HZ/Su, branded as 'Shingrix', is one of the newest vaccines to be submitted for multi-national regulatory approval. It is targeted to prevent shingles, a global concern with aging populations. A live ...attenuated vaccine for shingles has been available for over a decade, however it is contraindicated in specific subgroups of people, and there are added concerns regarding long-term immunogenicity. HZ/Su is the first subunit vaccine developed to protect against shingles. This paper provides a critical appraisal of current evidence regarding HZ/Su.
•This review investigates neuroimaging in Japanese encephalitis and dengue.•Thalamic lesions frequently occurred in both Japanese encephalitis and dengue encephalitis.•Immunoglobulin M in the ...cerebrospinal fluid was associated with thalamic lesions in Japanese encephalitis but not in dengue.•In dengue cases diagnosed with antigen or polymerase chain reaction tests, brain lesions were common.•Magnetic resonance imaging revealed more brain lesions than x-ray computed tomography.
Japanese encephalitis virus (JEV) and dengue virus (DENV) represent important causes of encephalitis in Asia. Brain imaging may provide diagnostic clues about the etiology of infectious encephalitis. We performed a systematic review of brain imaging findings in Japanese encephalitis (JE) and DENV neurological infection (dengue) to identify characteristic lesions.
Five databases were searched. We included all study types and imaging techniques. Laboratory methods were categorized using diagnostic confidence levels. Imaging data were synthesized, and focal findings are presented as proportions for JE and dengue and for subgroups based on diagnostic confidence.
Thalamic lesions were the most reported magnetic resonance imaging finding in both diseases but appeared to occur more often in JE (74% in 23 studies) than dengue (29.4% in 58 studies). In cases diagnosed with antigen or nucleic acid tests, thalamic lesions were reported frequently in both JE (76.5% in 17 studies) and dengue (65.2% in 23 studies).
The results suggest that thalamic lesions frequently occur in both JE and dengue encephalitis. No radiological findings were found to be pathognomonic of either disease. Although brain imaging may support a diagnosis, laboratory confirmation with highly specific tests remains crucial.
Japanese encephalitis virus (JEV) is a major cause of encephalitis in Asia, and the commonest cause of mosquito-borne encephalitis worldwide. Detection of JEV RNA remains challenging due to the ...characteristic brief and low viraemia, with 0-25% of patients positive, and the mainstay of diagnosis remains detection of anti-JEV IgM antibody.
We performed a systematic review of published RT-PCR protocols, and evaluated them in silico and in vitro alongside new primers and probes designed using a multiple genome alignment of all JEV strains >9,000nt from GenBank, downloaded from the NCBI website (November 2016). The new assays included pan-genotype and genotype specific assays targeting genotypes 1 and 3.
Ten RT-qPCR assays were compared, a pre-existing in-house assay, three published assays and six newly designed assays, using serial RNA dilutions. We selected three assays, one published and two novel assays, with the lowest limit of detection (LOD) for further optimisation and validation. One of the novel assays, detecting NS2A, showed the best results, with LOD approximately 4 copies/ reaction, and no cross-reaction on testing closely related viruses in the JEV serocomplex, West Nile Virus and St. Louis Virus. The optimised assays were validated in consecutive patients with central nervous system infections admitted to hospitals in Laos, testing paired CSF and serum samples.
We succeeded in developing a JEV specific RT-qPCR assay with at least 1 log10 improved sensitivity as compared to existing assays. Further evaluation is required, field-testing the assay in a larger group of patients.
Japanese encephalitis (JE) virus (JEV) remains a leading cause of neurological infection across Asia. The high lethality of disease and absence of effective therapies mean that standardised animal ...models will be crucial in developing therapeutics. However, published mouse models are heterogeneous. We performed a systematic review, meta-analysis and meta-regression of published JEV mouse experiments to investigate the variation in model parameters, assess homogeneity and test the relationship of key variables against mortality.
