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Epstein-Barr virus (EBV) is typically found in a latent, asymptomatic state in immunocompetent individuals. Perturbations of the host immune system can stimulate viral reactivation. Furthermore, there are a myriad of EBV-associated illnesses including various cancers, post-transplant lymphoproliferative disease, and autoimmune conditions. A thorough understanding of this virus, and the interplay between stress and the immune system, is essential to establish effective treatment. This review will provide a summary of the interaction between both psychological and cellular stressors resulting in EBV reactivation. It will examine mechanisms by which EBV establishes and maintains latency and will conclude with a brief overview of treatments targeting EBV.

Since December 2019, the COVID-19 pandemic has affected more than 200 million individuals around the globe and caused millions of deaths. Although there are now multiple vaccines for SARS-CoV-2, their efficacy may be limited by current and future viral mutations. Therefore, effective antiviral compounds are an essential component to win the battle against the family of coronaviruses. Ginkgolic Acid (GA) is a pan-antiviral molecule with proven effective in vitro and in vivo activity. We previously demonstrated that GA inhibits Herpes Simplex Virus 1 (HSV-1) by disrupting viral structure, blocking fusion, and inhibiting viral protein synthesis. Additionally, we reported that GA displays broad-spectrum fusion inhibition encompassing all three classes of fusion proteins, including those of HIV, Ebola, influenza A, and Epstein Barr virus. Here, we report that GA exhibited potent antiviral activity against Human Coronavirus strain 229E (HCoV-229E) infection of human epithelial lung cells (MRC-5). GA significantly reduced progeny virus production, expression of viral proteins, and cytopathic effects (CPE). Furthermore, GA significantly inhibited HCoV-229E even when added post-infection. In light of our findings and the similarities of this family of viruses, GA holds promising potential as an effective antiviral treatment for SARS-CoV-2.

Hepatitis D virus (HDV) is classified according to eight genotypes. The various genotypes are included in the HDVdb database, where each HDV sequence is specified by its genotype. In this contribution, a mathematical analysis is performed on RNA sequences in HDVdb. The RNA folding predicted structures of the Genbank HDV genome sequences in HDVdb are classified according to their coarse-grain tree-graph representation. The analysis allows discarding in a simple and efficient way the vast majority of the sequences that exhibit a rod-like structure, which is important for the virus replication, to attempt to discover other biological functions by structure consideration. After the filtering, there remain only a small number of sequences that can be checked for their additional stem-loops besides the main one that is known to be responsible for virus replication. It is found that a few sequences contain an additional stem-loop that is responsible for RNA editing or other possible functions. These few sequences are grouped into two main classes, one that is well-known experimentally belonging to genotype 3 for patients from South America associated with RNA editing, and the other that is not known at present belonging to genotype 7 for patients from Cameroon. The possibility that another function besides virus replication reminiscent of the editing mechanism in HDV genotype 3 exists in HDV genotype 7 has not been explored before and is predicted by eigenvalue analysis. Finally, when comparing native and shuffled sequences, it is shown that HDV sequences belonging to all genotypes are accentuated in their mutational robustness and thermodynamic stability as compared to other viruses that were subjected to such an analysis.

The hepatitis C virus (HCV) is capable of spreading within a host by two different transmission modes: cell-free and cell-to-cell. However, the contribution of each of these transmission mechanisms to HCV spread is unknown. To dissect the contribution of these different transmission modes to HCV spread, we measured HCV lifecycle kinetics and used an in vitro spread assay to monitor HCV spread kinetics after a low multiplicity of infection in the absence and presence of a neutralizing antibody that blocks cell-free spread. By analyzing these data with a spatially explicit mathematical model that describes viral spread on a single-cell level, we quantified the contribution of cell-free, and cell-to-cell spread to the overall infection dynamics and show that both transmission modes act synergistically to enhance the spread of infection. Thus, the simultaneous occurrence of both transmission modes represents an advantage for HCV that may contribute to viral persistence. Notably, the relative contribution of each viral transmission mode appeared to vary dependent on different experimental conditions and suggests that viral spread is optimized according to the environment. Together, our analyses provide insight into the spread dynamics of HCV and reveal how different transmission modes impact each other.

