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MBio Jul 2024Polyomaviruses are species-specific DNA viruses that can cause disease in immunocompromised individuals. Despite their role as the causative agents for several diseases,...
UNLABELLED
Polyomaviruses are species-specific DNA viruses that can cause disease in immunocompromised individuals. Despite their role as the causative agents for several diseases, there are no currently approved antivirals for treating polyomavirus infection. Brincidofovir (BCV) is an antiviral approved for the treatment of poxvirus infections and has shown activity against other double-stranded DNA viruses. In this study, we tested the efficacy of BCV against polyomavirus infection and using mouse polyomavirus (MuPyV). BCV inhibited virus production in primary mouse kidney cells and brain cortical cells. BCV treatment of cells transfected with MuPyV genomic DNA resulted in a reduction in virus levels, indicating that viral inhibition occurs post-entry. Although BCV treatment had a limited effect on viral DNA and RNA levels, drug treatment was associated with a reduction in viral protein, raising the possibility that BCV acts post-transcriptionally to inhibit MuPyV infection. In mice, BCV treatment was well tolerated, and prophylactic treatment resulted in a reduction in viral DNA levels and a potent suppression of infectious virus production in the kidney and brain. In mice with chronic polyomavirus infection, therapeutic administration of BCV decreased viremia and reduced infection in the kidney. These data demonstrate that BCV exerts antiviral activity against polyomavirus infection , supporting further investigation into the use of BCV to treat clinical polyomavirus infections.
IMPORTANCE
Widespread in the human population and able to persist asymptomatically for the life of an individual, polyomavirus infections cause a significant disease burden in the immunocompromised. Individuals undergoing immune suppression, such as kidney transplant patients or those treated for autoimmune diseases, are particularly at high risk for polyomavirus-associated diseases. Because no antiviral agent exists for treating polyomavirus infections, management of polyomavirus-associated diseases typically involves reducing or discontinuing immunomodulatory therapy. This can be perilous due to the risk of transplant rejection and the potential development of adverse immune reactions. Thus, there is a pressing need for the development of antivirals targeting polyomaviruses. Here, we investigate the effects of brincidofovir, an FDA-approved antiviral, on polyomavirus infection using mouse polyomavirus. We show that the drug is well-tolerated in mice, reduces infectious viral titers, and limits viral pathology, indicating the potential of brincidofovir as an anti-polyomavirus therapeutic.
PubMed: 38953354
DOI: 10.1128/mbio.01049-24 -
MSystems Jul 2024Nanopore direct RNA sequencing (DRS) enables the capture and full-length sequencing of native RNAs, without recoding or amplification bias. Resulting data sets may be...
UNLABELLED
Nanopore direct RNA sequencing (DRS) enables the capture and full-length sequencing of native RNAs, without recoding or amplification bias. Resulting data sets may be interrogated to define the identity and location of chemically modified ribonucleotides, as well as the length of poly(A) tails, on individual RNA molecules. The success of these analyses is highly dependent on the provision of high-resolution transcriptome annotations in combination with workflows that minimize misalignments and other analysis artifacts. Existing software solutions for generating high-resolution transcriptome annotations are poorly suited to small gene-dense genomes of viruses due to the challenge of identifying distinct transcript isoforms where alternative splicing and overlapping RNAs are prevalent. To resolve this, we identified key characteristics of DRS data sets that inform resulting read alignments and developed the nanopore guided annotation of transcriptome architectures (NAGATA) software package (https://github.com/DepledgeLab/NAGATA). We demonstrate, using a combination of synthetic and original DRS data sets derived from adenoviruses, herpesviruses, coronaviruses, and human cells, that NAGATA outperforms existing transcriptome annotation software and yields a consistently high level of precision and recall when reconstructing both gene sparse and gene-dense transcriptomes. Finally, we apply NAGATA to generate the first high-resolution transcriptome annotation of the neglected pathogen human adenovirus type F41 (HAdV-41) for which we identify 77 distinct transcripts encoding at least 23 different proteins.
