Maintenance of Elective Patient Care at Berlin University Children's Hospital During the COVID-19 Pandemic

Background: In Germany, so far the COVID-19 pandemic evolved in two distinct waves, the first beginning in February and the second in July, 2020. The Berlin University Children's Hospital at Charité (BCH) had to ensure treatment for children not infected and infected with SARS-CoV-2. Prevention of nosocomial SARS-CoV-2 infection of patients and staff was a paramount goal. Pediatric hospitals worldwide discontinued elective treatments and established a centralized admission process. Methods: The response of BCH to the pandemic adapted to emerging evidence. This resulted in centralized admission via one ward exclusively dedicated to children with unclear SARS-CoV-2 status and discontinuation of elective treatment during the first wave, but maintenance of elective care and decentralized admissions during the second wave. We report numbers of patients treated and of nosocomial SARS-CoV-2 infections during the two waves of the pandemic. Results: During the first wave, weekly numbers of inpatient and outpatient cases declined by 37% (p < 0.001) and 29% (p = 0.003), respectively. During the second wave, however, inpatient case numbers were 7% higher (p = 0.06) and outpatient case numbers only 6% lower (p = 0.25), compared to the previous year. Only a minority of inpatients were tested positive for SARS-CoV-2 by RT-PCR (0.47% during the first, 0.63% during the second wave). No nosocomial infection of pediatric patients by SARS-CoV-2 occurred. Conclusion: In contrast to centralized admission via a ward exclusively dedicated to children with unclear SARS-CoV-2 status and discontinuation of elective treatments, maintenance of elective care and decentralized admission allowed the almost normal use of hospital resources, yet without increased risk of nosocomial infections with SARS-CoV-2. By this approach unwanted sequelae of withheld specialized pediatric non-emergency treatment to child and adolescent health may be avoided

The relevance of the proteins Bax and Bak to the induction of apoptosis by the BH3-only protein Harakiri

In malignen Zellen ist Apoptose häufig dysreguliert. Entscheidend bei der Regulierung der Apoptoseinduktion ist die Bcl-2-Proteinfamilie, deren Vertreter mittels Bcl-2-homologen Domänen (BH 1-4) interagieren. Die Proteinfamilie umfasst antiapoptotische Proteine wie Mcl-1 und proapoptotische wie Bax und Bak. Harakiri (Hrk) gehört zur proapoptotischen Untergruppe der lediglich die BH3-Domäne aufweisenden BH3 only-Proteine, die Bax und Bak durch Hemmung der antiapoptotischen Proteine aktivieren. Da die Expression von Hrk in verschiedenen Neoplasien erniedrigt ist, sollte in dieser Arbeit untersucht werden, welche Expressionsmuster von Bax und Bak Neoplasien einer Tumortherapie mittels Substitution von Hrk zugänglich machen. Um die durch Hrk aktivierten Signalwege zu untersuchen, wurde ein rekombinanter adenoviraler Vektor (Ad-Hrk) zur regulierbaren Überexpression von Hrk hergestellt. Mit dem Vektor transfizierte Hrk-negative HCT 116-Coloncarcinomzellen zeigen unter sog. On-Bedingungen eine deutliche Hrk-Expression. Die durchflusszytometrische Bestimmung der Rate hypodiploider Zellen erwies, dass die ektope Expression von Hrk in Wildtyp-HCT-116-Zellen Apoptose induziert. Um eine Abhängigkeit Hrk-induzierter Apoptose von Bax und Bak zu adressieren, wurde Hrk zusätzlich in HCT-116-Zellen mit spezifischem Verlust von Bax, Bak oder Bax und Bak überexprimiert. Im Gegensatz zu Bax-profizienten Zellen erwiesen sich Bax- defiziente HCT-116-Zellen unabhängig vom Bak-Expressionsstatus als resistent gegenüber Hrk. Hrk-Expression führte in Bax-profizienten Zellen, nicht aber in Bax-defizienten Zellen zum Verlust des mitochondrialen Membranpotentials, zur Caspase 3-Aktivierung und zur DNA-Fragmentierung. Die Hrk-Resistenz Bax- negativer/Bak-positiver HCT-116-Zellen konnte interessanterweise durch siRNA- vermittelte Herunterregulation des Bak-Inhibitors Mcl 1 überwunden werden. Die Ergebnisse zeigen, dass eine erniedrigte Bax-Expression in Kombination mit Mcl 1-Expression ein Resistenzfaktor gegenüber Hrk-induzierter Apoptose ist. Folglich kommen nur Bax exprimierende oder Mcl-1-negative Neoplasien für eine Hrk substituierende Tumortherapie in Frage. Da der Verlust von Bax und die Expression von Mcl-1 in Tumorzellen jedoch häufig vorkommen, ist vermutlich selbst in solchen Neoplasien ein Teil der Zellen resistent gegenüber Hrk- Substitution. Daher sollten entsprechende klinische Studien Kombinationstherapien mit einem Pharmakon nutzen, das diese Zellen mittels Inhibition von Mcl-1 sensibilisieren kann.Apoptosis is frequently dysregulated in malignant neoplasia. A crucial role in the regulation of apoptosis induction is played by the Bcl-2 family of proteins, which interact via Bcl-2 homology domains (BH1-4). The protein family comprises antiapoptotic proteins, such as Mcl-1, as well as proapoptotic proteins, such as Bax and Bak. Harakiri (Hrk) belongs to the subgroup of proapoptotic proteins which exhibit only the BH3 domain and are therefore called BH3-only proteins. These proteins activate Bax and Bak by inhibiting the antiapoptotic Bcl-2 family members. As the expression of hrk is suppressed in different types of neoplasia, Hrk is a potential target of a therapy that focusses on inducing apoptosis in tumour cells. The aim of this study is to determine which expression patterns of Bax and Bak in tumours are suitable for Hrk functionally substituting tumour therapies. To investigate the signaling pathways downstream of Hrk, a recombinant adenoviral vector system (Ad-Hrk) for controlled overexpression of the protein was established. HCT 116 colon carcinoma cells transfected with Ad-Hrk show a distinct expression of Hrk if incubated under so-called On-conditions. Flow cytometric analysis of the rate of hypodiploid cells revealed induction of apoptosis in wild type HCT 116 cells after ectopic expression of Hrk. To address a potential dependency of Hrk-induced apoptosis from Bax and Bak, Hrk was overexpressed also in HCT 116 cells with specific loss of Bax, Bak or both. In contrast to Bax-proficient cells, Bax-deficient HCT 116 cells turned out to be resistant to Hrk. This was irrespective of the expression status of Bak. In Bax proficient, but not in Bax deficient cells, expression of Hrk lead to loss of the mitochondrial membrane potential, activation of Caspase 3 and DNA fragmentation. Interestingly, the resistance of Bax negative/Bak positive HCT 116 cells towards Hrk was overcome by siRNA-mediated downregulation of the Bak inhibitor Mcl-1. The results demonstrate that a reduced expression of Bax in combination with the expression of Mcl 1 is a resistance factor against Hrk induced apoptosis. Hence only Bax expressing or Mcl-1 negative neoplasms are suitable for an Hrk substituting tumour therapy. As the loss of Bax and the expression of Mcl 1 are frequently found in tumour cells, presumably even in such neoplasms a part of the cells is resistant towards substitution of Hrk. Therefore accordant clinical studies ought to be based on combination therapies with drugs which can sensitize these cells by inhibition of Mcl 1

