Publications by authors named "Reinhard Berner"

103 Publications

Lower household transmission rates of SARS-CoV-2 from children compared to adults.

J Infect 2021 Apr 27. Epub 2021 Apr 27.

Department of Paediatrics, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.

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http://dx.doi.org/10.1016/j.jinf.2021.04.022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079264PMC
April 2021

[How Often is Rare Really Rare? A Survey on the Frequency of Rare Diseases at a University Hospital].

Gesundheitswesen 2021 Apr 15. Epub 2021 Apr 15.

Klinik und Poliklinik für Kinder- und Jugendmedizin, Dresden University Hospital, Dresden, Deutschland.

Aim Of Study: The prevalence of rare diseases in hospitals and in university hospitals is unknown. As the ICD-10 coding system does not adequately represent rare diagnoses, the prevalence of rare diseases cannot be estimated based on ICD-10 coded discharge diagnoses. The current hospital reimbursement system does not seem to be designed to capture performance-related higher expenditures in the treatment of rare diseases. The aim of this study was to help estimate the frequency of rare diseases among inpatients treated at a university hospital where documentation of rare diseases is obligatory by analyzing the case load of such diseases for a given year.

Method: Since 2017, rare diseases have been coded for all inpatients treated at the University Hospital Dresden. This coding is based on the Orpha identification number, which was implemented in the hospital information system ORBIS for this purpose. Result For illustrative purposes, cases in 2019 were evaluated. During this period, 19% of all 70,937 inpatients seen at the University Hospital Dresden were coded as having a rare disease.

Conclusion: For the first time, a prospective and complete documentation of rare diseases was implemented at a German university hospital. The prevalence of rare diseases of 6 to 8% as defined by the European Union was exceeded several fold. Probably it underestimates the actual prevalence considerably, since the quality of the coding correlates on user compliance. Nevertheless, the results of this survey underline the special role of patients with rare diseases in the medical care at university hospitals.
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http://dx.doi.org/10.1055/a-1388-7095DOI Listing
April 2021

Clinical Practice Guideline: Sore Throat.

Dtsch Arztebl Int 2021 03 19;118(Forthcoming). Epub 2021 Mar 19.

Background: Sore throat is a common reason for consultation of primary care physicians, pediatricians, and ENT specialists. The updated German clinical practice guideline on sore throat provides evidence-based recommendations for treatment in the German healthcare system.

Methods: Guideline revision by means of a systematic search of the literature for international guidelines and systematic reviews. All recommendations resulted from interdisciplinary cooperation and were agreed by formal consensus. The updated guideline applies to patients aged 3 years and over.

Results: In the absence of red flags such as immunosuppression, severe comorbidity, or severe systemic infection, acute sore throat is predominantly self-limiting. The mean duration is 7 days. Chronic sore throat usually has noninfectious causes. Laboratory tests are not routinely necessary. Apart from non-pharmacological self-management, ibuprofen and naproxen are recommended for symptomatic treatment. Scores can be used to assess the risk of bacterial pharyngitis: one point each is assigned for tonsil lesions, palpable cervical lymph nodes, patient age, disease course, and elevated temperature. If the risk is low (<3 points), antibiotics are not indicated; if at least moderate (3 points), delayed prescribing is recommended; if high (>3 points), antibiotics can be taken immediately. Penicillin remains the first choice, with clarithromycin as an alternative for those who do not tolerate penicillin. The antibiotic should be taken for 5-7 days.

Conclusion: After the exclusion of red flags, antibiotic treatment is unnecessary in many cases of acute sore throat. If administration of antibiotics is still considered in spite of consultation on the usual course of tonsillopharyngitis and the low risk of complications, a risk-adapted approach using clinical scores is recommended.
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http://dx.doi.org/10.3238/arztebl.m2021.0121DOI Listing
March 2021

Severe Bleeding Diathesis in Siblings with Platelet Dysfunction due to a Novel Nonsense Mutation.

TH Open 2020 Oct 25;4(4):e413-e416. Epub 2020 Dec 25.

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

Next-generation sequencing is increasingly applied during the diagnostic work-up of patients with bleeding diathesis and has facilitated the diagnosis of rare bleeding disorders such as inherited platelet function disorders. Mutations in RAS guanyl releasing protein 2 (RasGRP2), also known as calcium- and diacylglycerol-regulated guanine nucleotide exchange factor I (CalDAG-GEFI), underlie a recently described platelet signal transduction abnormality. Here we present the case of a consanguineous family originating from Afghanistan with two siblings affected by recurrent severe mucocutaneous bleedings. Platelet function testing demonstrated a marked reduction of aggregation induced by collagen and adenosine diphosphate. Whole exome sequencing revealed a novel homozygous nonsense mutation segregating with the bleeding disorder in the family.
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http://dx.doi.org/10.1055/s-0040-1718910DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762629PMC
October 2020

[Use of masks by children to prevent infection with SARS-CoV-2].

Monatsschr Kinderheilkd 2020 Dec 18:1-5. Epub 2020 Dec 18.

Dr. von Hauner'sche Kinderklinik, LMU München, Lindwurmstr. 4, 80337 München, Deutschland.