IMPORTANCE
The transcriptome of an organism denotes the full repertoire of encoded RNAs that may be expressed. This is critical to understanding the biology of an organism and for accurate transcriptomic and epitranscriptomic-based analyses. Annotating transcriptomes remains a complex task, particularly in small gene-dense organisms such as viruses which maximize their coding capacity through overlapping RNAs. To resolve this, we have developed a new software nanopore guided annotation of transcriptome architectures (NAGATA) which utilizes nanopore direct RNA sequencing (DRS) datasets to rapidly produce high-resolution transcriptome annotations for diverse viruses and other organisms.
PubMed: 38953320
DOI: 10.1128/msystems.00505-24 -
[Expression Levels and Regulation of Selenoprotein Genes in Patients With Coronavirus Disease 2019].Zhongguo Yi Xue Ke Xue Yuan Xue Bao.... Jun 2024Objective To investigate the expression levels of selenoprotein genes in the patients with coronavirus disease 2019 (COVID-19) and the possible regulatory...
Objective To investigate the expression levels of selenoprotein genes in the patients with coronavirus disease 2019 (COVID-19) and the possible regulatory mechanisms.Methods The dataset GSE177477 was obtained from the Gene Expression Omnibus,consisting of a symptomatic group (=11),an asymptomatic group (=18),and a healthy control group (=18).The dataset was preprocessed to screen the differentially expressed genes (DEG) related to COVID-19,and gene ontology functional annotation and Kyoto encyclopedia of genes and genomes enrichment analysis were performed for the DEGs.The protein-protein interaction network of DEGs was established,and multivariate Logistic regression was employed to analyze the effects of selenoprotein genes on the presence/absence of symptoms in the patients with COVID-19.Results Compared with the healthy control,the symptomatic COVID-19 patients presented up-regulated expression of GPX1,GPX4,GPX6,DIO2,TXNRD1,SELENOF,SELENOK,SELENOS,SELENOT,and SELENOW and down-regulated expression of TXNRD2 and SELENON (all <0.05).The asymptomatic patients showcased up-regulated expression of GPX2,SELENOI,SELENOO,SELENOS,SELENOT,and SELENOW and down-regulated expression of SELP (all <0.05).The results of multivariate Logistic regression analysis showed that the abnormally high expression of GPX1 (=0.067,95%=0.005-0.904,=0.042) and SELENON (=56.663,95%=3.114-856.999,=0.006) was the risk factor for symptomatic COVID-19,and the abnormally high expression of SELP was a risk factor for asymptomatic COVID-19 (=15.000,95%=2.537-88.701,=0.003).Conclusions Selenoprotein genes with differential expression are involved in the regulation of COVID-19 development.The findings provide a new reference for the prevention and treatment of COVID-19.
Topics: Humans; Selenoproteins; COVID-19; SARS-CoV-2; Protein Interaction Maps
PubMed: 38953254
DOI: 10.3881/j.issn.1000-503X.15834 -
PeerJ 2024The COVID-19 pandemic has had tremendous implications for billions of adolescents worldwide due to school closures, forcing students to embrace internet usage for daily...
BACKGROUND
The COVID-19 pandemic has had tremendous implications for billions of adolescents worldwide due to school closures, forcing students to embrace internet usage for daily tasks. Uncontrolled use of the internet among adolescents makes them vulnerable to internet addiction (IA). This study aims to determine the prevalence of IA among adolescents and assess its association with sociodemographic factors, smartphone use, and psychological distress during the pandemic.
METHOD
A cross-sectional self-administered online survey was conducted among students aged 13-17 from May 15, 2021, until May 30, 2021, using the Malay version of the Internet Addiction Test (MVIAT), the Depression, Anxiety, and Stress Scale (DASS-21), and the Coronavirus Impacts Questionnaires, as well as a sociodemographic information form. The data was analyzed with IBM SPSS Statistics version 23.
