Single hepatocytes show persistence and transcriptional inactivity of hepatitis B

© 2020, Balagopal et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.There is no cure for the more than 270 million people chronically infected with HBV. Nucleos(t)ide analogs (NUCs), the mainstay of anti-HBV treatment, block HBV reverse transcription. NUCs do not eliminate the intranuclear covalently closed circular DNA (cccDNA), from which viral RNAs, including pregenomic RNA (pgRNA), are transcribed. A key gap in designing a cure is understanding how NUCs affect HBV replication and transcription because serum markers yield an incomplete view of intrahepatic HBV. We applied single-cell laser capture microdissection and droplet digital PCR to paired liver biopsies collected from 5 HBV/HIV-coinfected persons who took NUCs over 2-4 years. From biopsy 1 to 2, proportions of HBV-infected hepatocytes declined with adherence to NUC treatment (P < 0.05); we extrapolated that eradication of HBV will take over 10 decades with NUCs in these participants. In individual hepatocytes, pgRNA levels diminished 28- to 73-fold during NUC treatment, corresponding with decreased tissue HBV core antigen staining (P < 0.01). In 4 out of 5 participants, hepatocytes with cccDNA but undetectable pgRNA (transcriptionally inactive) were present, and these were enriched in 3 participants during NUC treatment. Further work to unravel mechanisms of cccDNA transcriptional inactivation may lead to therapies that can achieve this in all hepatocytes, resulting in a functional cure.info:eu-repo/semantics/publishedVersio

Factors Associated with Elevated ALT in an International HIV/HBV Co-Infected Cohort on Long-Term HAART

Previous studies have demonstrated that hepatitis B virus (HBV) infection increases the risk for ALT elevations in HIV-HBV co-infected patients during the first year of HAART; however, there is limited data on the prevalence of ALT elevations with prolonged HAART in this patient group.To identify factors associated with ALT elevations in an HIV-HBV co-infected cohort receiving prolonged HAART, data from 143 co-infected patients on HAART enrolled in an international HIV-HBV co-infected cohort where ALT measurements were obtained every 6 months was analysed. A person-visit analysis was used to determine frequency of ALT elevation (≥ 2.5×ULN) at each visit. Factors associated with ALT elevation were determined using multivariate logistic regression with generalized estimating equations to account for correlated data. The median time on HAART at the end of follow-up was 5.6 years (range 0.4-13.3) years. During follow-up, median ALT was 36 U/L with 10.6% of person-visits classified as having ALT elevation. Most ALT elevations were grade 2 (86.5%), with only 13.5% of all ALT elevations grade 3 or higher. Univariate associations with ALT elevation (p<0.05) included history of AIDS, HBV DNA ≥ 2,000 IU/ml, HBeAg positive, study visit CD4 <200 cells/ml and nadir CD4 <200 cells/ml. In the multivariate analysis, only study visit CD4 <200 cells/ml (OR 2.07, 95%CI 1.04-4.11, p = 0.04) and HBeAg positive status (OR 2.22, 95%CI 1.03-4.79, p = 0.04) were independently associated with ALT elevation.In this HIV-HBV co-infected cohort, elevated ALT after >1 year of HAART was uncommon, and severe ALT elevations were rare. HIV-HBV co-infected patients on long-term HAART who are either HBeAg positive or have a CD4 count of <200 cells/ml are at increased risk for ALT elevations

Mineralocorticoid receptors modulate vascular endothelial function in human obesity