After initial reluctance masks have emerged as an important means of restricting the spread of SARS-CoV‑2, the new coronavirus causing COVID-19. Other simple measures are keeping a distance of at least 1 ½ m from other persons and observing hygiene recommendations, including washing or even disinfecting the hands, coughing into the crook of the arm and remaining at home when sick. Combining the initial letters of the German words for the three measures ( distance-hygiene-face mask) the acronym AHA was formed, a colloquial German word meaning that the speaker understood the information presented. This acronym was later extended by the letter "L", initial letter of "Lüften" meaning air ventilation for indoor rooms and arriving at AHA‑L, recommended by the federal German Health Institute the Robert Koch Institute. In fact, masks including surgical masks and face coverings can form an effective barrier against the spread of the virus: protecting other people from droplets expelled from the throat of the speaker wearing a mask and even in part protecting the wearer from inhaling droplets emanating from other peoples' throats. Studies to find out if wearing masks might impose risks did not find essential problems: alterations of respiratory parameters due to an increased airway resistance remained within normal limits in healthy adults and even in asthmatics whose disease was well controlled; however, many adults expressed their unease with masks describing them as cumbersome and inconvenient. Emotional resistance against masks made it increasingly more difficult for them to use a mask. Efficient application of masks requires, in addition to a logical explanation of its effect, the evocation of empathy for vulnerable people who can be protected from catching a possibly deadly disease. In children there are very few data on adverse effects of wearing a mask although there is ample experience in children with serious diseases compromising defense against infectious agents acquired via respiratory mucus membranes; however, when using masks appropriately in children relevant adverse effects have not been reported and are not to be expected. Masks should only be used in children when they are healthy and awake and can remove the masks themselves anytime they like. Children 10 years or older can use masks efficiently when they have been informed beforehand appropriate to their age. Under these conditions they can also be obliged to wear masks in certain situations, for example while walking through the school building to their desk in class. To limit the period of wearing a mask normally they will be allowed to remove the mask when sitting in class and keeping their distance. Children in primary schools may use masks, but they should not be obliged to wear them and children in kindergartens should not use masks. This exemption of younger children does not expose school and kindergarten teachers to additional risks since the infectivity with SARS-CoV‑2 is age-dependent and increases with age reaching adult values only after 12 years of age.
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http://dx.doi.org/10.1007/s00112-020-01090-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7747190PMC
December 2020

Prevalence of Capsular Serotype, Pilus Island Distribution, and Antibiotic Resistance in Pediatric and Adult Invasive Group B Streptococcus Isolates: Data From a Nationwide Prospective Surveillance Study in Germany.

Pediatr Infect Dis J 2021 01;40(1):76-82

Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

For neonates, group B Streptococcus is life threatening. Current prevention strategies remain insufficient, especially for cases of late-onset sepsis, where intrapartum antibiotic prophylaxis has demonstrated no benefit. One promising approach is the vaccination of pregnant women, which offers protective immunity via transplacental transmission of neutralizing antibodies. Our nationwide, prospective surveillance study aimed to characterize the prevalence of pilus antigen, capsular polysaccharide serotypes, and antibiotic resistance from invasive GBS infections in neonates and compare these results with those from children and adults in Germany. Our study includes 173 neonatal isolates of a total of 450 reported cases during the study period (incidence: 0.34/1000 live births), in addition to 2 pediatric and 803 adult isolates. The comparison between neonatal and adult isolates reveals age-dependent differences in capsular serotype and pilus type distribution and differences in antibiotic resistance patterns.
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http://dx.doi.org/10.1097/INF.0000000000002943DOI Listing
January 2021

[Children with acute respiratory tract infections in pediatric hospitals in autumn/winter 2020/2021].

Monatsschr Kinderheilkd 2020 Nov 6:1-4. Epub 2020 Nov 6.

Deutsche Gesellschaft für Krankenhaushygiene e. V. (DGKH), Berlin, Deutschland.

Due to the shortage of pediatric hospital beds in general and due to the large annual burden of hospital admissions for common respiratory tract infections, such as influenza or RSV [respiratory syncytial virus] in particular, it can be expected that hospitalization of children with suspected or confirmed SARS-CoV‑2 infections will face hospitals with an even more tense situation than usual in the winter 2020/2021. This tenuous shortage may touch various aspects but in the first place it will affect isolation and cohorting. In addition, this shortage will not only apply to acutely ill children with viral respiratory tract infections but all children with need for hospital care, either chronically ill or e.g. being premature babies or newborns. Therefore, approaches are required which on the one hand are based on pragmatic grounds but on the other hand fulfill the basics of hygiene and infection control. The recommendations proposed in this statement are intended to give assistance to hospitals for the management of testing, isolation and cohorting of pediatric patients with suspected or confirmed SARS-CoV‑2 infections. The most important factor navigating the essential measures is the cumulative incidence of newly diagnosed infections per 100,000 over the last 7 days, which is given by the RKI or the local public health authorities. In the situation of low (<25/100,000) or medium (25-50/100,000) incidence the respective diagnostic measures and hospital admission can be performed under standard hygiene precautions and the children will be cohorted according to their clinical presentation until the results of SARS-CoV‑2 test (or RSV [respiratory syncytial virus] or influenza test) are available. In the situation of high (>50/100,000) incidence the respective diagnostic measures and the admission have to be performed under SARS-CoV‑2 precautions as specified by the RKI, and the children have to be isolated until the results of SARS-CoV‑2 test are available. The assessment of the incidence figures and the respective measures may be adapted by the local public health authorities on an individual basis. In case of shortfalls in admission capacities, the requirement of acute emergency care may necessitate that isolation and cohorting in the hospital will have to be performed temporarily in a less restrictive way than recommended here for standard.
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http://dx.doi.org/10.1007/s00112-020-01058-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7645022PMC
November 2020