RESULTS
A total of 420 adolescents participated in the survey. The majority of them (70.7%) were female, with a mean age of 15.47 years (±1.49 years old). About 45.5% of the respondents were classified as internet addicted users. The Chi-square test analysis showed that age ( = 0.002), smartphone usage ( = 0.010), rate of midnight use ( < 0.001), frequency ( < 0.001), duration ( < 0.001) of device usage, and presence of depression, anxiety, and stress (p < 0.001) were all significantly associated with IA. Multiple logistic regression showed age (aOR = 1.16, 95% CI [1.00-1.35], = 0.048), smartphone usage (aOR =3.52, 95% CI [1.43-8.67], = 0.006), mild or moderate depression (aOR = 2.43, 95% CI [1.36-4.34], = 0.003), severe or extremely severe stress (aOR = 6.41, 95% CI [2.18-18.82], = 0.001) were significantly related to IA.
CONCLUSIONS
Late adolescence, the use of smartphones, and the presence of psychological distress like depression, and stress were potentially associated with IA. Wise use of smartphones and early identification of any psychological distress among adolescents are warranted, especially during the pandemic.
Topics: Humans; Adolescent; Female; Male; Internet Addiction Disorder; COVID-19; Cross-Sectional Studies; Psychological Distress; Prevalence; Surveys and Questionnaires; Smartphone; SARS-CoV-2; Malaysia; Depression; Stress, Psychological; Anxiety; Adolescent Behavior; Pandemics; Sociodemographic Factors
PubMed: 38952988
DOI: 10.7717/peerj.17489 -
Virus Evolution 2024Animal rotaviruses A (RVAs) are considered the source of emerging, novel RVA strains that have the potential to cause global spread in humans. A case in point was the...
Evolution of DS-1-like G8P[8] rotavirus A strains from Vietnamese children with acute gastroenteritis (2014-21): Adaptation and loss of animal rotavirus-derived during human-to-human spread.
Animal rotaviruses A (RVAs) are considered the source of emerging, novel RVA strains that have the potential to cause global spread in humans. A case in point was the emergence of G8 bovine RVA consisting of the P[8] VP4 and the DS-1-like backbone that appeared to have jumped into humans recently. However, it was not well documented what evolutionary changes occurred on the animal RVA-derived during circulation in humans. Rotavirus surveillance in Vietnam found that DS-1-like G8P[8] strains emerged in 2014, circulated in two prevalent waves, and disappeared in 2021. This surveillance provided us with a unique opportunity to investigate the whole process of evolutionary changes, which occurred in an animal RVA that had jumped the host species barrier. Of the 843 G8P[8] samples collected from children with acute diarrhoea in Vietnam between 2014 and 2021, fifty-eight strains were selected based on their distinctive electropherotypes of the genomic RNA identified using polyacrylamide gel electrophoresis. Whole-genome sequence analysis of those fifty-eight strains showed that the strains dominant during the first wave of prevalence (2014-17) carried animal RVA-derived VP1, NSP2, and NSP4 . However, the strains from the second wave of prevalence (2018-21) lost these , which were replaced with cognate human RVA-derived , thus creating strain with G8P[8] on a fully DS-1-like human RVA backbone. The G8 VP7 and P[8] VP4 s underwent some point mutations but the phylogenetic lineages to which they belonged remained unchanged. We, therefore, propose a hypothesis regarding the tendency for the animal RVA-derived to be expelled from the backbone of the progeny strains after crossing the host species barrier. This study underlines the importance of long-term surveillance of circulating wild-type strains in order to better understand the adaptation process and the fate of newly emerging, animal-derived RVA among the human population. Further studies are warranted to disclose the molecular mechanisms by which spillover animal RVAs become readily transmissible among humans, and the roles played by the expulsion of animal-derived and herd immunity formed in the local population.