Geographical Accessibility of Pediatric Inpatient, Nephrology, and Urology Services in Europe

Background: Although many children with diseases of the kidneys and the urinary tract may not tolerate long journeys, the number of facilities that provide specialized care for these patients is limited. Therefore, the geographical accessibility of the required health services is critical especially in this patient group. We have analyzed the geographical accessibility of pediatric inpatient and nephro-urology services in Germany, Ireland, and the United Kingdom (UK). Methods: This study introduces a model to compare countries or regions regarding the geographical accessibility of their health services. We calculated the geodesic distances, travel distances, and travel time by car from evenly distributed random points to the nearest facilities that provide pediatric inpatient or nephro-urology outpatient services (pediatric inpatient ward, urology clinic, nephrology clinic, hemodialysis unit). The results were weighted by population density. We compared the three countries with regard to the accessibility of the named services. Results: Weighted median travel times from the random points to the nearest pediatric inpatient ward are < 30 min in all countries. Weighted travel times to the nearest point of pediatric service are shortest in the UK (median <50 min) and longest in Ireland (median <90 min), regardless of the type of service (p < 0.0001). Non-weighted travel times to the nearest pediatric inpatient ward and hemodialysis unit, however, are shorter in Germany than in the UK (p < 0.0001). Conclusions: There is a surprising disparity between the travel times to the nearest facility with pediatric nephro-urology service in these three industrialized European countries. Reasons may be differences in the geographical distribution of the population, the focus of the health care system, and a different degree of clinical networking

A Case Report: First Long-Term Treatment With Burosumab in a Patient With Cutaneous-Skeletal Hypophosphatemia Syndrome

Epidermal nevus syndromes encompass a highly heterogeneous group of systemic disorders, characterized by epidermal nevi, and a spectrum of neuromuscular, ocular, and bone abnormalities. Cutaneous-skeletal hypophosphatemia syndrome (CSHS) constitutes a specific sub-entity in which elevated levels of fibroblast growth factor-23 cause hypophosphatemic rickets that are, to date, not amenable to causal therapy. Here, we report the first long-term follow-up of causal treatment with burosumab in a 3-year-old female patient with CSHS. 4 weeks after initiation of burosumab treatment, serum phosphate normalized to age-appropriate levels. Furthermore, long-term follow-up of 42 months revealed significant improvement of linear growth and gross physical functions, including respiratory insufficiency. Radiographic rickets severity as well as subjective bone pain were strongly reduced, and no side effects were observed over the course of treatment. In summary, we, here, report about a successful treatment of hypophosphatemic rickets in CSHS with burosumab over the time course of 42 months. In our patient, burosumab showed convincing efficacy and safety profile, without any loss of effect or increase of dose