A PubMed search was performed up to August 2020. 1991 publications were identified, of which 127 met inclusion criteria, with data for 5026 individual mice across 487 experimental groups. Quality assessment was performed using a modified CAMARADES criteria and demonstrated incomplete reporting with a median quality score of 10/17. The pooled estimate of mortality in mice after JEV challenge was 64.7% (95% confidence interval 60.9 to 68.3) with substantial heterogeneity between experimental groups (I^2 70.1%, df 486). Using meta-regression to identify key moderators, a refined dataset was used to model outcome dependent on five variables: mouse age, mouse strain, virus strain, virus dose (in log10PFU) and route of inoculation. The final model reduced the heterogeneity substantially (I^2 38.9, df 265), explaining 54% of the variability.
This is the first systematic review of mouse models of JEV infection. Better adherence to CAMARADES guidelines may reduce bias and variability of reporting. In particular, sample size calculations were notably absent. We report that mouse age, mouse strain, virus strain, virus dose and route of inoculation account for much, though not all, of the variation in mortality. This dataset is available for researchers to access and use as a guideline for JEV mouse experiments.
•Japanese encephalitis virus (JEV) remains a leading cause of neurological infection in Asia.•A systematic review identified 20,212 published human cases of laboratory-confirmed JEV infections from ...205 studies.•15,167 (75%) of cases were confirmed with the lowest confidence diagnostic test, i.e., level 3 or 4, or level 4.•Only 109 (53%) of the studies reported contemporaneous testing for dengue-specific antibodies.•A fundamental pre-requisite for the control of JE is lacking — that of a simple and specific diagnostic procedure that can be adapted for point-of-care tests and readily used throughout JE endemic regions of the world.
Japanese encephalitis virus infection (JE) remains a leading cause of neurological disease in Asia, mainly involving individuals living in remote areas with limited access to treatment centers and diagnostic facilities. Laboratory confirmation is fundamental for the justification and implementation of vaccination programs. We reviewed the literature on historical developments and current diagnostic capability worldwide, to identify knowledge gaps and instill urgency to address them.
Searches were performed in Web of Science and PubMed using the term 'Japanese encephalitis' up to 13th October 2019. Studies reporting laboratory-confirmed symptomatic JE cases in humans were included, and data on details of diagnostic tests were extracted. A JE case was classified according to confirmatory levels (Fischer et al., 2008; Campbell et al., 2011; Pearce et al., 2018; Heffelfinger et al., 2017), where level 1 represented the highest level of confidence.
20,212 published JE cases were identified from 205 studies. 15,167 (75%) of these positive cases were confirmed with the lowest-confidence diagnostic tests (level 3 or 4, or level 4). Only 109 (53%) of the studies reported contemporaneous testing for dengue-specific antibodies.
A fundamental pre-requisite for the control of JEV is lacking — that of a simple and specific diagnostic procedure that can be adapted for point-of-care tests and readily used throughout JE-endemic regions of the world.
Background The panel of fluid- and imaging-based biomarkers available for neurodegenerative disease research is growing and has the potential to close important gaps in research and the clinic. With ...this growth and increasing use, appropriate implementation and interpretation are paramount. Various biomarkers feature nuanced differences in strengths, limitations, and biases that must be considered when investigating disease etiology and clinical utility. For example, neuropathological investigations of Alzheimer's disease pathogenesis can fall in disagreement with conclusions reached by biomarker-based investigations. Considering the varied strengths, limitations, and biases of different research methodologies and approaches may help harmonize disciplines within the neurodegenerative disease field. Purpose of review Along with separate review articles covering fluid and imaging biomarkers in this issue of Alzheimer's Research and Therapy, we present the result of a discussion from the 2019 Biomarkers in Neurodegenerative Diseases course at the University College London. Here, we discuss themes of biomarker use in neurodegenerative disease research, commenting on appropriate use, interpretation, and considerations for implementation across different neurodegenerative diseases. We also draw attention to areas where biomarker use can be combined with other disciplines to understand issues of pathophysiology and etiology underlying dementia. Lastly, we highlight novel modalities that have been proposed in the landscape of neurodegenerative disease research and care. Keywords: Biomarkers, Neurodegenerative diseases, Alzheimer's disease, Tau, Amyloid, Neurofilament light chain, Magnetic resonance imaging, Positron emission tomography, Cerebrospinal fluid, Plasma biomarkers
Definitive identification of Angiostrongylus cantonensis parasites from clinical specimens is difficult. As a result, regional epidemiology and burden are poorly characterized. To ascertain presence ...of this parasite in patients in Laos with eosinophilic meningitis, we performed quantitative PCRs on 36 cerebrospinal fluid samples; 4 positive samples confirmed the parasite's presence.
