disease prevalence experienced significant performance drops (up to 0.21 AUROC) when applied to balanced test sets. Additionally, greater imbalances in sex-specific prevalence within the training data exacerbated underdiagnosis disparities between sexes. Finally, we identify evidence of shortcut learning by demonstrating the effective reuse of learned feature representations between PAD diagnosis and sex classification tasks. Conclusion: CNN-based models trained on PAT data may engage in shortcut learning by leveraging sex-related features, leading to biased and unreliable diagnostic predictions. Addressing demographic-specific prevalence imbalances and preventing shortcut learning is critical for developing models in the medical field that are both accurate and equitable across diverse patient populations.
CRIS-Team Scopus Importer:2025-05-16
Keywords: Peripheral artery disease (PAD); Photoacoustic tomography (PAT); Sex Bias in AI; Shortcut learning

Short-term adverse effects of testosterone used for priming in prepubertal boys before growth hormone stimulation test - Albrecht, Andrea; Penger, Theresa; Marx, Martin; Hirsch, Karin; Dörr, Helmuth-Günther (Journal of Pediatric Endocrinology & Metabolism, 2018)
BACKGROUND: Despite the fact that priming with sex steroids in prepubertal children before growth hormone (GH) provocative tests is recommended, there is an ongoing controversial discussion about the appropriate age of the children, the drug used for priming, the dose and the period between priming and the GH test. Interestingly, there is no discussion on the safety of this procedure. To date, only little data have been available on the possible side effects of priming with testosterone. METHODS: We analyzed the outcome in 188 short-statured prepubertal boys who had been primed with testosterone enanthate (n=136: 50 mg; n=51: 125 mg, and accidentally one boy with 250 mg) 7 days prior to the GH test. Serum testosterone levels were measured on the day of the GH test in 99 boys. RESULTS: Overall, only five boys developed adverse side effects. Two boys (dose 125 mg) showed severe low-flow priapism and had to undergo decompression of the corpora cavernosa. One boy suffered from self-limiting priapism and testicular pain (dose 50 mg). Two patients reported testicular pain (each dose 50 mg). The single patient with 250 mg testosterone did not show any adverse effects. The total side effect rate was 2.7%. The serum testosterone levels of the boys with side effects were not different from the testosterone levels of the boys without any side effects. CONCLUSIONS: Parents and patients should be informed about the possible side effects of priming with testosterone such as priapism and testicular pain. However, the overall side effect rate is low. We found no correlation between the outcome and the testosterone dose used and/or the level of serum testosterone.
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Short-term response of metabolic hormones to coronary artery bypass surgery - Nemeth, Adam; Cziraki, Attila; Sulyok, Endre; Horvath, Ivan Gabor; Alotti, Nasri; Rauh, Manfred; Rascher, Wolfgang; Szabados, Sandor (Advances in Medical Sciences, 2014)
To explore the response pattern of plasma adipokine and ghrelin levels to coronary artery bypass graft (CABG) surgery in patients with (on-pump) and without (off-pump) cardiopulmonary bypass (CPB).Sixteen consecutive patients (age: 62 ± 10 years, male: 10) with obstructive coronary artery disease (CAD) who underwent elective CABG surgery with CPB and intraoperative GIK infusion were selected for on-pump group and 19 CAD patients (age: 63 ± 10 years, male: 16) were included in the off-pump group. Blood samples were taken before, during and after surgery. Intraoperative samples were withdrawn simultaneously for peripheral vein and sinus coronarius (SC). Plasma adipokine concentrations were measured by ELISA, those of ghrelin by RIA kits.In response to surgical intervention there was an early, transient fall in plasma levels of adiponectin (p<0.0001) and resistin (p=0.002) followed by an increase to approach their initial values. Plasma ghrelin also increased (p=0.045), this increase, however, was confined to the period of GIK supported CPB. Plasma insulin (p=0.003) and resistin (p=0.009) was significantly higher in the peripheral vein than in SC. The perioperative hormone profile of patients without CPB (off-pump) proved to be comparable to that of on-pump patients in spite of the insulin administration and greater oxidative and inflammatory stress.Adipose tissue-derived factors appear to mediate the metabolic and vascular changes that occur in patients with CABG surgery. Epicardial adipose tissue is unlikely to have major contribution to the development of CAD as adipokines are not elevated in SC independent of the mode of intervention.
EVALuna2:18893