PubMed: 38952820
DOI: 10.1093/ve/veae045 -
Frontiers in Public Health 2024COVID-19 has rapidly spread across the world. In March 2020, shortly after the first confirmed case of COVID-19 in Ethiopia in March 2020, the government of Ethiopia...
Exploring how stay-at-home orders during the COVID-19 pandemic impedes engagement along the HIV/AIDS care continuum in public hospitals of Southwest Ethiopia: a qualitative study.
INTRODUCTION
COVID-19 has rapidly spread across the world. In March 2020, shortly after the first confirmed case of COVID-19 in Ethiopia in March 2020, the government of Ethiopia took several measures.
PURPOSE
This study aims to explore how stay-at-home orders during the COVID-19 pandemic hinder engagement with HIV/AIDS care in public hospitals in Southwest Ethiopia. Additionally, we aim to explore the psychosocial challenges faced in accessing services during stay-at-home orders.
METHODS
A descriptive qualitative study was conducted from 20 May to 3 June 2020, using semi-structured, in-depth interviews. In total, 27 study participants were recruited from purposively selected people living with HIV/AIDS (PLWHA) who had experienced delays, declines, or discontinuation of care after COVID-19 was confirmed in Ethiopia on 13 March 2020. The participants were interviewed over the phone and their responses were audio-recorded. Data were transcribed verbatim, translated, and analyzed using inductive thematic analysis in the Atlas ti.7.1 software package.
RESULTS
The main themes and sub-themes that emerged were psychosocial issues (such as depression, hopelessness, and fear), risk perception (including high risk, susceptibility, and severity), forceful enforcement of stay-at-home orders (such as police beatings, community leaders disgracing, and influence of families and relatives), socioeconomic factors (such as stigma, religion, and transportation costs), misinformation about COVID-19 (such as lockdowns and ART stock-outs), and healthcare factors (such as inadequate health information and long distances to healthcare facilities).
CONCLUSION
Overall, these findings were similar to the challenges experienced by PLWHA in adhering to the recommended continuum of care. However, there are additional factors due to COVID-19, such as misinformation and the forceful implementation of the stay-at-home-orders, that impede the continuum of care. Therefore, it is important to strengthen information, education, and communication.
Topics: Humans; Ethiopia; COVID-19; Qualitative Research; Hospitals, Public; Female; Male; Adult; HIV Infections; Continuity of Patient Care; Middle Aged; SARS-CoV-2; Health Services Accessibility; Interviews as Topic; Pandemics; Social Stigma
PubMed: 38952732
DOI: 10.3389/fpubh.2024.1273448 -
Frontiers in Public Health 2024To assess the impact of the COVID-19 pandemic on the health condition of people ≥75 years of age and on their family caregivers in Spain.
AIMS
To assess the impact of the COVID-19 pandemic on the health condition of people ≥75 years of age and on their family caregivers in Spain.
DESIGN
Multicentric, mixed method concurrent study.
METHODS
This work, which will be conducted within the primary care setting in 11 administrative regions of Spain, will include three coordinated studies with different methodologies. The first is a population-based cohort study that will use real-life data to analyze the rates and evolution of health needs, care provision, and services utilization before, during, and after the pandemic. The second is a prospective cohort study with 18 months of follow-up that will evaluate the impact of COVID-19 disease on mortality, frailty, functional and cognitive capacity, and quality of life of the participants. Finally, the third will be a qualitative study with a critical social approach to understand and interpret the social, political, and economic dimensions associated with the use of health services during the pandemic. We have followed the SPIRIT Checklist to address trial protocol and related documents. This research is being funded by the Instituto de Salud Carlos III since 2021 and was approved by its ethics committee (June 2022).
DISCUSSION
The study findings will reveal the long-term impact of the COVID-19 pandemic on the older adults and their caregivers. This information will serve policymakers to adapt health policies to the needs of this population in situations of maximum stress, such as that produced by the COVID-19 pandemic.
