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Pediatric diseases, pain and hospitalization have an important impact on children and their families. This is especially significant when considering common invasive procedures, such as blood drawing. The objectives of the study were to assess the experience of children and families during the blood drawing procedure and suggest methods for improvement. The study was conducted in a children’s hospital in Barcelona, Spain, between 2018 and 2020. A mix-method design or combination of qualitative and quantitative methodologies was developed. We carried out a search of the literature, a design thinking approach, and a survey. Results from the qualitative approach identified areas for improvement, such as, the lack of information about the process of blood collection before testing, management of fear or pain, and characteristics of the physical space, among others. Regarding the quantitative approach, 277 persons (patients and families) were interviewed. And, although there were high levels of satisfaction among them about the blood drawing procedure, they also stressed the importance of the information received prior the test, the distraction techniques, and the physical space. From these results, we made different actions like information leaflets and fact sheets, distraction elements in the waiting room (wall vinyl, therapeutic dogs and clowns), and modification of the cabins. Although these results cannot be generalized to the population, they serve as an example of how to improve patient and family experience and include them in the decision-making process. In the current pandemic, further research should be done to adapt these results to the “new normal.” Experience Framework This article is associated with the Quality & Clinical Excellence lens of The Beryl Institute Experience Framework (https://www.theberylinstitute.org/ExperienceFramework). Access other PXJ articles related to this lens. Access other resources related to this lens.

Prospective cohort studies significantly contribute to answering specific research questions in a defined population. Since 2008, the Swiss Transplant Cohort Study (STCS) systematically enrolled >95 % of all transplant recipients in Switzerland, collecting predefined data at determined time points. Designed as an open cohort, the STCS has included >3900 patients to date, with a median follow-up of 2.96 years (IQR 1.44-4.73). This review highlights some relevant findings in the field of transplant-associated infections gained by the STCS so far. Three key general aspects have crystallized: (i) Well-run cohort studies are a powerful tool to conduct genetic studies, which are crucially dependent on a meticulously described phenotype. (ii) Long-term real-life observations are adding a distinct layer of information that cannot be obtained during randomized studies. (iii) The systemic collection of data, close interdisciplinary collaboration, and continuous analysis of some key outcome data such as infectious diseases endpoints can improve patient care.

B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most common childhood malignancy. The two-step BCP-ALL pathogenesis requires in utero-induced chromosomal aberrations and additional mutagenic events for overt leukemia. In mouse models, activation-induced cytidine deaminase (AID/AICDA) was suggested to contribute to BCP-ALL pathogenesis by off-target mutagenic activity. The role of AID in patients, however, remains unclear. Moreover, AID is usually not expressed in precursor B-cells but in germinal center B-cells, where it is induced upon T-helper (Th) cell stimulation. We have previously demonstrated that autologous Th-cells supportively interacted with BCP-ALL-cells. Here, we hypothesize that this interaction additionally induces AID expression in BCP-ALL-cells, leading to off-target mutagenic activity. We show that co-culture with autologous bone marrow Th-cells induced high AICDA expression in primary BCP-ALL-cells. This induction was mediated by a mechanism similar to the induction in mature B-cells involving IL-13/Stat6, CD40L/NF-κB and TGFβ/Smad2/3 signaling. Even though Th-cell-induced AID seemed to be active in vitro in a BCP-ALL reporter cell line, extensive mutational signature analysis revealed no major contribution of AID activity to the mutational landscape in BCP-ALL patients. AID activity was neither detected in mutation clusters nor in known AID targets. Moreover, no recurrently mutated gene showed a relevant enrichment of mutations in the AID motif. Together, the lack of AID-induced mutational consequences argues towards a Th-cell-promoted yet AID-independent BCP-ALL pathogenesis and favors therapeutic research focusing on Th-cell-derived support of BCP-ALL-cells rather than AID-induced effects. Supplementary Information The online version contains supplementary material available at 10.1007/s00262-020-02835-x.

