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Enteroviruses (EVs) are highly prevalent viruses world-wide, causing a wide range of diseases in both children and adults. Insight in the global prevalence of EVs is important to define their clinical significance and total disease burden, and assists in making therapeutic decisions. While many studies have been conducted to describe epidemiology of EVs in specific (sub)populations and patient cohorts, little effort has been made to aggregate the available evidence. In the current study, we conducted a search in the PubMed and Embase (Ovid) databases to identify articles reporting EV prevalence and type distribution. We summarized the findings of 153 included studies. We found that EVs are highly prevalent viruses in all continents. Enterovirus B was the most detected species worldwide, while the other species showed continent-specific differences, with Enterovirus C more detected in Africa and Enterovirus A more detected in Asia. Echovirus 30 was by far the most detected type, especially in studies conducted in Europe. EV types in species Enterovirus B—including echovirus 30—were often detected in patient groups with neurological infections and in cerebrospinal fluid, while Enterovirus C types were often found in stool samples.

Airway organoids are polarized 3D epithelial structures that recapitulate the organization and many of the key functions of the in vivo tissue. They present an attractive model that can overcome some of the limitations of traditional 2D and Air–Liquid Interface (ALI) models, yet the limited accessibility of the organoids’ apical side has hindered their applications in studies focusing on host–pathogen interactions. Here, we describe a scalable, fast and efficient way to generate airway organoids with the apical side externally exposed. These apical-out airway organoids are generated in an Extracellular Matrix (ECM)-free environment from 2D-expanded bronchial epithelial cells and differentiated in suspension to develop uniformly-sized organoid cultures with robust ciliogenesis. Differentiated apical-out airway organoids are susceptible to infection with common respiratory viruses and show varying responses upon treatment with antivirals. In addition to the ease of apical accessibility, these apical-out airway organoids offer an alternative in vitro model to study host–pathogen interactions in higher throughput than the traditional air–liquid interface model.

Human parechoviruses (HPeV) of the species Parechovirus A are highly prevalent disease-causing pathogens in children worldwide. HPeVs are capable of causing severe disease in adults as well, but the prevalence in adults may be much lower. The aim of our present study was to determine the prevalence of HPeV in clinical samples from adults sent in for diagnostic procedures in a tertiary hospital in the Netherlands. From a total of 10,645 samples obtained from 6175 patients, 20 samples from 11 patients (0.18%) tested positive for HPeV by RT-PCR. Two patients were positive for HPeV-1, two for HPeV-3, and one for HPeV-6. Six HPeVs could not be typed. Eight of the 11 HPeV-positive patients were immunocompromised. Due to comorbidity, we were unable to attribute the patients’ clinical symptoms to the HPeV infection. The HPeV prevalence in adults found in this study is low compared to HPeV prevalence in children. This may be largely explained by the high seropositivity rates in adults, although there could be other mechanisms involved.

Background Fever without a source (FWS) in children poses a diagnostic challenge. To distinguish a self-limiting infection from a serious infection, multiple guidelines have been developed to aid physicians in the management of FWS. Currently, there is no comparison of existing FWS guidelines. Methods This comparative review describes consistencies and differences in guideline definitions and diagnostic and therapeutic recommendations. A literature search was performed to include secondary care FWS guidelines of high-income countries, composed by national or regional pediatric or emergency care associations, available in English or Dutch. Results Ten guidelines of five high-income countries were included, with varying age ranges of children with FWS. In children younger than one month with FWS, the majority of the guidelines recommended laboratory testing, blood and urine culturing and antibiotic treatment irrespective of the clinical condition of the patient. Recommendations for blood culture and antibiotic treatment varied for children aged 1–3 months. In children aged above three months, urine culture recommendations were inconsistent, while all guidelines consistently recommended cerebral spinal fluid testing and antibiotic treatment exclusively for children with a high risk of serious infection. Conclusions We found these guidelines broadly consistent, especially for children with FWS younger than one month. Guideline variation was seen most in the targeted age ranges and in recommendations for children aged 1–3 months and above three months of age. The findings of the current study can assist in harmonizing guideline development and future research for the management of children with FWS.