Hospitalization for Acute Respiratory Tract Infection in a Low-Antibiotic-Prescribing Setting: Cross-Sectional Data from General Practice.

Antibiotics (Basel) 2020 Sep 29;9(10). Epub 2020 Sep 29.

Institute of General Practice, Rostock University Medical Center, 18057 Rostock, Germany.

Background: Acute respiratory tract infections (ARTI) are the main cause of inappropriate antibiotic prescribing. To date, there is limited evidence concerning whether low levels of antibiotic prescribing may impact patient safety. We investigate whether antibiotic prescribing for patients seeking primary care for ARTI correlates with the odds for hospitalization.

Methods: Analysis of patient baseline data ( = 3669) within a cluster-randomized controlled trial. Adult patients suffering from ARTI in German primary care are included. The main outcome measure is acute hospitalization for respiratory infection and for any acute disease from 0 to 42 days after initial consultation.

Results: Neither the antibiotic status of individual patients (OR 0.91; 95% CI: 0.49 to 1.69; -value = 0.769) nor the physician-specific antibiotic prescription rates for ARTI (OR 1.22; 95% CI: 1.00 to 1.49; -value = 0.054) had a significant effect on hospitalization. The following factors increased the odds for hospitalization: patient's age, the ARTI being defined as lower respiratory tract infections (such as bronchitis) by the physician, the physician's perception of disease severity, and being cared for within group practices (versus treated in single-handed practices).

Conclusions: In a low-antibiotic-prescribing primary care setting such as Germany, lack of treatment with antibiotics for ARTI did not result in higher odds for hospitalization in an adult population.
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http://dx.doi.org/10.3390/antibiotics9100653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7600502PMC
September 2020

Measures to maintain regular operations and prevent outbreaks of SARS-CoV-2 in childcare facilities or schools under pandemic conditions and co-circulation of other respiratory pathogens.

GMS Hyg Infect Control 2020 15;15:Doc22. Epub 2020 Sep 15.

German Society of Hospital Hygiene, Berlin, Germany.

After the lockdown and the end of the summer holidays, day-cares and schools need to be reopened and (despite the continued circulation of the new coronavirus SARS-CoV-2) kept open. The need for opening up arises from the right of children to education, participation, support and care. This is possible if appropriate hygiene measures are implemented and community transmission remains stable. In addition, the safety of educators, teachers and carers must be a priority and needs to be addressed by appropriate measures. Finally, the needs of families must also be taken into account. The following document describes in detail how these objectives can be achieved.
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http://dx.doi.org/10.3205/dgkh000357DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492754PMC
September 2020

Group B streptococcus vaccines: one step further.

Authors:
Reinhard Berner

Lancet Infect Dis 2021 02 3;21(2):158-160. Epub 2020 Sep 3.

Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden 01307, Germany. Electronic address:

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http://dx.doi.org/10.1016/S1473-3099(20)30451-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7470735PMC
February 2021

Hospital Admission in Children and Adolescents With COVID-19.

Dtsch Arztebl Int 2020 05;117(21):373-374

Klinik und Poliklinik für Kinderund Jugendmedizin, Universitätsklinikum Carl Gustav Carus an der Technischen Universität Dresden; Gesundheitsverbund Landkreis Konstanz, Klinikum Singen, Zentrum für Kinderund Jugendgesundheit; Klinik für Pädiatrische Onkologie und Hämatologie, Universitätsklinikum des Saarlandes, Homburg/Saar; Pädiatrische Infektiologie und Rheumatologie, Zentrum für Kinder und Jugendmedizin, Universitätsklinikum Freiburg; Klinik für Kinderund Jugendmedizin, Klinikum Dortmund gGmbH; Abteilung Pädiatrische Infektiologie, Dr. von Haunersches Kinderspital, Klinikum der Ludwig-Maximilian-Universität München; Deutsche Gesellschaft für Pädiatrische Infektiologie e.V., Berlin.

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http://dx.doi.org/10.3238/arztebl.2020.0373DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271745PMC
May 2020

Management of Care for Neonates Born to SARS-CoV-2 Positive Women with or without Clinical Symptoms (COVID-19).

Klin Padiatr 2020 07 5;232(4):173-177. Epub 2020 Jun 5.

Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

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http://dx.doi.org/10.1055/a-1168-2845DOI Listing
July 2020

Neonatal and young infant sepsis by Group B Streptococci and Escherichia coli: a single-center retrospective analysis in Germany-GBS screening implementation gaps and reduction in antibiotic resistance.