Short-term safety results from compassionate use of risdiplam in patients with spinal muscular atrophy in Germany - Hahn, Andreas; Guenther, Rene; Ludolph, Albert; Schwartz, Oliver; Trollmann, Regina; Weydt, Patrick; Weiler, Markus; Neuland, Kathrin; Schwaderer, Martin Sebastian; Hagenacker, Tim (Orphanet Journal of Rare Diseases, 2022)
Background The oral, selective SMN2-splicing modifier risdiplam obtained European approval in March 2021 for the treatment of patients >= 2 months old with a clinical diagnosis of 5q-associated spinal muscular atrophy (SMA) 1/2/3 or with 1-4 SMN2 gene copies. For the preceding 12 months, this compassionate use program (CUP) made risdiplam available to patients with SMA1/2 in Germany who could not receive any approved SMA therapy. Patients and methods Patients with SMA1/2, aged >= 2 months at enrollment, could be included if they were not eligible for, no longer responsive to, or not able to tolerate nusinersen or not able to receive onasemnogene abeparvovec. Oral risdiplam dosing ranged from 0.2 mg/kg to 5 mg depending on age and weight. All treatment decisions were made by the attending physicians, who were required to report all adverse events (AEs). Results Between March 12, 2020 and March 30, 2021, 36 patients with SMA1 and 98 patients with SMA2 were enrolled, with 31 patients and 80 patients receiving >= 1 risdiplam dose, respectively. The median (range) age was 10.5 (3-52) years in the SMA1 cohort, and 26.5 (3-60) years in the SMA2 cohort. 22.2% of patients with SMA1 and 48.0% with SMA2 were treatment-naive. Most patients were not eligible/could not continue to receive nusinersen due to scoliosis/safety risk (SMA1: 75.0%; SMA2: 96.9%), risks associated with sedation (77.8%; 63.3%), or loss of efficacy (30.6%; 12.2%). Safety data were generally in line with the safety profile of risdiplam in ongoing clinical studies. Gastrointestinal disorders were the most common AEs. For patients with SMA1, 30 AEs were reported in 13 cases with 2 serious AEs in 1 patient. For SMA2, 100 AEs were documented in 31 case reports, including 8 serious AEs in 2 patients. Conclusions We present the first real-world safety data of risdiplam in patients with SMA in Germany. Our observations indicated no new safety signals under real-world conditions. Real-world SMA1/2 populations comprise considerable numbers of patients who are not eligible for gene therapy and cannot tolerate or have failed nusinersen treatment. This medical need may be addressed by oral risdiplam.
CRIS-Team WoS Importer:2022-07-29

SIADH as a Rare Complication of Foramen Magnum Stenosis in an Infant With Achondroplasia. - Cebeci, Ayse Nurcan; Hébert, Steven; Reutter, Heiko Martin; Rompel, Oliver; Wölfle, Joachim (JCEM Case Reports, 2024)
Achondroplasia is the most common skeletal dysplasia and is associated with serious complications such as foramen magnum stenosis (FMS). This case report describes an infant with achondroplasia who presented with a syndrome of inappropriate antidiuretic hormone secretion (SIADH), secondary to significant FMS and myelocompression. A 2-month-old boy with prenatally diagnosed achondroplasia was referred due to disordered breathing and altered consciousness. On admission, apathy, hypotonus, and hypothermia with typical features of achondroplasia were noticed. Laboratory investigations revealed severe hyponatremia and hypochloridaemia with normal glucose and urea levels. The diagnosis of SIADH was made based on low serum osmolality in the presence of high urine osmolality, along with an elevated copeptin level. An emergency computerized tomography showed a high-grade stenosis at the cranio-cervical junction; subsequent magnetic resonance imaging demonstrated myelocompression. The patient underwent decompression surgery the next day; serum osmolality increased after the operation. Spontaneous breathing after extubation was sufficient whereas tetraplegia persisted despite intensive physiotherapy. Clinicians should be aware of SIADH as a presenting sign of FMS in children with achondroplasia. Further discussion is warranted regarding improving parental education and timing of screening recommendations.
EVALuna2:582017

