Abstract Background Inherited vitreoretinopathies arise as a consequence of congenital retinal vascularisation abnormalities. They represent a phenotypically and genetically heterogeneous group of disorders that can have a major impact on vision. Several genes encoding proteins and effectors of the canonical Wnt/β-catenin pathway have been associated and precise diagnosis, although difficult, is essential for proper clinical management including syndrome specific management where appropriate. This work aimed to investigate the molecular basis of disease in a single proband born to consanguineous parents, who presented with microphthalmia, persistent foetal vasculature, posterior lens vacuoles, vitreoretinal dysplasia, microcephaly, hypotelorism and global developmental delay, and was registered severely visually impaired by 5 months of age. Methods Extensive genomic pre-screening, including microarray comparative genomic hybridisation and sequencing of a 114 gene panel associated with cataract and congenital ophthalmic disorders was conducted by an accredited clinical laboratory. Whole exome sequencing (WES) was undertaken on a research basis and in vitro TOPflash transcriptional reporter assay was utilised to assess the impact of the putative causal variant. Results In the proband, WES revealed a novel, likely pathogenic homozygous mutation in the cadherin-associated protein beta-1 gene (CTNNB1), c.884C>G; p.(Ala295Gly), which encodes a co-effector molecule of the Wnt/β-catenin pathway. The proband’s parents were shown to be heterozygous carriers but ophthalmic examination did not detect any abnormalities. Functional assessment of the missense variant demonstrated significant reduction of β-catenin activity. Conclusions This is the first report of a biallelic disease-causing variation in CTNNB1. We conclude that this biallelic, transcriptional inactivating mutation of CTNNB1 causes a severe, syndromic form of microphthalmia, persistent foetal vasculature and vitreoretinal dysplasia that results in serious visual loss in infancy.

151 Table 1 Comparison of baseline characteristics and clinical outcomes between low and high E/e’ groups Abstracts A116 Heart 2021;107(Suppl 1):A1–A185 on Jne 6, 2021 by gest. P rocted by coright. httpeart.bm jcom / H ert: frst pulished as 10.113artjnl-2021-B C S .48 on 4 Jne 221. D ow nladed fom

Aims Studies of remote monitoring (RM) in heart failure (HF) speculate that patients with atrial fibrillation (AF) derive the greatest benefit. We compared the impact of RM vs. usual care on clinical outcomes for patients with and without AF enrolled in the Remote Management of Heart Failure Using Implanted Electronic Devices (REM-HF) trial. Methods and results Rhythm status was available for 1561 patients (94.6%). Three categories were defined based on total AF duration during the first year of follow-up: (i) no AF (n = 1211, 77.6%), (ii) paroxysmal AF (>= 6 min to <= 7 days; n = 92, 5.9%), and (iii) persistent/permanent AF (>7 days; n = 258, 16.5%). Clinical activity, mortality, and hospitalisation rates were compared between treatment strategies for each group. RM resulted in a greater volume of clinical activity in patients with any AF, vs. no AF, with the highest per-patient intervention required for patients with persistent/permanent AF. During 2.8 +/- 0.8 years of follow-up, RM was not associated with a reduction in all-cause or cardiovascular mortality for patients with AF. However, in patients with persistent/permanent AF, RM conferred an increased risk of recurrent cardiovascular [hazard ratio (HR) 1.40, 95% confidence interval (CI) 1.06-1.85, P = 0.018] and HF-related (HR 2.05, 95% CI 1.14-3.69, P = 0.016) hospitalisations. Conclusion In patients with HF and a cardiac implanted electronic device, RM generated greater clinical activity for patients with AF, with no associated reduction in mortality, and conversely, greater risk of cardiovascular hospitalisation amongst patients with persistent/permanent AF. RM strategies may vary in their capability to guide HF management; modified approaches may be needed to improve outcomes for HF patients with AF.

Background: Polymerase chain reaction analyses of cardiac tissues have detected viral sequences in up to 67% of cases of myocarditis. However, viruses have not been implicated in giant cell myocarditis (GCM). Furthermore, efforts to detect viruses implicated in myocarditis have been unsuccessful in more accessible samples such as peripheral blood. Methods: We used Virome Capture Sequencing for Vertbrate Viruses (VirCapSeq-VERT), a method that simultaneously screens for all known vertebrate viruses, to investigate viruses in 33 patients with myocarditis. We investigated peripheral blood mononuclear cells (n=24), plasma (n=27), endomyocardial biopsies (n=2), and cardiac tissue samples from explanted hearts (n=13). Results: Nine patients (27%) had GCM and 4 patients (13%) had fulminant myocarditis. We found the following viruses in the blood of patients with myocarditis: Epstein Barr virus (n=11, 41%), human pegivirus (n=1, 4%), human endogenous retrovirus K (n=27, 100%), and anellovirus (n=15, 56%). All tissue samples from fulminant myocarditis (n=2) and GCM (n=13) contained human endogenous retrovirus K. Conclusions: No nucleic acids from viruses previously implicated in myocarditis or other human illnesses were detected in relevant amounts in cardiac tissue samples from GCM or in blood samples from other types of myocarditis. These findings do not exclude a role for viral infection in GCM but do suggest that if viruses are implicated, the mechanism is likely to be indirect rather than due to cytotoxic infection of myocardium.