Background The burden and timeline of posttransplant infections are not comprehensively documented in the current era of immunosuppression and prophylaxis. Methods In this prospective study nested within the Swiss Transplant Cohort Study (STCS), all clinically relevant infections were identified by transplant–infectious diseases physicians in persons receiving solid organ transplant (SOT) between May 2008 and December 2014 with ≥12 months of follow-up. Results Among 3541 SOT recipients, 2761 (1612 kidney, 577 liver, 286 lung, 213 heart, and 73 kidney-pancreas) had ≥12 months of follow-up; 1520 patients (55%) suffered 3520 infections during the first year posttransplantation. Burden and timelines of clinically relevant infections differed between transplantations. Bacteria were responsible for 2202 infections (63%) prevailing throughout the year, with a predominance of Enterobacteriaceae (54%) as urinary pathogens in heart, lung, and kidney transplant recipients, and as digestive tract pathogens in liver transplant recipients. Enterococcus spp (20%) occurred as urinary tract pathogens in kidney transplant recipients and as digestive tract pathogens in liver transplant recipients, and Pseudomonas aeruginosa (9%) in lung transplant recipients. Among 1039 viral infections, herpesviruses predominated (51%) in kidney, liver, and heart transplant recipients. Among 263 fungal infections, Candida spp (60%) prevailed as digestive tract pathogens in liver transplant recipients. Opportunistic pathogens, including Aspergillus fumigatus (1.4%) and cytomegalovirus (6%), were rare, scattering over 12 months across all SOT recipients. Conclusions In the current era of immunosuppression and prophylaxis, SOT recipients experience a high burden of infections throughout the first year posttransplantation, with rare opportunistic pathogens and a predominance of bacteria., Data on burden and timeline of infections following solid organ transplantation are currently lacking. This Swiss nationwide cohort study found a high burden of infections throughout the first year posttransplantation, with rare opportunistic pathogens and a predominance of bacteria.

Aim: The European Network of Excellence for Paediatric Clinical Research, known as the TEDDY Network, carried out a survey to determine the capacity and competence of paediatric centres to perform research studies. Methods: A cross-sectional, web-based pilot survey was conducted from October 2016 to April 2017 with paediatric clinical research centres in 11 countries: Albania, Austria, Belgium, Denmark, Iceland, Ireland, Italy, Norway, Spain, Switzerland and the United Kingdom. All were registered with the TEDDY Network database. Results: We approached 107 centres and 63 provided data on their experiences and expertise in paediatric clinical trials. Four groups of performance indicators were identified, referring to scientific experience, trial readiness, trial competence, regulatory issues, ethics and patients. Most centres were actively involved in paediatric clinical research: 53 centres (84.1%) had received funds for more than five paediatric studies in the last 5 years, and 42 (66.7%) had a specific clinical trial unit and dedicated study coordinators. We concluded that the European centres we studied had the capability and capacity to conduct paediatric trials, but there was still room for improvement, including enhanced collaboration. Conclusion: This pilot survey demonstrated that there is potential for performing paediatric trials across Europe, but improvements are possible.

Nasal natural killer/T-cell lymphoma (NNKTL) is closely associated with Epstein-Barr virus (EBV) and is characterized by poor prognosis, resulting from rapid progression of lesions in the affected organs. Recent data have shown that NNKTL is associated with the aberrant expression of cyclin-dependent kinase 1 (CDK1) and its downstream target survivin, but little is known about the functional roles of CDK1 and survivin in NNKTL. In the current study, we show that knockdown of the EBV-encoded oncoprotein latent membrane protein 1 (LMP1) induces downregulation of CDK1 and survivin in NNKTL cells. Immunohistochemistry detected CDK1 and survivin expression in LMP1-positive cells of NNKTL biopsy specimens. Inhibition of CDK1 and survivin in NNKTL cells with several inhibitors led to a dose-dependent decrease in cell proliferation. In addition, the Sp1 inhibitor mithramycin, which can downregulate both CDK1 and survivin, significantly suppressed the growth of established NNKTL in a murine xenograft model. Our results suggest that LMP1 upregulation of CDK1 and survivin may be essential for NNKTL progression. Furthermore, targeting CDK1 and survivin with Sp1 inhibitors such as mithramycin may be an effective approach to treat NNKTL, which is considered to be a treatment-refractory lymphoma.

