Background. Dengue is the most common arboviral infection of humans. There are currently no specific treatments for dengue. Balapiravir is a prodrug of a nucleoside analogue (called R1479) and an ...inhibitor of hepatitis C virus replication in vivo. Methods. We conducted in vitro experiments to determine the potency of balapiravir against dengue viruses and then an exploratory, dose-escalating, randomized placebo-controlled trial in adult male patients with dengue with <48 hours of fever. Results. The clinical and laboratory adverse event profile in patients receiving balapiravir at doses of 1500 mg (n = 10) or 3000 mg (n = 22) orally for 5 days was similar to that of patients receiving placebo (n = 32), indicating balapiravir was well tolerated. However, twice daily assessment of viremia and daily assessment of NS1 antigenemia indicated balapiravir did not measurably alter the kinetics of these virological markers, nor did it reduce the fever clearance time. The kinetics of plasma cytokine concentrations and the whole blood transcriptional profile were also not attenuated by balapiravir treatment. Conclusions. Although this trial, the first of its kind in dengue, does not support balapiravir as a candidate drug, it does establish a framework for antiviral treatment trials in dengue and provides the field with a clinically evaluated benchmark molecule. Clinical Trials Registration. NCT01096576.
Responses by peripheral blood leukocytes may contribute to the pathogenesis of dengue hemorrhagic fever (DHF). We used DNA microarrays to reveal transcriptional patterns in the blood of 14 adults ...with DHF. Acute DHF was defined by an abundance of transcripts from cell cycle— and endoplasmic reticulum (ER)—related genes, suggesting a proliferative response accompanied by ER stress. Transcript-abundance levels for immunoresponse-associated genes, including cell surface markers, immunoglobulin, and innate response elements, were also elevated. Twenty-four genes were identified for which transcript abundance distinguished patients with dengue shock syndrome (DSS) from those without DSS. All the gene transcripts associated with DSS, many of which are induced by type I interferons, were less abundant in patients with DSS than in those without DSS. To our knowledge, these data provide the first snapshot of gene-expression patterns in peripheral blood during acute dengue and suggest that DSS is associated with attenuation of selected aspects of the innate host response.
DNA microarrays and specific reverse-transcription polymerase chain reaction assays were used to reveal transcriptional patterns in the blood of children presenting with dengue shock syndrome (DSS) ...and well-matched patients with uncomplicated dengue. The transcriptome of patients with acute uncomplicated dengue was characterized by a metabolically demanding “host-defense” profile; transcripts related to oxidative metabolism, interferon signaling, protein ubiquination, apoptosis, and cytokines were prominent. In contrast, the transcriptome of patients with DSS was surprisingly benign, particularly with regard to transcripts derived from apoptotic and type I interferon pathways. These data highlight significant heterogeneity in the type or timing of host transcriptional immune responses precipitated by dengue virus infection independent of the duration of illness. In particular, they suggest that, if transcriptional events in the blood compartment contribute to capillary leakage leading to hypovolemic shock, they occur before cardiovascular decompensation, a finding that has implications for rational adjuvant therapy in this syndrome.
Hypovolemic shock (dengue shock syndrome (DSS)) is the most common life-threatening complication of dengue. We conducted a genome-wide association study of 2,008 pediatric cases treated for DSS and ...2,018 controls from Vietnam. Replication of the most significantly associated markers was carried out in an independent Vietnamese sample of 1,737 cases and 2,934 controls. SNPs at two loci showed genome-wide significant association with DSS. We identified a susceptibility locus at MICB (major histocompatibility complex (MHC) class I polypeptide-related sequence B), which was within the broad MHC region on chromosome 6 but outside the class I and class II HLA loci (rs3132468, Pmeta = 4.41 × 10−11, per-allele odds ratio (OR) = 1.34 (95% confidence interval: 1.23-1.46)). We identified associated variants within PLCE1 (phospholipase C, epsilon 1) on chromosome 10 (rs3765524, Pmeta = 3.08 × 10−10, per-allele OR = 0.80 (95% confidence interval: 0.75-0.86)). We identify two loci associated with susceptibility to DSS in people with dengue, suggesting possible mechanisms for this severe complication of dengue.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Kawasaki disease (KD) is a multisystem vasculitis that predominantly targets the coronary arteries in children. Phenotypic similarities between KD and recurrent fever syndromes point to the potential ...role of inflammasome activation in KD. Mutations in NLRP3 are associated with recurrent fever/autoinflammatory syndromes. We show that the KD-associated genetic polymorphism in inositol-triphosphate 3-kinase C (ITPKC) (rs28493229) has important functional consequences, governing ITPKC protein levels and thereby intracellular calcium, which in turn regulates NLRP3 expression and production of IL-1β and IL-18. Analysis of transcript abundance, protein levels, and cellular response profiles from matched, serial biospecimens from a cohort of genotyped KD subjects points to the critical role of ITPKC in mediating NLRP3 inflammasome activation. Treatment failure in those with the high-risk ITPKC genotype was associated with the highest basal and stimulated intracellular calcium levels and with increased cellular production of IL-1β and IL-18 and higher circulating levels of both cytokines. Mechanistic studies using Itpkc-deficient mice in a disease model support the genomic, cellular, and clinical findings in affected children. Our findings provide the mechanism behind the observed efficacy of rescue therapy with IL-1 blockade in recalcitrant KD, and we identify that regulation of calcium mobilization is fundamental to the underlying immunobiology in KD.
