High prevalence of anelloviruses in vitreous fluid of children with seasonal hyperacute panuveitis.

Seasonal hyperacute panuveitis (SHAPU) is a potentially blinding ocular disease occurring in Nepal that principally affects young children. Random amplification of partially purified vitreous fluid (VF)-derived nucleic acid revealed the presence of human anelloviruses in VF of SHAPU patients. In a comparative study of patients with different ocular pathologies, SHAPU patients were at highest risk of harboring anelloviruses in their eyes. The majority of SHAPU patients had multiple anelloviruses in their VF. The ocular anellovirus load in SHAPU and non-SHAPU patients did not differ and no SHAPU-specific anellovirus variant was detected. Analysis of paired serum and VF samples from SHAPU and non-SHAPU patients showed that the anellovirus detected in VF samples most likely originated from the systemic viral pool during viremia, potentially through breakdown of the blood-ocular barrier. The detection of anelloviruses in VF samples of uveitis patients, profoundly so in SHAPU patients, is imperative and warrants elucidation of its clinical significance

Islands of linkage in an ocean of pervasive recombination reveals two-speed evolution of human cytomegalovirus genomes

Human cytomegalovirus (HCMV) infects most of the population worldwide, persisting throughout the host's life in a latent state with periodic episodes of reactivation. While typically asymptomatic, HCMV can cause fatal disease among congenitally infected infants and immunocompromised patients. These clinical issues are compounded by the emergence of antiviral resistance and the absence of an effective vaccine, the development of which is likely complicated by the numerous immune evasins encoded by HCMV to counter the host's adaptive immune responses, a feature that facilitates frequent super-infections. Understanding the evolutionary dynamics of HCMV is essential for the development of effective new drugs and vaccines. By comparing viral genomes from uncultivated or low-passaged clinical samples of diverse origins, we observe evidence of frequent homologous recombination events, both recent and ancient, and no structure of HCMV genetic diversity at the whole-genome scale. Analysis of individual gene-scale loci reveals a striking dichotomy: while most of the genome is highly conserved, recombines essentially freely and has evolved under purifying selection, 21 genes display extreme diversity, structured into distinct genotypes that do not recombine with each other. Most of these hyper-variable genes encode glycoproteins involved in cell entry or escape of host immunity. Evidence that half of them have diverged through episodes of intense positive selection suggests that rapid evolution of hyper-variable loci is likely driven by interactions with host immunity. It appears that this process is enabled by recombination unlinking hyper-variable loci from strongly constrained neighboring sites. It is conceivable that viral mechanisms facilitating super-infection have evolved to promote recombination between diverged genotypes, allowing the virus to continuously diversify at key loci to escape immune detection, while maintaining a genome optimally adapted to its asymptomatic infectious lifecycle

People in Personal Learning Networks: Analysing their Characteristics and Identifying Suitable Tools

In recent years, the concept of a Personal Learning Network (PLN) as a structure to support personal learning has become more and more widespread. A Personal Learning Network refers to the network of people a self-directed learner connects with for the specific purpose of supporting their learning. An effective use of PLNs as learning resources depends on various networking skills of the learners. These skills include content-related skills such as such as being able to engage in conversations and being able to communicate ideas, thoughts and opinions to the listener, but also (ii) skills regarding the process of networking itself to continuously build, maintain and activate PLNs, in particular to be able to identify the experience and expertise of the connections in their PLNs. Relationships for learning in a PLN are often supported through various technical instruments and platforms. Although many technologies are being developed to support learners' construction and maintenance of their Personal Learning Network, the design is often based on certain assumptions on what learners consider important for their own social learning. However, there has been little investigation on what a learner considers important in a PLN. This article presents the results of a study on the concepts that determine whether a learner considers a contact to be valuable to their learning, the perceived relevance or importance of these concepts to the learner, and the extent to which these concepts are perceived to be supported by current popular networking platforms. The methodology used consists of a two-stage process: a scaffold activity on name generation and abstraction of concepts by participants in a workshop on networking skills, followed by a survey rating the importance of the elicited concepts and their association with 5 chosen PLN-supporting platforms. The conclusions of the study are (i) 18 concepts are generally accepted as driving a learner's PLN, (ii) that social learning via PLNs still remains very hidden, but reflective activities encourage more control over this type of learning, and (iii) that different social networking platforms fullfil different aspects of the supporting personal learning networks, with the exception of Twitter as a learning platform, that emerges from the study as the most widely applicable tool

Varicella zoster virus glycoprotein C increases chemokine-mediated leukocyte migration

Varicella zoster virus (VZV) is a highly prevalent human pathogen that establishes latency in neurons of the peripheral nervous system. Primary infection causes varicella whereas reactivation results in zoster, which is often followed by chronic pain in adults. Following infection of epithelial cells in the respiratory tract, VZV spreads within the host by hijacking leukocytes, including T cells, in the tonsils and other regional lymph nodes, and modifying their activity. In spite of its importance in pathogenesis, the mechanism of dissemination remains poorly understood. Here we addressed the influence of VZV on leukocyte migration and found that the purified recombinant soluble ectodomain of VZV glycoprotein C (rSgC) binds chemokines with high affinity. Functional experiments show that VZV rSgC potentiates chemokine activity, enhancing the migration of monocyte and T cell lines and, most importantly, human tonsillar leukocytes at low chemokine concentrations. Binding and potentiation of chemokine activity occurs through the C-terminal part of gC ectodomain, containing predicted immunoglobulin-like domains. The mechanism of action of VZV rSgC requires interaction with the chemokine and signalling through the chemokine receptor. Finally, we show that VZV viral particles enhance chemokine-dependent T cell migration and that gC is partially required for this activity. We propose that VZV gC activity facilitates the recruitment and subsequent infection of leukocytes and thereby enhances VZ