SIADH as presenting feature of foramen magnum stenosis in a 2-month-old infant with achondroplasia (ACH): case report and discussion on management of infants with ACH in order to reduce the risk of serious complications - Cebeci, Ayse Nurcan; Hébert, Steven; Reutter, Heiko Martin; Wölfle, Joachim (HORMONE RESEARCH IN PAEDIATRICS, 2022)
CRIS-Team WoS Importer:2022-10-07

Sickle cell disease in Germany: Results from a national registry - Kunz, Joachim B.; Lobitz, Stephan; Grosse, Regine; Oevermann, Lena; Hakimeh, Dani; Jarisch, Andrea; Cario, Holger; Beier, Rita; Schenk, Daniela; Schneider, Dominik; Gross-Wieltsch, Ute; Prokop, Aram; et al. (Pediatric Blood & Cancer, 2019)
Background Limited data on the prevalence and medical care of sickle cell disease (SCD) in Germany are available. Here, we make use of a patient registry to characterize the burden of disease and the treatment modalities for patients with SCD in Germany. Procedure A nationwide German registry for patients with SCD documents basic data on diagnosis and patient history retrospectively at the time of registration. A prospective annual documentation provides more details on complications and treatment of SCD. For the current analyses, data of 439 patients were available. Results Most patients had homozygous SCD (HbSS 75.1%, HbS/beta-thalassemia 13.2%, and HbSC 11.3%). The median age at diagnosis was 1.9 years (interquartile range, 0.6-4.4 years), most patients were diagnosed when characteristic symptoms occurred. Sepsis and stroke had affected 3.2% and 4.2% of patients, respectively. During the first year of observation, 48.3% of patients were admitted to a hospital and 10.1% required intensive care. Prophylactic penicillin was prescribed to 95.6% of patients with homozygous SCD or HbS/beta thalassemia below the age of six and hydroxycarbamide to 90.4% of patients above the age of two years. At least one annual transcranial Doppler ultrasound was documented for 74.8% of patients between 2 and 18 years. Conclusion With an estimated number of at least 2000, the prevalence of SCD in Germany remains low. Prospectively, we expect that the quality of care for children with SCD will be further improved by an earlier diagnosis after the anticipated introduction of a newborn screening program for SCD.
CRIS-Team WoS Importer:2020-01-07

Side Effects and Sequelae of Treatment for Chronic Myeloid Leukemia in Childhood and Adolescence - Suttorp, Meinolf; Metzler, Markus (Springer International Publishing, 2020)
Targeted therapy by tyrosine kinase inhibitors (TKIs) has dramatically improved survival rates in CML. Today stem cell transplantation is no longer the first-line treatment also in children. However, in the majority of patients, TKIs probably have to be administered over decades to control instead of eradicating completely the malignant cell clone. Thus, CML nowadays has to be regarded in sensu stricto as “chronic” which is in sharp contrast to the other pediatric malignancies dealt with in the context of this book. Lifelong TKI administration requires assessment of any side or “late” effect as a possible “untargeted consequence of a targeted treatment, " which represents a novelty in pediatric oncology. Systematic investigations on TKI late effects in adults are missing, and the cumulative toxicity of ongoing exposure in a growing organism with regard to young and old adulthood is presently hard to be judged on. Side effects so far observed include longitudinal growth impairment, disturbed osseous metabolism, endocrine alterations (hyperparathyroidism, low vitamin D, low growth hormone, altered thyroid metabolism, blood glucose level, impaired fertility), and cardiovascular side effects. Any change in laboratory findings or reported health problems should as causative agent take TKIs into consideration. Most TKIs are substrates and inhibitors of cytochrome P450. If patients are treated with polypharmacy because of TKI side effects or other underlying diseases, drug-drug interactions are always a significant safety concern. While men wanting to become fathers can safely remain on imatinib, women of childbearing potential must be advised on the teratogenic potential of all TKIs. Thus, proper contraception should start early in teenagers. Future strategies including new drugs or vaccination targeting specifically at CML stem cells are currently being explored. First results look promising; however, it seems not unlikely that side effects and late effects may also be associated with these new approaches.
CRIS-Team Scopus Importer:2024-12-16