IMPORTANCE: To date, there is no diagnostic test for Kawasaki disease (KD). Diagnosis is based on clinical features shared with other febrile conditions, frequently resulting in delayed or missed ...treatment and an increased risk of coronary artery aneurysms. OBJECTIVE: To identify a whole-blood gene expression signature that distinguishes children with KD in the first week of illness from other febrile conditions. DESIGN, SETTING, AND PARTICIPANTS: The case-control study comprised a discovery group that included a training and test set and a validation group of children with KD or comparator febrile illness. The setting was pediatric centers in the United Kingdom, Spain, the Netherlands, and the United States. The training and test discovery group comprised 404 children with infectious and inflammatory conditions (78 KD, 84 other inflammatory diseases, and 242 bacterial or viral infections) and 55 healthy controls. The independent validation group comprised 102 patients with KD, including 72 in the first 7 days of illness, and 130 febrile controls. The study dates were March 1, 2009, to November 14, 2013, and data analysis took place from January 1, 2015, to December 31, 2017. MAIN OUTCOMES AND MEASURES: Whole-blood gene expression was evaluated using microarrays, and minimal transcript sets distinguishing KD were identified using a novel variable selection method (parallel regularized regression model search). The ability of transcript signatures (implemented as disease risk scores) to discriminate KD cases from controls was assessed by area under the curve (AUC), sensitivity, and specificity at the optimal cut point according to the Youden index. RESULTS: Among 404 patients in the discovery set, there were 78 with KD (median age, 27 months; 55.1% male) and 326 febrile controls (median age, 37 months; 56.4% male). Among 202 patients in the validation set, there were 72 with KD (median age, 34 months; 62.5% male) and 130 febrile controls (median age, 17 months; 56.9% male). A 13-transcript signature identified in the discovery training set distinguished KD from other infectious and inflammatory conditions in the discovery test set, with AUC of 96.2% (95% CI, 92.5%-99.9%), sensitivity of 81.7% (95% CI, 60.0%-94.8%), and specificity of 92.1% (95% CI, 84.0%-97.0%). In the validation set, the signature distinguished KD from febrile controls, with AUC of 94.6% (95% CI, 91.3%-98.0%), sensitivity of 85.9% (95% CI, 76.8%-92.6%), and specificity of 89.1% (95% CI, 83.0%-93.7%). The signature was applied to clinically defined categories of definite, highly probable, and possible KD, resulting in AUCs of 98.1% (95% CI, 94.5%-100%), 96.3% (95% CI, 93.3%-99.4%), and 70.0% (95% CI, 53.4%-86.6%), respectively, mirroring certainty of clinical diagnosis. CONCLUSIONS AND RELEVANCE: In this study, a 13-transcript blood gene expression signature distinguished KD from other febrile conditions. Diagnostic accuracy increased with certainty of clinical diagnosis. A test incorporating the 13-transcript disease risk score may enable earlier diagnosis and treatment of KD and reduce inappropriate treatment in those with other diagnoses.