Background: Cardiac implanted electronic devices (CIEDs) can detect short durations of previously unrecognised atrial fibrillation (AF). The prognostic significance of device-detected subclinical AF, in the context of contemporary heart failure (HF) therapy, is unclear. Methods: Amongst patients enrolled in the Remote Monitoring in HF with implanted devices (REM-HF) trial, three categories were defined based on total AF duration in the first year of follow-up: no AF, subclinical AF (>= 6 min to <= 24 h), and AF >24 h. All-cause mortality, stroke, and cardiovascular hospitalisation were assessed. Results: 1561 patients (94.6%) had rhythm data: 71 (4.6%) had subclinical AF (median of 4 episodes, total duration 3.1 h) and 279 (17.9%) had AF >24 h. During 2.8 +/- 0.8 years' follow-up, 39 (2.5%) patients had a stroke. Stroke rate was highest amongst patients with subclinical AF (2.0 per 100-person years) versus no AF or AF >24 h (0.8 and 1.0 per 100-person years, respectively). In the overall cohort, AF >24 h was not an independent predictor of stroke. However, amongst patients with no history of AF (n= 932), new-onset subclinical AF conferred a three-fold higher stroke risk (adjusted HR 3.35, 95%CI 1.15-9.77, p = 0.027). AF >24 h was associated with more frequent emergency cardiovascular hospitalisation (adjusted HR 1.46, 95%CI 1.19-1.79, p < 0.0005). Neither AF classification was associated with mortality. Conclusions: In patients with HF and a CIED, subclinical AF was infrequent but, as a new finding, was associated with an increased risk of stroke. Anticoagulation remains an important consideration in this population, particularly when the clinical profile indicates a high stroke risk. (c) 2020 Published by Elsevier B.V.

Mouse kidney parvovirus (MKPV) is a member of the provisional genus Chapparvovirus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated nephropathy in immune-suppressed kidney transplant patients. Here we map four major MKPV transcripts, created by alternative splicing, to a common initiator region, and use mass spectrometry to identify "p10" and "p15" as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and the splicing-dependent putative accessory protein NS2 are conserved in all near-complete amniote chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with >60% amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that many mammal chapparvoviruses are likely to be nephrotropic.

Metagenomics revealed an impressive breadth of previously unrecognized viruses. Here, we report the virome of the Culex annulirostris Skuse mosquito, an important vector of pathogenic arboviruses in Australia. Mosquitoes were collected from three sites in the Kimberley region of Western Australia. Unbiased high-throughput sequencing (HTS) revealed the presence of 16 novel viral sequences that share less than 90% identity with known viruses. None were closely related to pathogenic arboviruses. Viruses were distributed unevenly across sites, indicating a heterogeneous Cx. annulirostris virome. Polymerase chain reaction assays confirmed HTS data and identified marked variation between the virus prevalence identified at each site.

Currently, there are over 1.9 million confirmed cases of coronavirus disease 2019 (COVID-19) globally with over 590,000 cases in the United States.1 The number of COVID-19–positive children in the United States is unknown. A report summarizing 72,314 COVID-19 cases from the Chinese Center for Disease Control and Prevention noted 416 COVID-19–positive children younger than 10.2 An observational study at Wuhan Children's Hospital noted 31 COVID-19–positive children younger than 1 year with the youngest confirmed case in a 1-day-old.3 Cases were largely characterized by upper respiratory tract infection or pneumonia, fever, cough, and pharyngeal erythema.3 Concomitant neurologic problems have been reported among COVID-19–positive adult patients.4

The discovery of hepaciviruses in non-human hosts has accelerated following the advancement of high-throughput sequencing technology. Hepaciviruses have now been described in reptiles, fish, birds, and an extensive array of mammals. Using metagenomic sequencing on pooled samples of field-collected Culex annulirostris mosquitoes, we discovered a divergent hepacivirus-like sequence, named Jogalong virus, from the Kimberley region in northern Western Australia. Using PCR, we screened the same 300 individual mosquitoes and found just a single positive sample (1/300, 0.33%). Phylogenetic analysis of the hepacivirus NS5B protein places Jogalong virus within the genus Hepacivirus but on a distinct and deeply rooted monophyletic branch shared with duck hepacivirus, suggesting a notably different evolutionary history. Vertebrate barcoding PCR targeting two mitochondrial genes, cytochrome c oxidase subunit I and cytochrome b, indicated that the Jogalong virus-positive mosquito had recently fed on the tawny frogmouth (Podargus strigoides), although it is currently unknown whether this bird species contributes to the natural ecology of this virus.