Background: Diagnostic yields for spondylodiscitis from CT guided biopsy is low. In the recent years, minimally invasive surgery (MIS) has shown to have a low morbidity and faster recovery. For spinal infections, MIS surgery may offer an opportunity for early pain control while obtaining a higher diagnostic yield than CT-guided biopsies. The aim of this study was to review our patients who underwent MIS surgery for spinal infection and report outcomes. Methods: A retrospective review of seven patients who underwent MIS decompression and/or discectomy in the setting of discitis, osteomyelitis, spondylodiscitis, and/or an epidural abscess was identified. Patient data including symptoms, visual analog score (VAS), surgical approach, antibiotic regimen, and postoperative outcomes were obtained. Results: Of the 7 patients, 5 patients had lumbar infections and two had thoracic infections. All seven patients improved in VAS immediately after surgery and at discharge. The average VAS improved by 4.4 ± 1.9 points. An organism was obtained in 6 of the 7 (85%) patients by the operative cultures. All patients made an excellent clinical recovery without the need for further spine surgery. All patients who received postoperative imaging on follow-up showed complete resolution or dramatically improved magnetic resonance imaging changes. The follow-up ranged from 2 to 9 months. Conclusions: MIS surgery provides an opportunity for early pain relief in patients with discitis, osteomyelitis, spondylodiscitis, and/or epidural abscess by directly addressing the primary cause of pain. MIS surgery for discitis provides a higher diagnostic yield to direct antibiotic treatment. MIS surgery results in good long-term recovery.

Background & aimsAcute hepatitis C (AHC) is not frequently identified because patients are usually asymptomatic, although may be recognized after iatrogenic exposures such as needle stick injuries, medical injection, and acupuncture. We describe an outbreak of AHC among 12 patients who received IV saline flush from a single multi-dose vial after intravenous contrast administration for a computerized tomography (CT) scan. The last patient to receive IV contrast with saline flush from a multi-dose vial at the clinic on the previous day was known to have chronic HCV genotype 1b (termed potential source, PS). Here we sought to confirm (via genetic analysis) the source of infection and to predict the minimal contaminating level of IV saline flush needed to transmit infectious virus to all patients.MethodsIn order to confirm the source of infection, we sequenced the HCV E1E2 region in 7 CT patients, in PS, and in 2 control samples from unrelated patients also infected with HCV genotype 1b. A transmission probabilistic model was developed to predict the contamination volume of blood that would have been sufficient to transmit infectious virus to all patients.ResultsViral sequencing showed close clustering of the cases with the PS. The transmission probabilistic model predicted that contamination of the multi-dose saline vial with 0.6-8.7 microliters of blood would have been sufficient to transmit infectious virus to all patients.ConclusionAnalysis of this unique cohort provides a new understanding of HCV transmission with respect to contaminating volumes and viral titers.

[This corrects the article DOI: 10.1371/journal.pone.0210173.].

Parameter estimation in mathematical models that are based on differential equations is known to be of fundamental importance. For sophisticated models such as age-structured models that simulate biological agents, parameter estimation that addresses all cases of data points available presents a formidable challenge and efficiency considerations need to be employed in order for the method to become practical. In the case of age-structured models of viral hepatitis dynamics under antiviral treatment that deal with partial differential equations, a fully numerical parameter estimation method was developed that does not require an analytical approximation of the solution to the multiscale model equations, avoiding the necessity to derive the long-term approximation for each model. However, the method is considerably slow because of precision problems in estimating derivatives with respect to the parameters near their boundary values, making it almost impractical for general use. In order to overcome this limitation, two steps have been taken that significantly reduce the running time by orders of magnitude and thereby lead to a practical method. First, constrained optimization is used, letting the user add constraints relating to the boundary values of each parameter before the method is executed. Second, optimization is performed by derivative-free methods, eliminating the need to evaluate expensive numerical derivative approximations. The newly efficient methods that were developed as a result of the above approach are described for hepatitis C virus kinetic models during antiviral therapy. Illustrations are provided using a user-friendly simulator that incorporates the efficient methods for both the ordinary and partial differential equation models.