Eur J Pediatr 2020 Nov 23;179(11):1769-1777. Epub 2020 May 23.

Department of Pediatrics, University Hospital and Medical Faculty Carl Gustav Carus, Technische Universität (TU) Dresden, Fetscherstraße 74, D-01307, Dresden, Germany.

The last nationwide surveillance study on neonatal and young infant sepsis due to Group B Streptococci (GBS) and Escherichia coli in Germany was conducted between 2009 and 2010. The aim of this study is to provide longitudinal epidemiological data on neonatal and young infant sepsis caused by GBS and E. coli to reevaluate existing data and to inform clinical decision-making. Every positive blood culture for GBS and E. coli within the first 90 days of life that occurred at our center from 2008 until 2018 was identified. The epidemiological, clinical, laboratory, and microbiological data of all affected patients were analyzed through retrospective chart review, along with the pathogen's antimicrobial susceptibility results. In total, 106 episodes of neonatal sepsis were described; 31% (n = 33) being caused by GBS and 69% (n = 73) by E. coli; 87% of GBS early-onset disease (EOD) cases did not receive intrapartum antibiotic prophylaxis (IAP). Contrary to general trends, the proportion of resistant E. coli isolates decreased for all tested antibiotics over time. Coincidentally, antenatal antibiotic use beyond IAP during that period decreased significantly in our center.Conclusions: (1) Data at our center suggests at least a regional implementation gap in GBS screening and IAP. (2) The decline in the resistance rate of E. coli for all antimicrobial substances might indicate that the reduction of prenatal antibiotics use is beneficial and that neonatal antibiotic stewardship programs should include pregnant women as well. What is Known: • GBS screening and intrapartum antibiotic prophylaxis led to a 32%-reduction in GBS disease in Germany with a 0.75 (92:122) ratio of early-onset disease to late-onset disease in 2009-2010. • Prenatal antibiotic use might increase the risk of E. coli early-onset disease and antibiotic resistances. What is New: • The GBS early-onset disease rates were twice as high as those of late-onset disease, the ratio was 1.75 (21:12) in 2008-2018 at our institution. This suggests that there are at least regional implementation gaps in the antenatal GBS screening in Germany. • We found a decline in E. coli resistance rates over time for all antimicrobial substances. Reduction in use of prenatal antibiotics might be an explanation.
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http://dx.doi.org/10.1007/s00431-020-03659-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7547982PMC
November 2020

Janus kinase inhibition in complement component 1 deficiency.

J Allergy Clin Immunol 2020 12 20;146(6):1439-1442.e5. Epub 2020 Apr 20.

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany. Electronic address:

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http://dx.doi.org/10.1016/j.jaci.2020.04.002DOI Listing
December 2020

Survival of Group A Streptococcus (GAS) is Enhanced Under Desiccated Culture Conditions.

Curr Microbiol 2020 Aug 2;77(8):1518-1524. Epub 2020 Apr 2.

Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.

Streptococcus pyogenes or Group A Streptococcus (GAS) infections are the leading cause of bacterial tonsillopharyngitis. The bacterium can survive and persist within the human host for a long time as it is observed in up to 40% of the population who are considered as carriers. Recurrent tonsillopharyngitis is a particular problem in children which is caused either by relapses due to failed bacterial clearance or by reinfection. A prolonged survival in tonsillar crypts or on inanimate surfaces might be sources for reinfection. We therefore examined 64 clinical GAS isolates from children with tonsillopharyngitis for their long-term survival under either liquid or desiccated culture conditions. After 6 weeks, the overall GAS survival rate was 400-fold increased under desiccated culture conditions compared to liquid culture conditions, but varied depending on the emm-type between 20-fold (emm4) and 14000-fold (emm3). The survival rates of isolates from emm75 were significantly lower which is probably due to their production of hydrogen peroxide up to fatal doses. No hydrogen peroxide production could be detected for other emm-types. Furthermore, 11 isolates from patients with recurrent tonsillopharyngitis were compared to isolates of the same emm-type from patients with single episodes of tonsillopharyngitis. A significant elevated pH value and an increased survival rate for isolates from patients with recurrent infections were observed. In conclusion, significant differences in long-term survival of different GAS isolates as well as survival under desiccated culture conditions might contribute to both failed bacterial clearance and reinfection in patients with recurrent tonsillopharyngitis.
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http://dx.doi.org/10.1007/s00284-020-01967-8DOI Listing
August 2020

Microarray Analysis of Group B Streptococci Causing Invasive Neonatal Early- and Late-onset Infection.

Pediatr Infect Dis J 2020 05;39(5):449-453

From the Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany.

Background: Group B Streptococcus is the leading cause of meningitis and sepsis in newborns. Until now, there is no data of fast and simple typing of group B Streptococcus virulence factors using a genetic microarray and comparing these data to clinical manifestations.

Methods: A prospective active surveillance study was conducted via 2 independent and nationwide reporting systems, the German Pediatric Surveillance Unit (ESPED) and the Laboratory Sentinel Group at Robert Koch-Institute. Surveillance was performed between 2001 and 2003 and between 2008 and 2010. Typing of virulence factors, serotypes, pilus islands and alpha-like proteins was done by means of a newly developed microarray method.