Parechovirus A is a species in the Parechovirus genus within the Picornaviridae family that can cause severe disease in children. Relatively little is known on Parechovirus A epidemiology and pathogenesis. This review aims to explore the Parechovirus A literature and highlight the differences between Parechovirus A genotypes from a pathogenesis standpoint. In particular, the curious case of Parechovirus-A3 and the genotype-specific disease association will be discussed. Finally, a brief outlook on Parechovirus A research is provided.

Background The first human brain organoid protocol was presented in the beginning of the previous decade, and since then, the field witnessed the development of many new brain region-specific models, and subsequent protocol adaptations and modifications. The vast amount of data available on brain organoid technology may be overwhelming for scientists new to the field and consequently decrease its accessibility. Here, we aimed at providing a practical guide for new researchers in the field by systematically reviewing human brain organoid publications. Methods Articles published between 2010 and 2020 were selected and categorised for brain organoid applications. Those describing neurodevelopmental studies or protocols for novel organoid models were further analysed for culture duration of the brain organoids, protocol comparisons of key aspects of organoid generation, and performed functional characterisation assays. We then summarised the approaches taken for different models and analysed the application of small molecules and growth factors used to achieve organoid regionalisation. Finally, we analysed articles for organoid cell type compositions, the reported time points per cell type, and for immunofluorescence markers used to characterise different cell types. Results Calcium imaging and patch clamp analysis were the most frequently used neuronal activity assays in brain organoids. Neural activity was shown in all analysed models, yet network activity was age, model, and assay dependent. Induction of dorsal forebrain organoids was primarily achieved through combined (dual) SMAD and Wnt signalling inhibition. Ventral forebrain organoid induction was performed with dual SMAD and Wnt signalling inhibition, together with additional activation of the Shh pathway. Cerebral organoids and dorsal forebrain model presented the most cell types between days 35 and 60. At 84 days, dorsal forebrain organoids contain astrocytes and potentially oligodendrocytes. Immunofluorescence analysis showed cell type-specific application of non-exclusive markers for multiple cell types. Conclusions We provide an easily accessible overview of human brain organoid cultures, which may help those working with brain organoids to define their choice of model, culture time, functional assay, differentiation, and characterisation strategies.

Gut organoids are stem cell derived 3D models of the intestinal epithelium that are useful for studying interactions between enteric pathogens and their host. While the organoid model has been used for both bacterial and viral infections, this is a closed system with the luminal side being inaccessible without microinjection or disruption of the organoid polarization. In order to overcome this and simplify their applicability for transepithelial studies, permeable membrane based monolayer approaches are needed. In this paper, we demonstrate a method for generating a monolayer model of the human fetal intestinal polarized epithelium that is fully characterized and validated. Proximal and distal small intestinal organoids were used to generate 2D monolayer cultures, which were characterized with respect to epithelial cell types, polarization, barrier function, and gene expression. In addition, viral replication and bacterial translocation after apical infection with enteric pathogens Enterovirus A71 and were evaluated, with subsequent monitoring of the pro-inflammatory host response. This human 2D fetal intestinal monolayer model will be a valuable tool to study host-pathogen interactions and potentially reduce the use of animals in research.

Pathogenesis of viral infections of the central nervous system (CNS) is poorly understood, and this is partly due to the limitations of currently used preclinical models. Brain organoid models can overcome some of these limitations, as they are generated from human derived stem cells, differentiated in three dimensions (3D), and can mimic human neurodevelopmental characteristics. Therefore, brain organoids have been increasingly used as brain models in research on various viruses, such as Zika virus, severe acute respiratory syndrome coronavirus 2, human cytomegalovirus, and herpes simplex virus. Brain organoids allow for the study of viral tropism, the effect of infection on organoid function, size, and cytoarchitecture, as well as innate immune response; therefore, they provide valuable insight into the pathogenesis of neurotropic viral infections and testing of antivirals in a physiological model. In this review, we summarize the results of studies on viral CNS infection in brain organoids, and we demonstrate the broad application and benefits of using a human 3D model in virology research. At the same time, we describe the limitations of the studies in brain organoids, such as the heterogeneity in organoid generation protocols and age at infection, which result in differences in results between studies, as well as the lack of microglia and a blood brain barrier.