Endemic Burkitt lymphoma (eBL) is an aggressive B cell cancer characterized by an IgH/c-myc translocation and the harboring of Epstein–Barr virus (EBV). Evidence accumulates that CD4 + T cells might contribute to eBL pathogenesis. Here, we investigate the presence of CD4 + T cells in primary eBL tissue and their potential dichotomous impact on an EBV-infected pre-eBL cell model using ex vivo material and in vitro co-cultures. In addition, we establish a novel method to study the effect of IgH/c-myc translocation in primary B cells by employing a CRISPR/Cas9 knock-in approach to introduce and tag de novo translocation. We unprecedently document that CD4 + T cells are present in primary eBL tumor tissue. Furthermore, we demonstrate that CD4 + T cells on the one hand suppress eBL development by killing pre-eBL cells lacking IgH/c-myc translocation in vitro and on the other hand indirectly promote eBL development by inducing crucial EBV Latency III to Latency I switching in pre-eBL cells. Finally, we show that while the mere presence of an IgH/c-myc translocation does not suffice to escape CD4 + T-cell-mediated killing in vitro, the CD4 + T-cell-mediated suppression of EBV’s Latency III program in vivo may allow cells harboring an IgH/c-myc translocation and additional mutations to evade immune control and proliferate by means of deregulated c-myc activity, resulting in neoplasia. Thus, our study highlights the dichotomous effects of CD4 + T cells and the mechanisms involved in eBL pathogenesis, suggests mechanisms of their impact on eBL progression, and provides a novel in vitro model for further investigation of IgH/c-myc translocation.

BACKGROUND Fever in neutropenia is the most frequent complication of chemotherapy for cancer. The temperature limit defining fever used clinically varies. A higher limit can avoid unnecessary diagnoses in patients spontaneously recovering from fever. This trial primarily aimed to determine if a limit of 39·0°C ear temperature is non-inferior to 38·5°C regarding safety. METHODS This cluster-randomised, multiple crossover, non-blinded, non-inferiority trial was done in six Swiss Paediatric Oncology Group centres (clusters) in Switzerland. Patients (aged 1 to

BACKGROUND A clinical research application must be submitted for approval by a competent ethics committee (EC) before a study can be executed. There is very limited information on how such submissions could be optimised, especially regarding research in children and adolescents, which requires particular caution and age-adapted patient information. METHODS We assessed all research applications from the University Children’s Hospital Zurich submitted to the EC of the Canton of Zurich in 2014–2015, i.e., in the first two years after Switzerland’s new Human Research Act came into effect. Moreover, we validated our findings by assessing a randomly selected sample of applications from the same hospital in 2018–2019. RESULTS We assessed a total of 86 applications from 2014–2015, originating from 29 departments and sub-specialties. The EC judged that it was not responsible for three applications and declined an assessment for another three because the studies had already been conducted. Thus, we included 80 applications in the present analysis (18 clinical trials, 52 research projects, 10 further use projects). Applicants withdrew four applications before the EC’s final decision and the EC rejected two after assessment. The EC had objections in 46 (62%) of the remaining 74 applications. Formal, including formal legal, objections (n = 503) and legal objections (n = 287) accounted for the vast majority of objections. There were also 71 ethical and 82 scientific objections. The most frequent formal and formal legal objections were incomplete or missing age-adapted patient information (49%) and incorrect templates for informed consent and signature forms (46%). A review of the 20 randomly selected applications from 2018–2019 confirmed that four out of the five most frequent deficiencies relating to informed consent were identical to those observed in the 2014–2015 applications. CONCLUSIONS Careful preparation of submission documents by the investigators and close adherence to formal and legal requirements have the potential to considerably optimise and expedite the EC review process, and thus the commencement of the clinical research. Keywords: age-adapted patient information, formal deficiencies, legal deficiencies, ethical deficiencies, scientific deficiencies

Djaoud et al. show that Epstein–Barr virus infection triggers two types of human innate immune response, one mediated by the combination of NK cells and γδ T cells and the other committed to a strong NK cell response with little involvement of γδ T cells., Most humans become infected with Epstein–Barr virus (EBV), which then persists for life. Infrequently, EBV infection causes infectious mononucleosis (IM) or Burkitt lymphoma (BL). Type I EBV infection, particularly type I BL, stimulates strong responses of innate immune cells. Humans respond to EBV in two alternative ways. Of 24 individuals studied, 13 made strong NK and γδ T cell responses, whereas 11 made feeble γδ T cell responses but stronger NK cell responses. The difference does not correlate with sex, HLA type, or previous exposure to EBV or cytomegalovirus. Cohorts of EBV+ children and pediatric IM patients include both group 1 individuals, with high numbers of γδ T cells, and group 2 individuals, with low numbers. The even balance of groups 1 and 2 in the human population points to both forms of innate immune response to EBV having benefit for human survival. Correlating these distinctive responses with the progress of EBV infection might facilitate the management of EBV-mediated disease.