The unexpected seroconversion of sentinel mice in our facility to murine T lymphotrophic virus (MTLV) positivity led to our identification of a novel murine astrovirus that we designated murine astrovirus 2 (MuAstV-2). During our investigation, MuAstV-2 was found to be a contaminant of the T helper cell line (D10.G4.1) that was used to generate the MTLV antigen that we included in the multiplex fluorometric immunoassay (MFIA) that we used for sentinel screening. We eventually determined that cross-reactivity with the astrovirus generated a positive result in the MTLV assay. A confirmatory immunofluorometric assay (IFA) using the same MTLV-infected cell line yielded a similar result. However, the use of antigen prepared from MTLV-infected neonatal mouse thymus did not reproduce a positive result, leading us to suspect that the seroreactivity we had observed was not due to infection with MTLV. A mouse antibody production test showed that mice inoculated with naïve D10.G4.1 cells and their contact sentinels tested positive for MTLV using cell-line generated antigen, but tested negative in assays using MTLV antigen produced in mice. Metagenomic analysis was subsequently used to identify MuAstV-2 in feces from 2 sentinel mice that had recently seroconverted to MTLV. Two closely related astrovirus sequences (99.6% capsididentity) were obtained and shared 95% capsid amino acid identity with the MuAstV-2 virus sequenced from the D10.G4.1 cell line. These viruses are highly divergent from previously identified murine astroviruses, displaying <30% capsid identity, yet were closely related to murine astrovirus 2 (85% capsid identity), which had recently been isolated from feral mice in New York City. A MuAstV-2 specific PCR assay was developed and used to eradicate MuAstV-2 from the infected colony using a test and cull strategy. The newly identified MuAstV2 readily transmits to immunocompetent mouse strains by fecal-oral exposure, but fails to infect NOD Prkdcem26Cd52Il2rgem26Cd22/NjuCrl (NCG) mice, which have significantly impaired adaptive and innate immune systems. Neither immunocompetent nor immunodeficient mice showed any astrovirus-associated pathology. MuAstV-2 may provide a valuable model for the study of specific aspects of astrovirus pathogenesis and virus-host interactions.

fl uenza and seasonal infl uenza diagnosed in Western Australia during the 2009 infl uenza season. From 3,178 eligible reports, 984 pandemic and 356 seasonal infl uenza patients were selected; 871 (88.5%) and 288 (80.9%) were interviewed, respectively. Patients in both groups reported a median of 6 of 11 symptoms; the difference between groups in the proportion reporting any given symptom was <10%. Fewer than half the patients in both groups had >1 underlying condition, and only diabetes was associated with pandemic (H1N1) 2009 infl uenza (odds ratio [OR] 1.9, 95% confi dence interval [CI] 1.1–3.5). A total of 129 (14.8%) persons with pandemic (H1N1) 2009 and 36 (12.5%) persons with seasonal infl uenza were hospitalized (p = 0.22). After controlling for age, we found that patient hospitalization was associated with pandemic (H1N1) 2009 infl uenza (OR 1.5; 95% CI 1.1–2.1). Contemporaneous pandemic and seasonal infl uenza infections were substantially similar in terms of patients’ symptoms, risk factors, and proportion hospitalized.

Recent advances in high-throughput sequencing technology have led to a rapid expansion in the number of viral sequences associated with samples from vertebrates, invertebrates and environmental samples. Accurate host identification can be difficult in assays of complex samples that contain more than one potential host. Using unbiased metagenomic sequencing, we investigated wild house mice (Mus musculus) and brown rats (Rattus norvegicus) from New York City to determine the aetiology of liver disease. Light microscopy was used to characterize liver disease, and fluorescent microscopy with in situ hybridization was employed to identify viral cell tropism. Sequences representing two novel negative-sense RNA viruses were identified in homogenates of wild house mouse liver tissue: Amsterdam virus and Fulton virus. In situ hybridization localized viral RNA to Capillaria hepatica, a parasitic nematode that had infected the mouse liver. RNA from either virus was found within nematode adults and unembryonated eggs. Expanded PCR screening identified brown rats as a second rodent host for C. hepatica as well as both nematode-associated viruses. Our findings indicate that the current diversity of nematode-associated viruses may be underappreciated and that anatomical imaging offers an alternative to computational host assignment approaches.