Side effects of radiotherapy in breast cancer patients : The Internet as an information source - Janssen, S.; Kaesmann, L.; Fahlbusch, F. B.; Rades, D.; Vordermark, D. (Strahlentherapie und Onkologie, 2018)
AIM: Breast cancer is the most common cancer type among women necessitating adjuvant radiotherapy. As the Internet has become a major source of information for cancer patients, this study aimed to evaluate the quality of websites giving information on side effects of radiotherapy for breast cancer patients. METHODS: A patients' search for the English terms "breast cancer - radiotherapy - side effects" and the corresponding German terms "Brustkrebs - Strahlentherapie - Nebenwirkungen" was carried out twice (5 months apart) using the search engine Google. The first 30 search results each were evaluated using the validated 16-question DISCERN Plus instrument, the Health on the Net Code of Conduct (HONcode) certification and the Journal of the American Medical Association (JAMA) benchmark criteria. The overall quality (DISCERN score) of the retrieved websites was further compared to queries via Bing and Yahoo search engines. RESULTS: The DISCERN score showed a great range, with the majority of websites ranking fair to poor. Significantly superior results were found for English websites, particularly for webpages run by hospitals/universities and nongovernmental organizations (NGO), when compared to the respective German categories. In general, only a minority of websites met all JAMA benchmarks and was HONcode certified (both languages). We did not determine a relevant temporal change in website ranking among the top ten search hits, while significant variation occurred thereafter. Mean overall DISCERN score was similar between the various search engines. CONCLUSION: The Internet can give breast cancer patients seeking information on side effects of radiotherapy an overview. However, based on the currently low overall quality of websites and the lack of transparency for the average layperson, we emphasize the value of personal contact with the treating radio-oncologist in order to integrate and interpret the information found online.
EVALuna2:34297

Significant advantages for first line treatment with TNF-alpha inhibitors in pediatric patients with inflammatory bowel disease – Data from the multicenter CEDATA-GPGE registry study - Claßen, Merle; de Laffolie, Jan; Claßen, Martin; Schnell, Alexander; Sohrabi, Keywan; Hörning, André (Frontiers in Pediatrics, 2022)
Background and aims: In recent years, biological agents, such as anti-TNF-α blockers, have been introduced and have shown efficacy in pediatric patients with inflammatory bowel disease (IBD). Here, the prescription mode differentiated into a first/second line application, and efficacy and side effects are evaluated beginning from 2004 until today. Methods: Statistical analyses of the prospective and ongoing CEDATA multicenter registry data from the Society of Pediatric Gastroenterology and Nutrition (GPGE) were performed for patients receiving a biological agent at least once during the period from June 2004 until November 2020 (n = 487). The analyzed parameters were patient demographics, disease extent and behavior, prior or concurrent therapies, duration and outcome of biological therapy, disease-associated complications, drug-related complications, laboratory parameters and treatment response as determined by the Physician’s Global Assessment. Results: Crohn’s disease (CD) was present in 71.5% of patients, and 52% were boys. Patients showed high disease activity when receiving a first-line TNF-α blocker. After 2016, patients who failed to respond to anti-TNF-α induction therapy were treated with off-label biologics (vedolizumab 4.3% and ustekinumab 2.1%). Propensity score matching indicated that patients with CD and higher disease activity benefitted significantly more from early anti-TNF-α therapy. This assessment was based on a clinical evaluation and lab parameters related to inflammation compared to delayed second-line treatment. Additionally, first-line treatment resulted in less treatment failure and fewer extraintestinal manifestations during TNF-α blockade. Conclusion: First-line treatment with anti-TNF-α drugs is effective and safe. An earlier start significantly reduces the risk of treatment failure and is associated with fewer extraintestinal manifestations during longitudinal follow-up.
CRIS-Team Scopus Importer:2022-11-04
Keywords: anti-TNF-α inhibitor therapy; Crohn’s disease; first-line therapy; pediatric inflammatory bowel disease (IBD); ulcerative colitis