The identification and analysis of making-do waste: insights from two Brazilian construction sites

Making-do has been pointed out as an important category of waste in the construction industry. It refers to a situation in which a task starts or continues without having available all the inputs required for its completion, such as materials, machinery, tools, personnel, external conditions, and information. By contrast, the literature points out that improvisation is a ubiquitous human practice even in highly structured business organizations, and plays an important role when rules and methods fail. The aim of this paper is to provide some insights on the nature of making-do as a type of waste, based on two exploratory case studies carried out on construction sites. The main contributions of this research work are concerned with the identification of different categories of making-do and its main causes. This paper also discusses some strategies for reducing making-do on construction sites

The Dutch National TissueArchive Portal enables efficient, consistent, and transparent procurement of diagnostic tissue samples for scientific use

Biobanks play a crucial role in enabling biomedical research by facilitating scientific use of valuable human biomaterials. The PALGA foundation-a nationwide network and registry of histo- and cytopathology in the Netherlands-was established to promote the provision of data within and between pathology departments, and to make the resulting knowledge available for healthcare. Apart from the pathology data, we aimed to utilize PALGA's nationwide network to find and access the rich wealth of Formalin-Fixed Paraffin-Embedded (FFPE) tissue samples for scientific use. We implemented the Dutch National TissueArchive Portal (DNTP) to utilize PALGA's nationwide network for requesting FFPE tissue samples. The DNTP consists of (1) a centrally organized internet portal to improve the assessing, processing, harmonization, and monitoring of the procurement process, while (2) dedicated HUB-employees provide practical support at peripheral pathology departments. Since incorporation of the DNTP, both the number of filed requests for FFPE tissue samples and the amount of HUB-mediated support increased 55 and 29% respectively. In line, the sample procurement duration time decreased significantly (- 47%). These findings indicate that implementation of the DNTP improved the frequency, efficiency, and transparency of FFPE tissue sample procurement for research in the Netherlands. To conclude, the need for biological resources is growing persistently to enable precision medicine. Here, we access PALGA's national, pathology network by implementation of the DNTP to allow for efficient, consistent, and transparent exchange of FFPE tissue samples for research across the Netherlands

Brain immune cells undergo cGAS-STING-dependent apoptosis during herpes simplex virus type 1 infection

Protection of the brain from viral infections involves the type I interferon (IFN-I) system, defects in which renders humans susceptible to herpes simplex encephalitis (HSE). However, excessive cerebral IFN-I levels leads to pathologies, suggesting the need for tight regulation of responses. Based on data from mouse models, human HSE cases, and primary cell culture systems, we here show that microglia and other immune cells undergo apoptosis in the HSV-1-infected brain through a mechanism dependent on the cyclic GMP-AMP synthase (cGAS) - stimulator of interferon genes (STING) pathway, but independent of IFN-I. HSV-1 infection of microglia induced cGAS-dependent apoptosis at high viral doses, while lower viral doses led to IFN-I responses. Importantly, inhibition of caspase activity prevented microglial cell death and augmented IFN-I responses. Accordingly, HSV-1-infected organotypic brain slices, or mice treated with caspase inhibitor, exhibited lower viral load and improved outcome of infection. Collectively, we identify an activation-induced apoptosis program in brain immune cells which down-modulates local immune responses

Detection, classification, and characterization of proximal humerus fractures on plain radiographs:do convolutional neural networks still outperform humans when the task becomes increasingly complex?

Aims The purpose of this study was to develop a convolutional neural network (CNN) for fracture detection, classification, and identification of greater tuberosity displacement ≥ 1 cm, neck-shaft angle (NSA) ≤ 100°, shaft translation, and articular fracture involvement, on plain radiographs. Methods The CNN was trained and tested on radiographs sourced from 11 hospitals in Australia and externally validated on radiographs from the Netherlands. Each radiograph was paired with corresponding CT scans to serve as the reference standard based on dual independent evaluation by trained researchers and attending orthopaedic surgeons. Presence of a fracture, classification (non- to minimally displaced; two-part, multipart, and glenohumeral dislocation), and four characteristics were determined on 2D and 3D CT scans and subsequently allocated to each series of radiographs. Fracture characteristics included greater tuberosity displacement ≥ 1 cm, NSA ≤ 100°, shaft translation (0% to &lt; 75%, 75% to 95%, &gt; 95%), and the extent of articular involvement (0% to &lt; 15%, 15% to 35%, or &gt; 35%). Results For detection and classification, the algorithm was trained on 1,709 radiographs (n = 803), tested on 567 radiographs (n = 244), and subsequently externally validated on 535 radiographs (n = 227). For characterization, healthy shoulders and glenohumeral dislocation were excluded. The overall accuracy for fracture detection was 94% (area under the receiver operating characteristic curve (AUC) = 0.98) and for classification 78% (AUC 0.68 to 0.93). Accuracy to detect greater tuberosity fracture displacement ≥ 1 cm was 35.0% (AUC 0.57). The CNN did not recognize NSAs ≤ 100° (AUC 0.42), nor fractures with ≥ 75% shaft translation (AUC 0.51 to 0.53), or with ≥ 15% articular involvement (AUC 0.48 to 0.49). For all objectives, the model's performance on the external dataset showed similar accuracy levels. Conclusion CNNs proficiently rule out proximal humerus fractures on plain radiographs. Despite rigorous training methodology based on CT imaging with multi-rater consensus to serve as the reference standard, artificial intelligence-driven classification is insufficient for clinical implementation. The CNN exhibited poor diagnostic ability to detect greater tuberosity displacement ≥ 1 cm and failed to identify NSAs ≤ 100°, shaft translations, or articular fractures.</p