Results: We evaluated 475 isolates of invasive neonatal infections. Predominant virulence factors were serotype III (63%), pilus island 2b and pilus island 1 (50%) and alp rib (64%) (alp - alpha-like protein, rib -resistance to proteases, immunity, group B). There was no significant change over time or geographically within Germany. Serotype III, pilus island 2b + 1 and alp rib showed significant associations with late-onset disease and meningitis, whereas alp 5 had a significant association with early-onset disease. Based on serotypes, pilus islands and alpha-like proteins, it was possible to cluster 86% of all isolates into 5 genetic groups.

Conclusions: The molecular epidemiology of a large collection of invasive neonatal infections showed similar distributions, as shown in smaller cohorts before. The microarray used proved to be a fast and reliable technique. Using this new tool, we were able to cluster the isolates according to their virulence factors. The clusters showed a better association with clinical data than single virulence factors.
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http://dx.doi.org/10.1097/INF.0000000000002627DOI Listing
May 2020

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.

BMC Pediatr 2020 01 31;20(1):48. Epub 2020 Jan 31.

Institute of Medical Sociology (IMS), Martin Luther University Halle-Wittenberg, Magdeburger Str. 8, 06112, Halle (Saale), Germany.

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.
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http://dx.doi.org/10.1186/s12887-020-1943-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6995139PMC
January 2020

High-dose intravenous methylprednisolone in juvenile non-infectious uveitis: A retrospective analysis.

Clin Immunol 2020 02 18;211:108327. Epub 2019 Dec 18.

Pediatric Rheumatology, Department of Pediatrics, Universitätsklinikum Carl Gustav Carus, Technische Universität Dresden, Germany; Department of Women's & Children's Health, Institute of Translational Medicine, University of Liverpool, Liverpool, United Kingdom; Department of Paediatric Rheumatology, Alder Hey Children's NHS Foundation Trust Hospital, Liverpool, United Kingdom. Electronic address:

Non-infectious uveitis is associated with visual impairment and blindness. Non-biologic treatment for non-infectious uveitis is not based on strong evidence. A retrospective chart review was conducted to investigate treatment response to high-dose intravenous methylprednisolone (IVMP) in children with non-infectious uveitis. Fifty-six patients (93 eyes affected) were included. In 29% uveitis was associated with juvenile idiopathic arthritis. Uveitis predominately affected the anterior segment, was bilateral and recurrent. Complications were common and included visual loss, synechiae, cataract and/or retinal lesions. Patients received up to 5 IVMP at monthly intervals. Visual acuity improved at 3 and 6 months. Anterior chamber cells, synechiae, keratic precipitates, papillary and/or macular edema improved at 3 months. Children treated with ≥3 IVMP (vs 1 IVMP) experienced trends towards fewer relapses, fewer cataracts and less frequently required treatment with biologic agents. High-dose IVMP induce rapid improvement in children with non-infectious uveitis. Prospective randomized trials are required to confirm results.
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http://dx.doi.org/10.1016/j.clim.2019.108327DOI Listing
February 2020

Orbital inflammation and colitis in pediatric IgG4-related disease: A case report and review of the literature.

Eur J Rheumatol 2019 Dec 3:1-7. Epub 2019 Dec 3.

Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany.

IgG4-related disease (IgG4-RD) is an inflammatory disorder characterized by tumor-like swelling in one or more organs, elevated serum IgG4 levels, and histological alterations with infiltration of IgG4-positive plasma cells. IgG4-RD is rare and likely underdiagnosed in children. We report a case of a 16-year-old girl with IgG4-positive colitis that developed weeks after IgG4-related ophthalmic disease and discuss diagnosis and treatment in the context of the literature available. Since the pathophysiology of IgG4-RD is unknown, treatment options are empiric and, for the most part, untargeted. Systemic corticosteroid treatment is the basis of anti-inflammatory treatment in IgG4-RD and induced early remission in our patient. During corticosteroid taper, the patient developed weight loss and intestinal inflammation. Histopathological assessment of the intestinal walls confirmed IgG4-positive colitis. Immune-modulating treatment with non-biologic (e.g., methotrexate (MTX) and mycophenolate mofetil) or biologic (rituximab) disease-modifying antirheumatic drugs has been reported in treatment refractory or corticosteroid-dependent patients. The patient responded to treatment with anti-inflammatory therapy with food rich in TGF-β2 (modulen) and MTX. This is one of the first pediatric patients reported with IgG4-related colitis extending the phenotype of pediatric IgG4-RD. International collaboration to prospectively document clinical presentation and treatment responses may help to further establish the phenotype and treatment options and to raise awareness for IgG4-RD.
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http://dx.doi.org/10.5152/eurjrheum.2019.19165DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7004272PMC
December 2019

Long-term, single-center surveillance of non-invasive group A streptococcal (GAS) infections, emm types and emm clusters.

Eur J Clin Microbiol Infect Dis 2020 Feb 22;39(2):273-280. Epub 2019 Nov 22.

Department of Pediatrics, Carl Gustav Carus University Hospital, Technical University Dresden, Dresden, Germany.