Simulation of cardiac electromechanics of a rat left ventricle - Duong, Minh Tuan; Holz, David; Ach, Theresa; Binnewitt, Svea Vanessa; Stegmann, Hedwig; Dittrich, Sven; Alkassar, Muhannad; Leyendecker, Sigrid (Proc. Appl. Math. Mech. (PAMM), 2018)

SIRT1 regulates Mxd1 during malignant melanoma progression - Meliso, Fabiana M.; Micali, Danilo; Silva, Camila T.; Sabedot, Thais S.; Coetzee, Simon G.; Koch, Anna Maria; Fahlbusch, Fabian B.; Noushmehr, Houtan; Schneider-Stock, Regine; Jasiulionis, Miriam G. (Oncotarget, 2017)
In a murine melanoma model, malignant transformation promoted by a sustained stress condition was causally related to increased levels of reactive oxygen species resulting in DNA damage and massive epigenetic alterations. Since the chromatin modifier Sirtuin-1 (SIRT1) is a protein attracted to double-stranded DNA break (DSB) sites and can recruit other components of the epigenetic machinery, we aimed to define the role of SIRT1 in melanomagenesis through our melanoma model. The DNA damage marker, γH2AX was found increased in melanocytes after 24 hours of deadhesion, accompanied by increased SIRT1 expression and decreased levels of its target, H4K16ac. Moreover, SIRT1 started to be associated to DNMT3B during the stress condition, and this complex was maintained along malignant progression. Mxd1 was identified by ChIP-seq among the DNA sequences differentially associated with SIRT1 during deadhesion and was shown to be a common target of both, SIRT1 and DNMT3B. In addition, Mxd1 was found downregulated from pre-malignant melanocytes to metastatic melanoma cells. Treatment with DNMT inhibitor 5AzaCdR reversed the Mxd1 expression. Sirt1 stable silencing increased Mxd1 mRNA expression and led to down-regulation of MYC targets, such as Cdkn1a, Bcl2 and Psen2, whose upregulation is associated with human melanoma aggressiveness and poor prognosis. We demonstrated a novel role of the stress responsive protein SIRT1 in malignant transformation of melanocytes associated with deadhesion. Mxd1 was identified as a new SIRT1 target gene. SIRT1 promoted Mxd1 silencing, which led to increased activity of MYC oncogene contributing to melanoma progression.
EVALuna2:33949

Sleep-Disordered Breathing in Children with Prader-Willi Syndrome in Relation to Growth Hormone Therapy Onset - Zimmermann, Maja; Laemmer, Constanze; Wölfle, Joachim; Fimmers, Rolf; Gohlke, Bettina (Hormone Research in Paediatrics, 2020)
Objective: The aim of this study was to consider sleep apnea in Prader-Willi syndrome (PWS) children depending on age at growth hormone (GH) therapy onset. Study Design: We analyzed longitudinally cardiorespiratory polygraphy of 62 PWS children (aged 0-2.5 years at baseline). Twenty-one children (Group A) started GH-therapy during and 41 children (Group B) after their first year of life. Data were acquired before, at 3 and 6 months, then 1.2, 2.2, and 3.2 years after GH onset. Outcomes were determined with the obstructive apnea hypopnea index (OAHI), central apnea index (CAI), oxygen desaturation index (ODI), and by measuring obstructive sleep apnea (OSA) and peripheral blood oxygen saturation (SpO2). Results: We observed no significant differences in OAHI, CAI, ODI, and SpO2 depending on treatment onset. At baseline, 5/21 patients (23.8%) in Group A versus 15/41 patients (36.6%) in Group B showed pathological sleep apnea (OAHI ≥1.5). Pathological OSA increased significantly in Group A during the first 3 months of therapy but dropped below baseline after 1 year in both groups. ODI changed during GH therapy in both groups (from 4.0 to 2.6 in Group A, and 3.6 to 1.6 in Group B; baseline to 3.2 years; p < 0.05). Conclusions: OSA in PWS children appears to develop independently of treatment onset. Treatment may therefore safely be initiated early but should be accompanied by regular sleep analysis.
CRIS-Team Scopus Importer:2020-07-10