Remote-sensing tools and satellite data are often used to map and monitor changes in vegetation cover in forests and other perennial woody vegetation. Large-scale vegetation mapping from remote sensing is usually based on the classification of its spectral properties by means of spectral Vegetation Indices (VIs) and a set of rules that define the connection between them and vegetation cover. However, observations show that, across a gradient of precipitation, similar values of VI can be found for different levels of vegetation cover as a result of concurrent changes in the leaf density (Leaf Area Index—LAI) of plant canopies. Here we examine the three-way link between precipitation, vegetation cover, and LAI, with a focus on the dry range of precipitation in semi-arid to dry sub-humid zones, and propose a new and simple approach to delineate woody vegetation in these regions. By showing that the range of values of Normalized Difference Vegetation Index (NDVI) that represent woody vegetation changes along a gradient of precipitation, we propose a data-based dynamic lower threshold of NDVI that can be used to delineate woody vegetation from non-vegetated areas. This lower threshold changes with mean annual precipitation, ranging from less than 0.1 in semi-arid areas, to over 0.25 in mesic Mediterranean area. Validation results show that this precipitation-sensitive dynamic threshold provides a more accurate delineation of forests and other woody vegetation across the precipitation gradient, compared to the traditional constant threshold approach.

Mathematical modeling of Ebola virus (EBOV)−host dynamics during infection and treatment in vivo is in its infancy due to few studies with frequent viral kinetic data, lack of approved antiviral therapies, and limited insight into the timing of EBOV infection of cells and tissues throughout the body. Current in-host mathematical models simplify EBOV infection by assuming a single homogeneous compartment of infection. In particular, a recent modeling study assumed the liver as the largest solid organ targeted by EBOV infection and predicted that nearly all cells become refractory to infection within seven days of initial infection without antiviral treatment. We compared our observations of EBOV kinetics in multiple anatomic compartments and hepatocellular injury in a critically ill patient with Ebola virus disease (EVD) with this model’s predictions. We also explored the model’s predictions, with and without antiviral therapy, by recapitulating the model using published inputs and assumptions. Our findings highlight the challenges of modeling EBOV−host dynamics and therapeutic efficacy and emphasize the need for iterative interdisciplinary efforts to refine mathematical models that might advance understanding of EVD pathogenesis and treatment.

The multiscale model of hepatitis C virus (HCV) dynamics, which includes intracellular viral RNA (vRNA) replication, has been formulated in recent years in order to provide a new conceptual framework for understanding the mechanism of action of a variety of agents for the treatment of HCV. We present a robust and efficient numerical method that belongs to the family of adaptive stepsize methods and is implicit, a Rosenbrock type method that is highly suited to solve this problem. We provide a Graphical User Interface that applies this method and is useful for simulating viral dynamics during treatment with anti-HCV agents that act against HCV on the molecular level.

High cure rates are achieved in HCV genotype-1b patients treated with daclatasvir and asunaprevir, DCV/ASV. Here we analyzed early HCV kinetics in genotype-1b infected Japanese subjects treated with DCV/ASV and retrospectively projected, using mathematical modeling, whether shorter treatment durations might be effective.HCV RNA levels were measured frequently during DCV/ASV therapy in 95 consecutively treated patients at a single center in Japan. Mathematical modeling was used to predict the time to cure, i.e,

Background: Some chronic hepatitis C virus (HCV), genotype 1 infected patients treated with direct antiviral agents (DAAs) remain viremic at end of treatment (EOT+), yet go on to achieve sustained virological response 12 weeks after completion of therapy (SVR 12 ). The incidence of EOT+/SVR in patients with genotype 1 and other genotypes, as well as whether such patients achieve SVR 24 remain in question. The aims of this study were to evaluate the frequency and durability of EOT+/SVR 12&24 and other response categories in HCV genotype 1, 2, or 3 infected patients treated with DAA in clinical practice. Methods: Data from patients treated with all oral sofosbuvir-based regimens at a university hepatology practice by 1 July 2015 were reviewed retrospectively. Responses were categorized based on virus levels during and post DAA treatment. HCV RNA levels were measured by Abbott RealTime HCV (ART) or by Roche CobasTaqMan v2.0 (RCTM) assays. Results: The study population included 89 patients. Participants were 62% genotype 1, 19% genotype 2 and 19% genotype 3, 54% cirrhotic and 46% treatment-experienced. A total of 45 received sofosbuvir–simeprevir, 38 sofosbuvir–ribavirin and 6 sofosbuvir–ledipasvir. The SVR 12 rate was 82%. A total of 5 patients (6%), all with genotype 1, had EOT+ by ART assay and each achieved SVR 12&24 . Conclusions: A total of 9% of genotype 1 patients (6% overall) treated with DAAs were EOT+ by ART and all EOT+ cases achieved SVR 24 . EOT+/SVR was not observed with genotype 2 or 3 or by the RCTM assay. In patients treated with DAAs, EOT+ by the ART assay does not indicate treatment failure.