Group A streptococci (GAS) are among the most frequent pathogens in children. Many epidemiological studies focus on specific GAS infections (such as tonsillopharyngitis or invasive disease), on GAS carriers or on post-streptococcal sequelae. By comparison, reports on regional GAS characteristics, particularly circulating non-invasive GAS in Europe, are rare. In a monocentric study, all GAS isolated from pediatric patients at a tertiary care hospital over a 6-year period (2006-2012) were characterized. GAS emm types and clusters were determined. Associated patient data were analyzed. Five hundred sixty-six GAS strains were collected. GAS tonsillopharyngitis was most common (71.6%), followed by pyoderma (6.0%), otitis media (3.7%), perineal dermatitis (3.4%), and invasive infections (1.4%). Colonizing strains represented 13.6% of GAS. GAS emm12 was most prevalent among invasive and non-invasive isolates. Emm1, emm4, emm28, and emm89 were the most frequent non-invasive GAS strains. The emm E4 cluster was most common, followed by the A-C4, A-C3, and E1. Among the GAS infections, different emm types and clusters were identified, e.g., emm4 was more common among patients with scarlet fever. Three new emm subtypes were characterized: emm29.13, emm36.7, and emm75.5. This comprehensive review of a large, local GAS cohort points to the differences between and similarities among GAS genotypes and disease manifestations, while minimizing regional variations. Considerable deviation from previous epidemiological findings is described, especially regarding the frequent detection of emm1 and emm89 in non-invasive GAS infections. Periodic updates on molecular and epidemiological GAS characteristics are needed to track the multifaceted pathogenic potential of GAS.
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http://dx.doi.org/10.1007/s10096-019-03719-4DOI Listing
February 2020

Oral insulin therapy for primary prevention of type 1 diabetes in infants with high genetic risk: the GPPAD-POInT (global platform for the prevention of autoimmune diabetes primary oral insulin trial) study protocol.

BMJ Open 2019 06 28;9(6):e028578. Epub 2019 Jun 28.

Centre for Regenerative Therapies Dresden (CRTD), Faculty of Medicine, Technische Universität Dresden, Dresden, Germany.

Introduction: The POInT study, an investigator initiated, randomised, placebo-controlled, double-blind, multicentre primary prevention trial is conducted to determine whether daily administration of oral insulin, from age 4.0 months to 7.0 months until age 36.0 months to children with elevated genetic risk for type 1 diabetes, reduces the incidence of beta-cell autoantibodies and diabetes.

Methods And Analysis: Infants aged 4.0 to 7.0 months from Germany, Poland, Belgium, UK and Sweden are eligible if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies as determined by genetic risk score or family history and human leucocyte antigen genotype. Infants are randomised 1:1 to daily oral insulin (7.5 mg for 2 months, 22.5 mg for 2 months, 67.5 mg until age 36.0 months) or placebo, and followed for a maximum of 7 years. Treatment and follow-up is stopped if a child develops diabetes. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies or diabetes. Other outcomes are: (1) Any persistent confirmed beta-cell autoantibody (glutamic acid decarboxylase (GADA), IA-2A, autoantibodies to insulin (IAA) and zinc transporter 8 or tetraspanin 7), or diabetes, (2) Persistent confirmed IAA, (3) Persistent confirmed GADA and (4) Abnormal glucose tolerance or diabetes.

Ethics And Dissemination: The study is approved by the ethical committees of all participating clinical sites. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the trial.

Trial Registration Number: NCT03364868.
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http://dx.doi.org/10.1136/bmjopen-2018-028578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6609035PMC
June 2019

Identification of infants with increased type 1 diabetes genetic risk for enrollment into Primary Prevention Trials-GPPAD-02 study design and first results.

Pediatr Diabetes 2019 09 13;20(6):720-727. Epub 2019 Jun 13.

Faculty of Medicine, Center for Regenerative Therapies Dresden (CRTD), Technische Universität Dresden, Dresden, Germany.

Primary prevention of type 1 diabetes (T1D) requires intervention in genetically at-risk infants. The Global Platform for the Prevention of Autoimmune Diabetes (GPPAD) has established a screening program, GPPAD-02, that identifies infants with a genetic high risk of T1D, enrolls these into primary prevention trials, and follows the children for beta-cell autoantibodies and diabetes. Genetic testing is offered either at delivery, together with the regular newborn testing, or at a newborn health care visits before the age of 5 months in regions of Germany (Bavaria, Saxony, Lower Saxony), UK (Oxford), Poland (Warsaw), Belgium (Leuven), and Sweden (Region Skåne). Seven clinical centers will screen around 330 000 infants. Using a genetic score based on 46 T1D susceptibility single-nucleotide polymorphisms (SNPs) or three SNPS and a first-degree family history for T1D, infants with a high (>10%) genetic risk for developing multiple beta-cell autoantibodies by the age of 6 years are identified. Screening from October 2017 to December 2018 was performed in 50 669 infants. The prevalence of high genetic risk for T1D in these infants was 1.1%. Infants with high genetic risk for T1D are followed up and offered to participate in a randomized controlled trial aiming to prevent beta-cell autoimmunity and T1D by tolerance induction with oral insulin. The GPPAD-02 study provides a unique path to primary prevention of beta-cell autoimmunity in the general population. The eventual benefit to the community, if successful, will be a reduction in the number of children developing beta-cell autoimmunity and T1D.
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http://dx.doi.org/10.1111/pedi.12870DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6851563PMC
September 2019

Otitis Externa.