Bats are implicated as natural reservoirs for a wide range of zoonotic viruses including SARS and MERS coronaviruses, Ebola, Marburg, Nipah, Hendra, Rabies and other lyssaviruses. Accordingly, many One Health surveillance and viral discovery programs have focused on bats. In this report we present viral metagenomic data from bats collected in the Kingdom of Saudi Arabia [KSA]. Unbiased high throughput sequencing of fecal samples from 72 bat individuals comprising four species; lesser mouse-tailed bat (Rhinopoma hardwickii), Egyptian tomb bat (Taphozous perforatus), straw-colored fruit bat (Eidolon helvum), and Egyptian fruit bat (Rousettus aegyptiacus) revealed molecular evidence of a diverse set of viral families: Picornaviridae (hepatovirus, teschovirus, parechovirus), Reoviridae (rotavirus), Polyomaviridae (polyomavirus), Papillomaviridae (papillomavirus), Astroviridae (astrovirus), Caliciviridae (sapovirus), Coronaviridae (coronavirus), Adenoviridae (adenovirus), Paramyxoviridae (paramyxovirus), and unassigned mononegavirales (chuvirus). Additionally, we discovered a bastro-like virus (Middle East Hepe-Astrovirus), with a genomic organization similar to Hepeviridae. However, since it shared homology with Hepeviridae and Astroviridae at ORF1 and in ORF2, respectively, the newly discovered Hepe-Astrovirus may represent a phylogenetic bridge between Hepeviridae and Astroviridae.

Mouse kidney parvovirus (MKPV) is a member of the provisional Chapparvovirus genus that causes renal disease in immune-compromised mice, with a disease course reminiscent of polyomavirus-associated nephropathy in immune-suppressed kidney transplant patients. Here we map four MKPV transcripts, created by alternative splicing, to a common transcription initiation region, and use mass spectrometry to identify “p10” and “p15” as novel chapparvovirus accessory proteins produced in MKPV-infected kidneys. p15 and a splicing-dependent putative accessory protein NS2 are conserved in all near-complete tetrapod chapparvovirus genomes currently available (from mammals, birds and a reptile). In contrast, p10 may be encoded only by viruses with >60% amino acid identity to MKPV. We show that MKPV is kidney-tropic and that the bat chapparvovirus DrPV-1 and a non-human primate chapparvovirus, CKPV, are also found in the kidneys of their hosts. We propose, therefore, that chapparvoviruses with >60% VP1 amino acid identity to MKPV be classified into a genus dubbed Nephroparvovirus , which is consistent with nomenclature for the genus Erythroparvovirus .

The microbiome of wild Mus musculus (house mouse), a globally distributed invasive pest that resides in close contact with humans in urban centers, is largely unexplored. Here, we report analysis of the fecal virome of house mice in residential buildings in New York City, NY. Mice were collected at seven sites in Manhattan, Queens, Brooklyn, and the Bronx over a period of 1 year. Unbiased highthroughput sequencing of feces revealed 36 viruses from 18 families and 21 genera, including at least 6 novel viruses and 3 novel genera. A representative screen of 15 viruses by PCR confirmed the presence of 13 of these viruses in liver. We identified an uneven distribution of diversity, with several viruses being associated with specific locations. Higher mouse weight was associated with an increase in the number of viruses detected per mouse, after adjusting for site, sex, and length. We found neither genetic footprints to known human viral pathogens nor antibodies to lymphocytic choriomeningitis virus. IMPORTANCE Mice carry a wide range of infectious agents with zoonotic potential. Their proximity to humans in the built environment is therefore a concern for public health. Laboratory mice are also the most common experimental model for investigating the pathobiology of infectious diseases. In this survey of mice trapped in multiple locations within New York City over a period of 1 year, we found a diverse collection of viruses that includes some previously not associated with house mice and others that appear to be novel. Although we found no known human pathogens, our findings provide insights into viral ecology and may yield models that have utility for clinical microbiology.

Volume 3, no. 4, e00311-18, 2018, [https://doi.org/10.1128/mSphere.00311-18][1]. Page 4 of the PDF, Fig. 1 legend: in the third line of the legend, “coding regions” should be replaced with “genes.” [1]: /lookup/doi/10.1128/mSphere.00311-18