Unter Enzephalitis versteht man eine Entzundung des Hirnparenchyms und unter Meningitis eine Entzundung der Hirnhaute. Erstere kann direkt erregerbedingt oder infektionsassoziiert sein oder eine nicht erregerbedingte Atiologie haben. Dieser Abschnitt behandelt die viral bedingten Enzephalitiden und die wichtigsten nichtinfektiosen Ursachen sowie die viralen Meningitiden.

Mykobakterien sind aerobe, sporenlose, unbewegliche Stabchen und werden eingeteilt in die 3 Spezies-Gruppen Tuberkulose-Komplex, nichttuberkulose Mykobakterien und Lepra. Erstere und letztere werden nur von Mensch-zu-Mensch ubertragen. Demgegenuber sind nichttuberkulose Mykobakterien ubiquitar, und die Infektionsquelle konnen unbelebte Natur oder Tiere sein. Das Krankheitsspektrum reicht insbesondere bei nichttuberkulosen Mykobakterien von unspezifischen Manifestationen bis zu spezifischen Bildern wie Lungentuberkulose oder lepromatose Lepra. Der Immunkompetente kann Infektionen mit Mykobakterien meist eingrenzen und zuweilen keine Symptome zeigen, wahrend der Immuninkompetente eine Dissemination der Infektion und schwersten Verlauf mit Tod erfahren kann. Beim Immuninkompetenten werden die „typischen“ Krankheitsbilder wegen der verminderten Eingrenzung der Infektion atypisch und entgehen deshalb oft einer fruhzeitigen klinischen Erkennung. Das klinische Verdachtsmoment ist weichenstellend fur Diagnose, Therapie und die Unterbrechung der Infektkette.

Virales hamorrhagisches Fieber ist ein klinisches Syndrom, das durch hohes Fieber, Blutungsneigung, Organversagen und Schock gekennzeichnet ist. Pathophysiologisch kommt es dabei zum Austritt von Plasma aus kleinen Blutgefasen (Kapillarleck) und zu Hamorrhagien. Es konnen allerdings oft leichtere Verlaufe mit nur unspezifischen Symptomen auftreten. Das Syndrom wird durch eine Vielzahl an Viren aus unterschiedlichen Familien verursacht, deren naturliches Reservoir kleine Nagetiere, Fledermause, Primaten oder Insekten sind. Das Vorkommen der meisten hamorrhagischen Fieberviren ist geografisch beschrankt und an die Ausbreitung des Reservoirs gebunden. Die Viren werden auch als Arboviren (Kurzform fur „arthropode-borne“) bezeichnet, da sie meist uber Vektoren (Moskitos, Zecken) ubertragen werden. Auch durch Kontakt mit dem Reservoir oder akut infizierten Menschen (z. B. Ebola, Marburg), sowie uber Aerosole (z. B. Lassa, Ebola) konnen Patienten sich anstecken.

Precursor B cell acute lymphoblastic leukemia (BCP-ALL) constitutes the leading cause of cancer-related death in children. While chromosomal alterations contribute to BCP-ALL pathogenesis, they are insufficient for leukemia development. Epidemiological data and evidence from a mouse model suggest that immune responses to infections may trigger the emergence of leukemia, but the mechanisms remain unclear. Here, we show that T helper (Th) cells from bone marrow of pediatric BCP-ALL patients can be attracted and activated by autologous BCP-ALL cells. Bone-marrow Th cells supportively interacted with BCP-ALL cells, inducing upregulation of important surface molecules and BCP-ALL cell proliferation. These Th cells displayed a Th1-like phenotype and produced high levels of IFN-γ. IFN-γ was responsible for the upregulation of CD38 in BCP-ALL cells, a molecule which we found to be associated with early relapse, and accountable for the production of IP-10, a chemokine involved in BCP-ALL migration and drug resistance. Thus, our data provide mechanistic support for an involvement of Th cell immune responses in the propagation of BCP-ALL and suggest that BCP-ALL cell-supportive Th cells may serve as therapeutic target.