Dtsch Arztebl Int 2019 03;116(13):224-234

Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Leipzig; Department of Pediatrics, University Hospital Carl Gustav Carus Dresden, TU Dresden; Institute of General Practice, Technical University of Munich; HNO-Praxis Lundershausen, Erfurt.

Background: Otitis externa has a lifetime prevalence of 10% and can arise in acute, chronic, and necrotizing forms.

Methods: This review is based on publications retrieved by a selective search of the pertinent literature.

Results: The treatment of acute otitis media consists of anal- gesia, cleansing of the external auditory canal, and the appli- cation of antiseptic and antimicrobial agents. Local antibiotic and corticosteroid preparations have been found useful, but there have been no large-scale randomized controlled trials of their use. Topical antimicrobial treatments lead to a higher cure rate than placebo, and corticosteroid preparations lessen swelling, erythema, and secretions. Oral antibiotics are indi- cated if the infection has spread beyond the ear canal or in patients with poorly controlled diabetes mellitus or immuno- suppression. Chronic otitis externa is often due to an under- lying skin disease. Malignant otitis externa, a destructive infection of the external auditory canal in which there is also osteomyelitis of the petrous bone, arises mainly in elderly diabetic or immunosuppressed patients and can be life- threatening.

Conclusion: With correct assessment of the different types of otitis externa, rapidly effective targeted treatment can be initi- ated, so that complications will be avoided and fewer cases will progress to chronic disease.
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http://dx.doi.org/10.3238/arztebl.2019.0224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6522672PMC
March 2019

Hydrogen Peroxide Production of Group A Streptococci (GAS) is emm-Type Dependent and Increased at Low Temperatures.

Curr Microbiol 2019 Jun 6;76(6):698-705. Epub 2019 Apr 6.

Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307, Dresden, Germany.

Group A streptococcus (GAS) is an important human pathogen whose clinical isolates differ in their ability to produce hydrogen peroxide (HO). HO is primarily produced by the enzyme lactate oxidase (LctO), an in depth in silico research revealed that all genome-sequenced GAS possess the required gene lctO. The importance of lctO for GAS is underlined by its highly conserved catabolite control element (cre box) as well as its perfect promotor sequence in comparison to the known consensus sequences of the Gram-positive model organism Bacillus subtilis. In this study, we provide further insight in the function and regulation of lactate oxidase by analyzing a large group of clinical GAS isolates. We found that HO production increased over time in the late stationary phase; after 4 days of incubation, 5.4% of the isolates showed a positive result at 37 °C, while the rate increased to 16.4% at 20 °C. This correlation between HO production and low temperatures suggests additional regulatory mechanisms for lctO besides catabolite control protein A (CcpA) and indicates that lctO might play a role for GAS energy metabolism at sub-body temperatures. Furthermore, we could identify that HO production was different among clinical isolates; we could correlate HO production to emm-types, indicating that emm-types 6 and 75 had the highest rate of HO production. The emm-type- and temperature-dependent HO production of clinical GAS isolates might contribute to their different survival strategies.
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http://dx.doi.org/10.1007/s00284-019-01683-yDOI Listing
June 2019

The prevalence of headache in German pupils of different ages and school types.

Cephalalgia 2019 Jul 18;39(8):1030-1040. Epub 2019 Mar 18.

1 Pain Center, University Hospital and Faculty of Medicine Carl Gustav Carus, TU Dresden, Dresden, Germany.

Background/objective: Headache in pupils is underestimated and has a negative impact on learning and life. The aim of this study was to investigate headache prevalence and its collateral effects, in pupils of different ages and school types in a German city.

Methods: Anonymized questionnaires were distributed to 5419 pupils attending primary and secondary schools. Demographics, headache frequency, analgesic use, school absence and, for secondary school children, data on lifestyle were collected.

Results: The questionnaire was returned by 2706 children (49%), 1362 (50.3%) girls, 1344 (49.7%) boys. Of these, 36.6% indicated a frequency of 1, and 31.5% a frequency of ≥ 2 headache days per month within the last 3 months. Headache prevalence increased with school grade, age and secondary school type: 63.6%, 67.2% and 79.5% for primary school children, pupils attending 8-year and pupils attending 6-year secondary schools, respectively. With secondary school level I certificates, pupils are prepared for general professional training in 6 years. Secondary school level II results, after 8 years of training, in university entrance level II certificates, which are the precondition for university studies. Girls reported significantly more headache than boys (73% vs. 63.1%). A significant relationship has been observed between headache frequency and school absence and between headache intensity and headache frequency. Of pupils with headache at least twice a month, 48.1% reported analgesic intake. Ibuprofen (49.1%) and paracetamol (32.8%) were the most frequently used analgesics. Of those pupils with headache ≥ 2 days/month, 68.3% did not have a specific headache diagnosis. Concomitant diseases and regular drug intake, analgesic intake for another reason than headache, caffeine consumption and lack of participation in sports were positively correlated with headache.