ABSTRACT
MED13L is a component subunit of the Mediator complex, an important regulator of transcription that is highly conserved across eukaryotes. Here, we report MED13L disruption in a ...translocation t(12;19) breakpoint of a patient with Pierre–Robin syndrome, moderate intellectual disability, craniofacial anomalies, and muscular defects. The phenotype is similar to previously described patients with MED13L haploinsufficiency. Knockdown of MED13L orthologue in zebrafish, med13b, showed early defective migration of cranial neural crest cells (NCCs) that contributed to cartilage structure deformities in the later stage, recapitulating craniofacial anomalies seen in human patients. Notably, we observed abnormal distribution of developing neurons in different brain regions of med13b morphant embryos, which could be rescued upon introduction of full‐length human MED13L mRNA. To compare with mammalian system, we suppressed MED13L expression by short‐hairpin RNA in ES‐derived human neural progenitors, and differentiated them into neurons. Transcriptome analysis revealed differential expression of components of Wnt and FGF signaling pathways in MED13L‐deficient neurons. Our finding provides a novel insight into the mechanism of overlapping phenotypic outcome targeting NCCs derivatives organs in patients with MED13L haploinsufficiency, and emphasizes a clinically recognizable syndromic phenotype in these patients.
Several reports have identified structural variants and mutations affecting MED13L in patients with heart defects, craniofacial anomalies, and intellectual disability. In this study we functionally demonstrated that depletion of its orthologue in zebrafish model could recapitulate the craniofacial abnormalities in human and the observed phenotype can be reversed by introducing intact human mRNA, suggesting that gene dosage is required for normal gene function.
We examine a general wireless sensor network (WSN) model which incorporates a large number of sensors distributed over a large and complex geographical area. The study proposes solutions for a ...flexible deployment, low cost and high reliability in a wireless sensor network. To achieve these aims, we propose the application of an unmanned aerial vehicle (UAV) as a flying relay to receive and forward signals that employ nonorthogonal multiple access (NOMA) for a high spectral sharing efficiency. To obtain an optimal number of subclusters and optimal UAV positioning, we apply a sensor clustering method based on
-means unsupervised machine learning in combination with the gap statistic method. The study proposes an algorithm to optimize the trajectory of the UAV, i.e., the centroid-to-next-nearest-centroid (CNNC) path. Because a subcluster containing multiple sensors produces cochannel interference which affects the signal decoding performance at the UAV, we propose a diagonal matrix as a phase-shift framework at the UAV to separate and decode the messages received from the sensors. The study examines the outage probability performance of an individual WSN and provides results based on Monte Carlo simulations and analyses. The investigated results verified the benefits of the
-means algorithm in deploying the WSN.
Parking space management systems help organize and optimize available parking spaces for consumers, making the process of finding and using parking spaces more efficient. Current parking space ...management systems include manual recognition, the employment of magnetic and ultrasonic sensors, and, recently, computer vision (CV). One relatively new region-based convolutional neural network (R-CNN) model, Mask R-CNN, has shown promise in its ability to detect objects and has demonstrated superior performance over many other popular CV methods. Building on Mask R-CNN, an updated version, Rotated Mask R-CNN, which can generate bounding boxes the axes of which are rotated with respect to the image’s axis, was proposed to address the limitation of Mask R-CNN. Albeit with the documented theoretical benefits, the application of the rotated version is rare because of its recent invention. To this end, the study aims to detect vehicle instances in one parking lot using various Rotated Mask R-CNN models based on unmanned aircraft system collected images. Both average precision and average recall were utilized to assess the performance of the alternative models with different backbone and head networks. The results reveal the high accuracy level associated with Rotated Mask R-CNN in real-time detection of vehicles. In addition, the results indicate that the inference speed and total loss are highly correlated with head networks and training schedules.
Surface distress is an indication of poor or unfavorable pavement performance or signs of impending failure that can be classified into a fracture, distortion, or disintegration. To mitigate the risk ...of failing roadways, effective methods to detect road distress are needed. Recent studies associated with the detection of road distress using object detection algorithms are encouraging. Although current methodologies are favorable, some of them seem to be inefficient, time-consuming, and costly. For these reasons, the present study presents a methodology based on the mask regions with convolutional neural network model, which is coupled with the new object detection framework Detectron2 to train the model that utilizes roadway imagery acquired from an unmanned aerial system (UAS). For a comprehensive understanding of the performance of the proposed model, different settings are tested in the study. First, the deep learning models are trained based on both high- and low-resolution datasets. Second, three different backbone models are explored. Finally, a set of threshold values are tested. The corresponding experimental results suggest that the proposed methodology and UAS imagery can be used as efficient tools to detect road distress with an average precision score up to 95%.
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