Study DesignRetrospective review.PurposeThis study aims to define the role of lumbar fusion for persistent back pains after the lumbar disc replacement.Overview of LiteratureLittle is written about lumbar fusion after optimally placed lumbar arthroplasty in patients with persistent lower back pains.MethodsRetrospective review of cases of lumbar artificial disc requiring subsequent fusion because of persistent back pains despite optimally placed artificial discs. Outcomes were evaluated using Oswestry Disability Index (ODI) and visual analogue scale (VAS). Clinical improvements indicated 25% improvement in ODI and VAS values.ResultsFive patients met the study criteria. The mean baseline ODI for the five patients was 52. The mean baseline VAS scores for back and leg pains were 76 and 26, respectively. All the five patients had optimally placed prosthesis. The indication for surgery was the constant low back pains found in all the patients. Revision surgery involved disc explantation and fusion in two of the patients and posterolateral fusion without removing the prosthesis in three. None of the patients achieved adequate pain control after the revision surgery despite the solid bony fusion documented by postoperative computed tomography. The mean ODI value after the fusion was 55. The mean values for back and leg pains VAS were 72 and 30, respectively.ConclusionsLack of good pain relief after successful lumbar artifical disc replacements may indicate different etiology for the back pains. The spine-treating surgeons should have a high threshold level to perform salvage fusion at that level.

Hepatitis E virus (HEV) infection causes chronic hepatitis in solid organ transplant (SOT) recipients. Antiviral therapy consists of three months of ribavirin, although response rates are not optimal. We characterized plasma HEV kinetic patterns in 41 SOT patients during ribavirin therapy. After a median pharmacological delay of three (range: 0−21) days, plasma HEV declined from a median baseline level of 6.12 (3.53−7.45) log copies/mL in four viral kinetic patterns: (i) monophasic (n = 18), (ii) biphasic (n = 13), (iii) triphasic (n = 8), and (iv) flat-partial response (n = 2). The mean plasma HEV half-life was estimated to be 2.0 ± 0.96 days. Twenty-five patients (61%) had a sustained virological response (SVR) 24 weeks after completion of therapy. Viral kinetic patterns (i)−(iii) were not associated with baseline characteristics or outcome of therapy. A flat-partial response was associated with treatment failure. All patients with a log concentration decrease of plasma HEV at day seven of >15% from baseline achieved SVR. In conclusion, viral kinetic modeling of plasma HEV under ribavirin therapy showed, for the first time, four distinct kinetic profiles, a median pharmacologic delay of three days, and an estimated HEV half-life of two days. Viral kinetic patterns were not associated with response to therapy, with the exception of a flat-partial response.

Backgrounds and Aims: We previously demonstrated that serum hepatitis B virus (HBV) DNA in HBV infected humanized mice exhibited a highly dynamic multiphasic kinetic pattern from infection initiation to steady-state. Here, we investigated whether this pattern is consistent across different HBV clones or in the presence of hepatitis D virus (HDV) co-infection. Methods: We analyzed early serum viral kinetics using 26 HBV genotype C (GtC) mono-infected mice [clones: PXB, Hiroshima GtC CL4 (CL4) and Hiroshima GtC CL5 (CL5)] and four HBV CL4/HDV genotype one co-infected mice. Results: The HBV kinetics observed with clones CL4 and CL5 were similar to that previously defined in HBV PXB infected mice. Additionally, no significant differences in HBV DNA levels were observed between HBV mono-infected and HBV/HDV co-infected mice through 4 weeks post-inoculation (p.i.). However, HBV DNA levels at 6 weeks p.i. in HBV/HDV co-infected mice were significantly lower than those in HBV mono-infected mice (P = 0.002), consistent with HDV suppression of chronic HBV. Conclusions: HBV infection initiation is multiphasic across multiple viral clones and is not altered by HDV co-infection. The latter suggests that higher HDV titers (>8 log IU/mL) and/or longer duration of HDV infection might be needed to trigger HDV-induced suppression on HBV.