Conclusions: The majority of pupils suffer from headache at least once a month. Since frequent headache results in educational and social limitations, pupils at risk should be identified and referred to headache education programs. Efforts are needed to improve the management of juvenile headache patients.
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http://dx.doi.org/10.1177/0333102419837156DOI Listing
July 2019

Real-time deformability cytometry reveals sequential contraction and expansion during neutrophil priming.

J Leukoc Biol 2019 06 5;105(6):1143-1153. Epub 2019 Mar 5.

Department of Pediatrics, University Clinic Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.

It has become increasingly apparent that the biomechanical properties of neutrophils impact on their trafficking through the circulation and in particularly through the pulmonary capillary bed. The retention of polarized or shape-changed neutrophils in the lungs was recently proposed to contribute to acute respiratory distress syndrome pathogenesis. Accordingly, this study tested the hypothesis that neutrophil priming is coupled to morpho-rheological (MORE) changes capable of altering cell function. We employ real-time deformability cytometry (RT-DC), a recently developed, rapid, and sensitive way to assess the distribution of size, shape, and deformability of thousands of cells within seconds. During RT-DC analysis, neutrophils can be easily identified within anticoagulated "whole blood" due to their unique granularity and size, thus avoiding the need for further isolation techniques, which affect biomechanical cell properties. Hence, RT-DC is uniquely suited to describe the kinetics of MORE cell changes. We reveal that, following activation or priming, neutrophils undergo a short period of cell shrinking and stiffening, followed by a phase of cell expansion and softening. In some contexts, neutrophils ultimately recover their un-primed mechanical phenotype. The mechanism(s) underlying changes in human neutrophil size are shown to be Na /H antiport-dependent and are predicted to have profound implications for neutrophil movement through the vascular system in health and disease.
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http://dx.doi.org/10.1002/JLB.MA0718-295RRDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7587463PMC
June 2019

Screening for asymptomatic β-cell autoimmunity in young children.

Lancet Child Adolesc Health 2019 05 10;3(5):288-290. Epub 2019 Feb 10.

DFG-Center for Regenerative Therapies Dresden, Faculty of Medicine, Technical University of Dresden, Dresden, Germany.

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http://dx.doi.org/10.1016/S2352-4642(19)30028-8DOI Listing
May 2019

A standardized microdilution susceptibility test to determine the resistance capacity of human pathogenic bacteria towards hydrogen peroxide.

J Microbiol Methods 2018 12 2;155:24-26. Epub 2018 Nov 2.

Department of Pediatrics, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse 74, 01307 Dresden, Germany.

The susceptibility protocol established in this study takes into account that complex media are capable to buffer HO which otherwise may adulterate test results. Furthermore, we demonstrate that clinical isolates of Staphylococcus aureus showed a higher resistance against HO than Streptococcus pyogenes after 30 mins of incubation but not after 24 h.
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http://dx.doi.org/10.1016/j.mimet.2018.11.001DOI Listing
December 2018

Canakinumab in patients with systemic juvenile idiopathic arthritis and active systemic features: results from the 5-year long-term extension of the phase III pivotal trials.

Ann Rheum Dis 2018 12 29;77(12):1710-1719. Epub 2018 Sep 29.

Division of Rheumatology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.

Objectives: To evaluate the long-term efficacy and safety of canakinumab in patients with active systemic juvenile idiopathic arthritis (JIA).

Methods: Patients (2-19 years) entered two phase III studies and continued in the long-term extension (LTE) study. Efficacy assessments were performed every 3 months, including adapted JIA American College of Rheumatology (aJIA-ACR) criteria, Juvenile Arthritis Disease Activity Score (JADAS) and ACR clinical remission on medication criteria (CR). Efficacy analyses are reported as per the intent-to-treat population.

Results: 144 of the 177 patients (81%) enrolled in the core study entered the LTE. Overall, 75 patients (42%) completed and 102 (58%) discontinued mainly for inefficacy (63/102, 62%), with higher discontinuation rates noted in the late responders group (n=25/31, 81%) versus early responders (n=11/38, 29%). At 2 years, aJIA-ACR 50/70/90 response rates were 62%, 61% and 54%, respectively. CR was achieved by 20% of patients at month 6; 32% at 2 years. A JADAS low disease activity score was achieved by 49% of patients at 2 years. Efficacy results were maintained up to 5 years. Of the 128/177 (72.3%) patients on glucocorticoids, 20 (15.6%) discontinued and 28 (22%) tapered to 0.150 mg/kg/day. Seven patients discontinued canakinumab due to CR. There were 13 macrophage activation syndrome (three previously reported) and no additional deaths (three previously reported). No new safety findings were observed.

Conclusion: Response to canakinumab treatment was sustained and associated with substantial glucocorticoid dose reduction or discontinuation and a relatively low retention-on-treatment rate. No new safety findings were observed on long-term use of canakinumab.

Trial Registration Numbers: NCT00886769, NCT00889863, NCT00426218 and NCT00891046.
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http://dx.doi.org/10.1136/annrheumdis-2018-213150DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6241618PMC
December 2018