Sleep quality, anxiety, symptoms of depression, and caregiver burden among those caring for patients with Dravet syndrome: a prospective multicenter study in Germany - Maltseva, Margarita; Schubert-Bast, Susanne; Zöllner, Johann Philipp; Bast, Thomas; Mayer, Thomas; von Spiczak, Sarah; Ruf, Susanne; Trollmann, Regina; Wolff, Markus; Hornemann, Frauke; Klotz, Kerstin A.; Jacobs, Julia; et al. (Orphanet Journal of Rare Diseases, 2023)
Background: This study measured sleep quality among caregivers of patients with Dravet syndrome (DS) and assessed the impacts of mental health problems and caregiver burden on sleep quality. Methods: This multicenter, cross-sectional study of patients with DS and their caregivers throughout Germany consisted of a questionnaire and a prospective 4-week diary querying disease characteristics, demographic data, living conditions, nocturnal supervision, and caregivers’ work situations. Sleep quality was assessed using the Pittsburgh Sleeping Quality Index (PSQI). The Hospital Anxiety and Depression Scale (HADS) and the Burden Scale for Family Caregivers (BSFC) were used to measure anxiety, symptoms of depression, and caregiver burden. Results: Our analysis included 108 questionnaires and 82 four-week diaries. Patients with DS were 49.1% male (n = 53), with a mean age of 13.5 ± 10.0 years. Caregivers were 92.6% (n = 100) female, with a mean age of 44.7 ± 10.6 years. The overall mean PSQI score was 8.7 ± 3.5, with 76.9% of participants (n = 83) scoring 6 or higher, indicating abnormal sleep quality. The HADS for anxiety and depression had overall mean scores of 9.3 ± 4.3 and 7.9 ± 3.7, respectively; 61.8% and 50.9% of participants scored above the cutoff value of 8 for anxiety and depression, respectively. Statistical analyses revealed caregiver anxiety levels and patients’ sleep disturbances as major factors influencing PSQI scores. The overall mean BSFC score of 41.7 ± 11.7 indicates a moderate burden, with 45.3% of caregivers scoring 42 or higher. Conclusions: Sleep quality is severely affected among caregivers of patients with DS, correlating with anxiety, comorbidities, and patients’ sleep disturbances. A holistic therapeutic approach should be implemented for patients with DS and their caregivers, focusing on the sleep quality and mental health of caregivers. Trial registration: German Clinical Trials Register (DRKS), DRKS00016967. Registered 27 May 2019, http://www.drks.de/DRKS00016967
CRIS-Team Scopus Importer:2023-05-12
Keywords: Encephalopathy; Epilepsy; Quality of life; Seizure