Background: Risk-stratified management of febrile neutropenia (FN) allows intensive management of high-risk cases and early discharge of low-risk cases. Most risk stratification systems predicting severe infection from admission variables have been derived from childhood or adult populations and consequently their value in adolescents/young adults (AYA) may vary. Our objective was to determine their value in this population.Methods: Data from the 'predicting infectious complications in children with cancer' (PICNICC) individual participant data collaboration were used to evaluate six previously described risk stratification schema in the AYA population. Complete case analyses were undertaken for five 'paediatric' rules, with imputation for specific missing variables of the 'adult' rule. The predictive performance of the rules or the outcome microbiologically defined infection (sensitivity, specificity and predictive values) were compared.Results: Among the 5,127 episodes of FN in 3,504 patients in the PICNICC collaboration data set, 603 episodes of FN from 478 patients in 20 studies were of patients 16-25 years old. The six rules demonstrated variable sensitivity (33-96%) and specificity (13-83%). Their overall discriminatory ability was poor (area under the receiver operator curve estimates 0.514-0.593).Conclusions: Both paediatric and adult FN risk stratification schema perform poorly in AYA with cancer. An alternative rule or clinical recognition of their limitations is required. (C) 2016 Elsevier Ltd. All rights reserved.

Avec cet appel conjoint, la SSP et SwissPedNet souhaitent promouvoir des etudes dans le domaine de la recherche sur les services de sante. Sont disponibles CHF 120 000.– pour trouver des reponses a des questions actuelles et urgentes emergeant du quotidien au cabinet medical.

Die SGP und SwissPedNet schreiben zusammen die Forderung einer klinischen Forschungsarbeit im Bereich der Versorgungsforschung aus. Es stehen CHF 120 000.– zur Verfugung, um Antworten auf eine aktuelle und dringende Frage aus dem Praxis-Alltag zu erhalten.

MATERIALS AND METHODS: In a pilot study, results of real-time broad-range (16S rRNA) polymerase chain reaction (PCR) performed on 45 blood samples of pediatric cancer patients with fever and neutropenia were compared with blood culture results. RESULTS: The PCR assay used, having proven a high sensitivity in artificially spiked blood samples, was positive in only three of ten blood culture-positive samples, and it was positive in 10 of 35 (29%) culture-negative samples. CONCLUSION: This broad-range PCR assay, which may identify not-grown bacteria potentially contributing to fever, needs improvement in sensitivity, and different reasons for positive PCR in negative blood culture samples need to be assessed before clinical application.

As an astute clinician, assisted by newly introduced laboratory methods, Walter Hitzig characterised the most severe inherited defect of immunity approximately 50 years ago. This deficiency first became known as “Swiss-type agammaglobulinaemia” and subsequently as “severe combined immunodeficiency” or “SCID”. Thirty years later, his team was able to cure the first Swiss infant from this lethal genetic disease by bone marrow transplantation. In the meantime, in a period of only one generation, a small group of dedicated colleagues from Europe and the USA had developed the field of paediatric immunology into a new discipline. Both the University and the Children’s Hospital (Kinderspital) of Zurich recognised the importance of this emerging specialty as well as the unique qualities of Walter Hitzig and appointed him to the first Chair of Paediatric Immunology in Continental Europe. This nomination rapidly attracted postgraduate physicians and innovative academic guests. Offers of professorships at the University Children’s Hospitals in Boston and Berlin, honourable and tempting as they were, were declined byWalter Hitzig who remained loyal to the Zurich Kinderspital. In Zurich, he continued to elucidate the role of the Haemoglobin Variant “Zurich” and the agammaglobulinemia as part of Transcobalamine II deficiency. When the younger generation remembers Walter Hitzig with high respect, this respect is also indelibly linked to his exemplary medical attitude. He cared for sick children in a holistic and humane way and promoted an intensive exchange between basic sciences and clinical practice to the benefit and well-being of his patients. This attitude was reflected in his legendary and stimulating rounds at Zurich Kinderspital with very fruitful interactions between the younger, specialised generation of paediatric haematologists, immunologists, oncologists, infectiologists, allergologists and rheumatologists, all emerging from his department. Walter Hitzig’s dedication to the comprehensive care of sick children was also reflected in his tireless engagement in the Medical Faculty of Zurich, the Swiss Society of Paediatrics and the Swiss Academy for Medical Sciences in the fields of Medical Ethics, Family Medicine and continuous medical education. Regarding his own patients, Walter Hitzig possessed a drawer full of reports of unsolved patient histories, which gave him no rest. Many of his patients, who had found the way to him only after a long medical odyssey, remained attached as adults and continued to ask for advice in important questions of everyday life. In response, they received personal letters from their fatherly Swiss paediatrician. Prof. Dr. Walter Hitzig, 1989 at a student lecture, in conversation with one of his patients