TRIAL REGISTRATION
Identifier: NCT05249868 [ClinicalTrials.gov].
Topics: Humans; COVID-19; Spain; Aged; Self Care; Prospective Studies; Caregivers; Female; Aged, 80 and over; Quality of Life; Male; Health Status; SARS-CoV-2; Pandemics; Primary Health Care
PubMed: 38952731
DOI: 10.3389/fpubh.2024.1389641 -
Trials Jun 2024Randomised trials are essential to reliably assess medical interventions. Nevertheless, interpretation of such studies, particularly when considering absolute effects,... (Comparative Study)
Comparative Study
Clinical trial results in context: comparison of baseline characteristics and outcomes of 38,510 RECOVERY trial participants versus a reference population of 346,271 people hospitalised with COVID-19 in England.
BACKGROUND
Randomised trials are essential to reliably assess medical interventions. Nevertheless, interpretation of such studies, particularly when considering absolute effects, is enhanced by understanding how the trial population may differ from the populations it aims to represent.
METHODS
We compared baseline characteristics and mortality of RECOVERY participants recruited in England (n = 38,510) with a reference population hospitalised with COVID-19 in England (n = 346,271) from March 2020 to November 2021. We used linked hospitalisation and mortality data for both cohorts to extract demographics, comorbidity/frailty scores, and crude and age- and sex-adjusted 28-day all-cause mortality.
RESULTS
Demographics of RECOVERY participants were broadly similar to the reference population, but RECOVERY participants were younger (mean age [standard deviation]: RECOVERY 62.6 [15.3] vs reference 65.7 [18.5] years) and less frequently female (37% vs 45%). Comorbidity and frailty scores were lower in RECOVERY, but differences were attenuated after age stratification. Age- and sex-adjusted 28-day mortality declined over time but was similar between cohorts across the study period (RECOVERY 23.7% [95% confidence interval: 23.3-24.1%]; vs reference 24.8% [24.6-25.0%]), except during the first pandemic wave in the UK (March-May 2020) when adjusted mortality was lower in RECOVERY.
CONCLUSIONS
Adjusted 28-day mortality in RECOVERY was similar to a nationwide reference population of patients admitted with COVID-19 in England during the same period but varied substantially over time in both cohorts. Therefore, the absolute effect estimates from RECOVERY were broadly applicable to the target population at the time but should be interpreted in the light of current mortality estimates.
TRIAL REGISTRATION
ISRCTN50189673- Feb. 04, 2020, NCT04381936- May 11, 2020.
Topics: Humans; COVID-19; Male; England; Female; Middle Aged; Aged; Hospitalization; Aged, 80 and over; SARS-CoV-2; Comorbidity; Adult; Randomized Controlled Trials as Topic; Frailty
PubMed: 38951929
DOI: 10.1186/s13063-024-08273-9 -
Microbiome Jul 2024Fecal microbiota transplantation (FMT) and fecal virome transplantation (FVT, sterile filtrated donor feces) have been effective in treating recurrent Clostridioides...
BACKGROUND
Fecal microbiota transplantation (FMT) and fecal virome transplantation (FVT, sterile filtrated donor feces) have been effective in treating recurrent Clostridioides difficile infections, possibly through bacteriophage-mediated modulation of the gut microbiome. However, challenges like donor variability, costly screening, coupled with concerns over pathogen transfer (incl. eukaryotic viruses) with FMT or FVT hinder their wider clinical application in treating less acute diseases.
METHODS
To overcome these challenges, we developed methods to broaden FVT's clinical application while maintaining efficacy and increasing safety. Specifically, we employed the following approaches: (1) chemostat-fermentation to reproduce the bacteriophage FVT donor component and remove eukaryotic viruses (FVT-ChP), (2) solvent-detergent treatment to inactivate enveloped viruses (FVT-SDT), and (3) pyronin-Y treatment to inhibit RNA virus replication (FVT-PyT). We assessed the efficacy of these processed FVTs in a C. difficile infection mouse model and compared them with untreated FVT (FVT-UnT), FMT, and saline.