Japanese encephalitis virus (JEV) is the most commonly identified cause of acute encephalitis syndrome (AES) in Asia. The WHO recommended test is anti-JEV ...IgM-antibody-capture-enzyme-linked-immunosorbent-assay (JEV MAC-ELISA). However, data suggest this has low positive predictive value, with false positives related to other Flavivirus infections and vaccination. JEV RT-PCR in cerebrospinal fluid (CSF) and/or serum is highly specific, but is rarely positive; 0-25% of patients that fulfil the WHO definition of JE (clinical Acute Encephalitis Syndrome (AES) and JEV MAC-ELISA positive). Testing other body fluids by JEV RT-qPCR may improve the diagnosis. As a pilot study thirty patients admitted to Mahosot Hospital 2014-2017, recruited to the South-East-Asia-Encephalitis study, were tested by JEV MAC-ELISA and two JEV real-time RT-PCR (RT-qPCR) assays (NS2A and NS3). Eleven (36.7%) were JEV MAC-ELISA positive. Available CSF and serum samples of these patients were JEV RT-qPCR negative but 2 (7%) had JEV RNA detected in their throat swabs. JEV RNA was confirmed by re-testing, and sequencing of RT-qPCR products. As the first apparent report of JEV RNA detection in human throat samples, the provides new perspectives on human JEV infection, potentially informing improving JEV detection. We suggest that testing patients' throat swabs for JEV RNA is performed, in combination with molecular and serological CSF and serum investigations, on a larger scale to investigate the epidemiology of the presence of JEV in human throats. Throat swabs are an easy and non-invasive tool that could be rolled out to a wider population to improve knowledge of JEV molecular epidemiology.
Current estimates suggest that even in the most resourced settings, the aetiology of encephalitis is identified in less than half of clinical cases. It is acknowledged that filling this gap needs a ...combination of rigorous sampling and improved diagnostic technologies. Next generation sequencing (NGS) methods are powerful tools with the potential for comprehensive and unbiased detection of pathogens in clinical samples. We reviewed the use of this new technology for the diagnosis of suspected infectious encephalitis, and discuss the feasibility for introduction of NGS methods as a frontline diagnostic test.
A systematic literature review was performed, using MESH and text word searches for variants of “sequencing” and “encephalitis” in Medline and EMbase, and searching bibliographies and citations using the Web of Science database. Two authors independently reviewed, extracted and summarised data.
The review identified 25 articles reporting 44 case reports of patients with suspected encephalitis for whom NGS was used as a diagnostic tool. We present the data and highlight themes arising from these cases. There are no randomly controlled trials to assess the utility of NGS as a diagnostic tool.
There is increasing evidence of a role for NGS in the work-up of undiagnosed encephalitis. Lower costs and increasing accessibility of these technologies will facilitate larger studies of these patients. We recommend NGS should be considered as a front-line diagnostic test in chronic and recurring presentations and, given current sample-to-result turn-around times, as second-line in acute cases of encephalitis.
Crimean-Congo haemorrhagic fever virus (CCHFV) is a pathogen of increasing public health concern, being a widely distributed arbovirus and the causative agent of the potentially fatal Crimean-Congo ...haemorrhagic fever. Hazara virus (HAZV) is a genetically and serologically related virus that has been proposed as a surrogate for antiviral and vaccine testing for CCHFV. Glycosylation analysis of HAZV has been limited; first, we confirmed for the first time the occupation of two N-glycosylation sites in the HAZV glycoprotein. Despite this, there was no apparent antiviral efficacy of a panel of iminosugars against HAZV, as determined by quantification of the total secretion and infectious virus titres produced following infection of SW13 and Vero cells. This lack of efficacy was not due to an inability of deoxynojirimycin (DNJ)-derivative iminosugars to access and inhibit endoplasmic reticulum α-glucosidases, as demonstrated by free oligosaccharide analysis in uninfected and infected SW13 and uninfected Vero cells. Even so, iminosugars may yet have potential as antivirals for CCHFV since the positions and importance of N-linked glycans may differ between the viruses, a hypothesis requiring further evaluation.
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