Background: Preoperative antimicrobial prophylaxis is widely used in pediatric patients undergoing appendectomy, but evidence showing a reduction of postoperative infectious complications is lacking. Methods: A prospective consecutive cohort study on changing from preoperative antimicrobial prophylaxis to no prophylaxis in children undergoing urgent appendectomy was undertaken. The impact of this change in management on postoperative infectious complications was evaluated by comparing the outcome in 100 patients receiving (group A) and a subsequent 100 patients not receiving prophylaxis (group B), which consisted of a preoperative single dose of intravenous metronidazole (10mg/kg body weight). Results: Histology confirmed acute appendicitis in 92 patients of group A and 95 patients of group B. In patients with histological simple appendicitis, postoperative infectious complications were noted in 2 (3.0%) of 69 patients from group A and in none of 70 patients from group B, and in patients with histological perforated appendicitis in 5 (22%) of 23 and 4 (16%) of 25 patients from groups A and B, respectively. Postoperative infectious complications were more frequent (p

Our previous study showed that 1H-magnetic resonance spectroscopy (1H-MRS) can detect lipid peaks characteristic for Mycobacterium tuberculosis infection in cerebral lesions of young children; therefore, we aimed to extend and validate the application of 1H-MRS for the diagnosis of active pulmonary tuberculosis lesions in three adolescent patients. Here, we document lipid peaks characteristic for M. tuberculosis infection by 1H-MRS from lung tissue surrounding lung cavities of two patients whose sputum samples were positive for acid-fast bacilli by microscopy and positive for M. tuberculosis by genetic testing, indicating active tuberculosis. A similar lipid peak was found also in the pleural effusion of a third patient with concurrent lung cavity compatible with active tuberculosis. However, in a patient with a pyogenic pulmonary abscess, 1H-MRS of the drained pus displayed different characteristic peaks but no lipid peak at all. Conclusion: Our findings further validate 1H-MRS as a rapid, non-invasive, and specific diagnostic tool for active tuberculosis in children with microbiologically documented infection outside the central nervous system, specifically in the lungs.

BACKGROUND Children travelling are potentially exposed to a wide spectrum of illness, which includes not only mild self-limiting disease but also severe illness requiring hospitalization. Risk factors for hospitalization need to be analyzed to inform prevention and treatment strategies for travel-related disease, to make travelling for children-from a medical perspective-more secure. METHODS We performed a cross-sectional analysis on children with travel-related disease presenting at the Emergency Room of University of Zurich Children's Hospital between July 2007 and December 2012. The profile of children being hospitalized was compared with that of children treated as outpatients. RESULTS Eight hundred and one children (57.4% male) were included in the study. Eighty-three children (10.4%) were treated as inpatients. Compared with outpatients, inpatients were significantly more likely to be male, to have travelled to Southern Asia, to have a diagnosis of Salmonella typhi or Salmonella paratyphi (3.6 % vs. 0.1%, P < 0.0001), pyogenic abscess (3.6% vs. 0.1 %, P < 0.0001) or malaria (1.4 % vs. 0.2%, P = 0.0384). Neurologic diagnoses (such as seizure disorder: 3.6% vs. 0.4%, P < 0.0001) were diagnosed more often among inpatients. Furthermore, inpatients presented more often with nonspecific findings such as dehydration (8.5% vs. 0.6%, P < 0.0001). No correlation with inpatient care was seen for visiting friends and relatives/immigrant travel. CONCLUSIONS Children acquire a wide spectrum of travel-related illness. A careful, detailed travel history is important in children presenting in the emergency room with symptoms suggesting infectious disease.