RESULTS
FVT-SDT, FVT-UnT, and FVT-ChP reduced the incidence of mice reaching the humane endpoint (0/8, 2/7, and 3/8, respectively) compared to FMT, FVT-PyT, and saline (5/8, 7/8, and 5/7, respectively) and significantly reduced the load of colonizing C. difficile cells and associated toxin A/B levels. There was a potential elimination of C. difficile colonization, with seven out of eight mice treated with FVT-SDT testing negative with qPCR. In contrast, all other treatments exhibited the continued presence of C. difficile. Moreover, the results were supported by changes in the gut microbiome profiles, cecal cytokine levels, and histopathological findings. Assessment of viral engraftment following FMT/FVT treatment and host-phage correlations analysis suggested that transfer of phages likely were an important contributing factor associated with treatment efficacy.
CONCLUSIONS
This proof-of-concept study shows that specific modifications of FVT hold promise in addressing challenges related to donor variability and infection risks. Two strategies lead to treatments significantly limiting C. difficile colonization in mice, with solvent/detergent treatment and chemostat propagation of donor phages emerging as promising approaches. Video Abstract.
Topics: Fecal Microbiota Transplantation; Animals; Mice; Bacteriophages; Clostridium Infections; Gastrointestinal Microbiome; Feces; Clostridioides difficile; Disease Models, Animal; Humans; Mice, Inbred C57BL; Female
PubMed: 38951925
DOI: 10.1186/s40168-024-01820-1 -
BMC Infectious Diseases Jun 2024Vaccination against COVID-19 was integral to controlling the pandemic that persisted with the continuous emergence of SARS-CoV-2 variants. Using a mathematical model...
Vaccination against COVID-19 was integral to controlling the pandemic that persisted with the continuous emergence of SARS-CoV-2 variants. Using a mathematical model describing SARS-CoV-2 within-host infection dynamics, we estimate differences in virus and immunity due to factors of infecting variant, age, and vaccination history (vaccination brand, number of doses and time since vaccination). We fit our model in a Bayesian framework to upper respiratory tract viral load measurements obtained from cases of Delta and Omicron infections in Singapore, of whom the majority only had one nasopharyngeal swab measurement. With this dataset, we are able to recreate similar trends in URT virus dynamics observed in past within-host modelling studies fitted to longitudinal patient data.We found that Omicron had higher R values than Delta, indicating greater initial cell-to-cell spread of infection within the host. Moreover, heterogeneities in infection dynamics across patient subgroups could be recreated by fitting immunity-related parameters as vaccination history-specific, with or without age modification. Our model results are consistent with the notion of immunosenescence in SARS-CoV-2 infection in elderly individuals, and the issue of waning immunity with increased time since last vaccination. Lastly, vaccination was not found to subdue virus dynamics in Omicron infections as well as it had for Delta infections.This study provides insight into the influence of vaccine-elicited immunity on SARS-CoV-2 within-host dynamics, and the interplay between age and vaccination history. Furthermore, it demonstrates the need to disentangle host factors and changes in pathogen to discern factors influencing virus dynamics. Finally, this work demonstrates a way forward in the study of within-host virus dynamics, by use of viral load datasets including a large number of patients without repeated measurements.
Topics: Humans; COVID-19; SARS-CoV-2; COVID-19 Vaccines; Middle Aged; Aged; Vaccination; Adult; Singapore; Age Factors; Viral Load; Young Adult; Bayes Theorem; Models, Theoretical; Male; Aged, 80 and over; Female; Adolescent
PubMed: 38951848
DOI: 10.1186/s12879-024-09572-x