Social inequalities in the participation and activity of children and adolescents with leukemia, brain tumors, and sarcomas (SUPATEEN): a protocol for a multicenter longitudinal prospective observational study - Roick, Julia; Berner, Reinhard; Bernig, Toralf; Erdlenbruch, Bernhard; Escherich, Gabriele; Faber, Jörg; Klein, Christoph; Bochennek, Konrad; Kratz, Christian; Kühr, Joachim; Längler, Alfred; Lode, Holger N.; et al. (BMC Pediatrics, 2020)
BACKGROUND: About 2000 children and adolescents under the age of 18 are diagnosed with cancer each year in Germany. Because of current medical treatment methods, a high survival rate can be reached for many types of the disease. Nevertheless, patients face a number of long-term effects related to the treatment. As a result, physical and psychological consequences have increasingly become the focus of research in recent years. Social dimensions of health have received little attention in health services research in oncology so far. Yet, there are no robust results that allow an estimation of whether and to what extent the disease and treatment impair the participation of children and adolescents and which factors mediate this effect. Social participation is of great importance especially because interactions with peers and experiences in different areas of life are essential for the development of children and adolescents. METHODS: Data are collected in a longitudinal, prospective, observational multicenter study. For this purpose, all patients and their parents who are being treated for cancer in one of the participating clinics throughout Germany will be interviewed within the first month after diagnosis (t1), after completion of intensive treatment (t2) and half a year after the end of intensive treatment (t3) using standardized questionnaires. Analysis will be done by descriptive and multivariate methods. DISCUSSION: The results can be used to identify children and adolescents in high-risk situations at an early stage in order to be able to initiate interventions tailored to the needs. Such tailored interventions will finally reduce the risk of impairments in the participation of children and adolescents and increase quality of life. TRIAL REGISTRATION: ClinicalTrials.gov: NCT04101123.
CRIS-Team Scopus Importer:2020-02-11
Keywords: Brain tumors; Cancer; Children and adolescents; Leukemia; Patient reported outcomes; Sarcomas; Social participation

SOCIO-ECONOMIC IMPACT OF DRAVET SYNDROME IN GERMANY: A REAL-WORLD STUDY - Irwin, J.; Strzelczyk, A.; Kalski, M.; Bast, T.; Wiemer-Kruel, A.; Bettendorf, U.; Kieslich, M.; Kluger, G.; Kurlemann, G.; Mayer, T.; Neubauer, B. A.; Polster, T.; et al. (VALUE IN HEALTH, 2018)
CRIS-Team WoS Importer:2019-03-15

Soluble CD83 Triggers Resolution of Arthritis and Sustained Inflammation Control in IDO Dependent Manner - Royzman, Dmytro; Andrev, Darja; Stich, Lena; Rauh, Manfred; Bäuerle, Tobias; Ellmann, Stephan; Boon, Louis; Kindermann, Markus; Peckert, Katrin; Bozec, Aline; Schett, Georg; Steinkasserer, Alexander; et al. (Frontiers in Immunology, 2019)
Interference with autoimmune-mediated cytokine production is a key yet poorly developed approach to treat autoimmune and inflammatory diseases such as rheumatoid arthritis. Herein, we show that soluble CD83 (sCD83) enhances the resolution of autoimmune antigen-induced arthritis (AIA) by strongly reducing the expression levels of cytokines such as IL-17A, IFN gamma, IL-6, and TNF alpha within the joints. Noteworthy, also the expression of RANKL, osteoclast differentiation, and joint destruction was significantly inhibited by sCD83. In addition, osteoclasts which were cultured in the presence of synovial T cells, derived from sCD83 treated AIA mice, showed a strongly reduced number of multinuclear large osteoclasts compared to mock controls. Enhanced resolution of arthritis by sCD83 was mechanistically based on IDO, since inhibition of IDO by 1-methyltryptophan completely abrogated sCD83 effects on AIA. Blocking experiments, using anti-TGF-beta antibodies further revealed that also TGF-beta is mechanistically involved in the sCD83 induced reduction of bone destruction and cartilage damage as well as enhanced resolution of inflammation. Resolution of arthritis was associated with increased numbers of regulatory T cells, which are induced in a sCD83-IDO-TGF-beta dependent manner. Taken together, sCD83 represents an interesting approach for downregulating cytokine production, inducing regulatory T cells and inducing resolution of autoimmune arthritis.
CRIS-Team WoS Importer:2019-04-12