Burkitt's lymphoma (BL) is the most common childhood cancer in equatorial Africa, and is endemic to areas where people are chronically co-infected with Epstein-Barr virus (EBV) and the malaria pathogen Plasmodium falciparum. The contribution of these pathogens in the oncogenic process remains poorly understood. We showed earlier that the activation of Toll-like receptor (TLR) 9 by hemozoin, a disposal product formed from the digestion of blood by P. falciparum, suppresses the lytic reactivation of EBV in BL cells. EBV lytic reactivation is regulated by the expression of transcription factor Zta (ZEBRA), encoded by the EBV gene BZLF1. Here, we explore in the BL cell line Akata, the mechanism involved in repression by TLR9 of expression of BZLF1. We show that BZLF1 repression is mediated upon TLR9 engagement by a mechanism that is largely independent of de novo protein synthesis. By CRISPR/Cas9-induced inactivation of TLR9, MyD88, IRAK4 and IRAK1 we confirm that BZLF1 repression is dependent on functional TLR9 and MyD88 signaling, and identify IRAK4 as an essential element for TLR9-induced repression of BZLF1 expression upon BCR cross-linking. Our results unprecedentedly show that TLR9-mediated inhibition of lytic EBV is largely independent of new protein synthesis and demonstrate the central roles of MyD88 and IRAK4 in this process contributing to EBV's persistence in the host's B-cell pool.

Depuis quelques années, le diagnostic d’infection sexuellement transmissible à Chlamydia trachomatis est de plus en plus souvent posé. Les infections à Chlamydia, qui touchent principalement les jeunes femmes, sont redoutées en raison du risque d’infection ascendante (maladie inflammatoire pelvienne) et des complications potentielles sévères, telles que grossesse extra-utérine et stérilité. Même si ces troubles sont beaucoup plus rares que ce que l’on pensait, la prise en charge des personnes atteintes doit être améliorée.

Epstein-Barr virus (EBV) infects >90% of the human population within the first 2 decades of life and establishes reversible latent infection in B cells. The stimuli that lead to switching from latent to lytic EBV infection in vivo are still elusive. Group A streptococci (GAS) are a common cause of bacterial pharyngotonsillitis in children and adolescents and colonize the tonsils and pharynx of up to 20% of healthy children. Thus, concomitant presence of EBV and GAS in the same individual is frequent. Here, we show that EBV carriers who are colonized with GAS shed EBV particles in higher numbers in their saliva, compared with EBV carriers not colonized with GAS. Messenger RNA levels of the master lytic regulatory EBV gene BZLF1 were more frequently detected in tonsils from EBV carriers colonized with GAS than from EBV carriers not colonized. Heat-killed GAS, potentially mimicking GAS colonization, elicited lytic EBV in latently infected lymphoblastoid cell lines (LCLs) partially via Toll-like receptor 2 triggering, as did purified GAS peptidoglycan. Thus, colonization by GAS might benefit EBV by increasing the EBV load in saliva and thereby enhancing the likelihood of EBV spread to other hosts.

Der Einsatz und Erfolg der kombinierten antiretroviralen Therapie hat dazu geführt, dass heterosexuelle sowie vertikale HIV-Transmissionen nur noch selten vorkommen. HIV-infizierte Frauen werden immer häufiger schwanger und können durch präventive Maßnahmen, v. a. in den industrialisierten Ländern, HIV-negative gesunde Kinder gebären. Im nachfolgenden Artikel gehen wir auf die Bedeutung einer HIV-Infektion und auf die wichtigsten diagnostischen sowie therapeutischen Aspekte in der Schwangerschaft ein.

Die Rate der vertikalen HIV-Übertragung von der infizierten Mutter auf das Kind liegt heute in der Schweiz bei < 1 %, wenn die Mutter erfolgreich gegen HIV behandelt und das Neugeborene sowohl eine Postexpositionsprophylaxe (PEP) erhält und nicht an der Brust ernährt wird. Die interdisziplinäre Festlegung von Anti-HIV-Therapie der Schwangeren, Geburtsmodus und PEP beim Kind sind essentiell. Beim Kind muss bei entsprechender Klinik dennoch an eine HIV-Infektion gedacht werden, da die Diagnose der HIV-Infektion bei der Mutter und somit der Übertragung zuweilen verpasst wird.