Mathematical models based on ordinary differential equations (ODE) that describe the population dynamics of viruses and infected cells have been an essential tool to characterize and quantify viral infection dynamics. Although an important aspect of viral infection is the dynamics of viral spread, which includes transmission by cell-free virions and direct cell-to-cell transmission, models used so far ignored cell-to-cell transmission completely, or accounted for this process by simple mass-action kinetics between infected and uninfected cells. In this study, we show that the simple mass-action approach falls short when describing viral spread in a spatially-defined environment. Using simulated data, we present a model extension that allows correct quantification of cell-to-cell transmission dynamics within a monolayer of cells. By considering the decreasing proportion of cells that can contribute to cell-to-cell spread with progressing infection, our extension accounts for the transmission dynamics on a single cell level while still remaining applicable to standard population-based experimental measurements. While the ability to infer the proportion of cells infected by either of the transmission modes depends on the viral diffusion rate, the improved estimates obtained using our novel approach emphasize the need to correctly account for spatial aspects when analyzing viral spread.

New direct-acting antivirals (DAAs) provide an opportunity to combat hepatitis C virus (HCV) infection in persons who inject drugs (PWID). Here we use a mathematical model to predict the impact of a DAA-treatment scale-up on HCV prevalence among PWID and the estimated cost in metropolitan Chicago.To estimate the HCV antibody and HCV-RNA (chronic infection) prevalence among the metropolitan Chicago PWID population, we used empirical data from three large epidemiological studies. Cost of DAAs is assumed $50,000 per person.Approximately 32,000 PWID reside in metropolitan Chicago with an estimated HCV-RNA prevalence of 47% or 15,040 cases. Approximately 22,000 PWID (69% of the total PWID population) attend harm reduction (HR) programs, such as syringe exchange programs, and have an estimated HCV-RNA prevalence of 30%. There are about 11,000 young PWID (

People who inject drugs (PWID) are at high risk for blood-borne pathogens transmitted during the sharing of contaminated injection equipment, particularly hepatitis C virus (HCV). HCV prevalence is influenced by a complex interplay of drug-use behaviors, social networks, and geography, as well as the availability of interventions, such as needle exchange programs. To adequately address this complexity in HCV epidemic forecasting, we have developed a computational model, the Agent-based Pathogen Kinetics model (APK). APK simulates the PWID population in metropolitan Chicago, including the social interactions that result in HCV infection. We used multiple empirical data sources on Chicago PWID to build a spatial distribution of an in silico PWID population and modeled networks among the PWID by considering the geography of the city and its suburbs. APK was validated against 2012 empirical data (the latest available) and shown to agree with network and epidemiological surveys to within 1%. For the period 2010-2020, APK forecasts a decline in HCV prevalence of 0.8% per year from 44(± 2)% to 36(± 5)%, although some sub-populations would continue to have relatively high prevalence, including Non-Hispanic Blacks, 48(± 5)%. The rate of decline will be lowest in Non-Hispanic Whites and we find, in a reversal of historical trends, that incidence among non-Hispanic Whites would exceed incidence among Non-Hispanic Blacks (0.66 per 100 per years vs 0.17 per 100 person years). APK also forecasts an increase in PWID mean age from 35(± 1) to 40(± 2) with a corresponding increase from 59(± 2)% to 80(± 6)% in the proportion of the population >30 years old. Our studies highlight the importance of analyzing subpopulations in disease predictions, the utility of computer simulation for analyzing demographic and health trends among PWID and serve as a tool for guiding intervention and prevention strategies in Chicago, and other major cities.