Abstract Obesity increases linearly with age and is associated with impaired vascular endothelial function and increased risk of cardiovascular disease. MRs (mineralocorticoid receptors) contribute to impaired vascular endothelial function in cardiovascular disease; however, their role in uncomplicated human obesity is unknown. Because plasma aldosterone levels are elevated in obesity and adipocytes may be a source of aldosterone, we hypothesized that MRs modulate vascular endothelial function in older adults in an adiposity-dependent manner. To test this hypothesis, we administered MR blockade (eplerenone; 100 mg/day) for 1 month in a balanced randomized double-blind placebo-controlled cross-over study to 22 older adults (ten men, 55--79 years) varying widely in adiposity [BMI (body mass index): 20--45 kg/m 2 ], but who were free from overt cardiovascular disease. We evaluated vascular endothelial function [brachial artery FMD (flow-mediated dilation)] via ultrasonography) and oxidative stress (plasma F 2 -isoprostanes and vascular endothelial cell protein expression of nitrotyrosine and NADPH oxidase p47 phox ) during placebo and MR blockade. In the whole group, oxidative stress (P &gt; 0.05) and FMD did not change with MR blockade (6.39 + − 0.67 compared with 6.23 + − 0.73 %; P = 0.7). However, individual improvements in FMD in response to eplerenone were associated with higher total body fat (BMI: r = 0.45, P = 0.02; and dual-energy X-ray absorptiometry-derived percentage body fat: r = 0.50, P = 0.009) and abdominal fat (total: r = 0.61, P = 0.005; visceral: r = 0.67, P = 0.002; and subcutaneous: r = 0.48, P = 0.03). In addition, greater improvements in FMD with eplerenone were related to higher baseline fasting glucose (r = 0.53, P = 0.01). MRs influence vascular endothelial function in an adiposity-dependent manner in healthy older adults

Disinfection capacity of PuriLens contact lens cleaning unit against Acanthamoeba

The PuriLens contact lens system is indicated for cleaning and disinfection of soft (hydrophilic) contact lenses by means of subsonic agitation to remove lens deposits and microorganisms, and ultraviolet irradiation of the storage solution for disinfection. The capacity of the PuriLens system to disinfect storage solutions contaminated with known concentrations of Staphylococcus aureus, Pseudomonas aeruginosa, and Acanthamoeba species was evaluated. An in vitro assessment of the antibacterial and antiparasitic efficacy of the PuriLens system was performed. Separated batches of the storage solution for the cleansing system were contaminated with stock strains of S. aureus and P. aeruginosa. A comparison of the microbiologic content was made between the solution before and after the cycle. The PuriLens system effectively eradicated S. aureus and P. aeruginosa organisms after a 15-minute cycle. However, viable cysts of acanthamoeba were recovered in the solution after the 15-minute cycle. The PuriLens system is highly efficient in protecting against contamination with common bacterial ocular pathogens. Acanthamoeba cysts, however, can survive in the solution or contact lens bath undergoing integrated subsonic debridement and indirect ultraviolet light disinfection. Use of chemical disinfecting solutions that contain agents such as chlorhexidine or other cationic antiseptics may be advisable in conjunction with use of the PuriLens device, especially in high-risk settings

The design of the borealis stream processing engine

Borealis is a second-generation distributed stream processing engine that is being developed at Brandeis University, Brown University, and MIT. Borealis inherits core stream processing functionality from Aurora [14] and distribution functionality from Medusa [51]. Borealis modifies and extends both systems in non-trivial and critical ways to provide advanced capabilities that are commonly required by newly-emerging stream processing applications. In this paper, we outline the basic design and functionality of Borealis. Through sample real-world applications, we motivate the need for dynamically revising query results and modifying query specifications. We then describe how Borealis addresses these challenges through an innovative set of features, including revision records, time travel, and control lines. Finally, we present a highly flexible and scalable QoS-based optimization model that operates across server and sensor networks and a new fault-tolerance model with flexible consistency-availability trade-offs

Comparison of HBV-active HAART regimens in an HIV–HBV multinational cohort

ObjectivesTo explore factors associated with short and long-term hepatitis B virus (HBV) DNA suppression in a multinational cohort of HIV-HBV co-infected patients receiving HBV-active antiretrovirals.MethodsOne hundred and fifteen HIV-HBV co-infected patients participating in one of the two global randomized clinical trials conducted by the Adult AIDS Clinical Trials Group of different antiretroviral regimens received either HBV monotherapy with either lamivudine or emtricitabine (N = 56), or HBV dual therapy with tenofovir disoproxil fumarate (TDF) + lamivudine or emtricitabine (N = 59). Associations of pretreatment characteristics with the primary (HBV DNA &lt;200 IU/ml at 24 weeks) and longitudinal outcomes through 144 weeks were explored using logistic regression. HBV drug-resistance mutations were determined by pol sequencing in those with viral rebound.ResultsThe proportion with HBV DNA below 200 IU/ml was 60% (95% confidence interval 50-69%) at 24 weeks and 79% (95% confidence interval 69-88%) at 144 weeks. Pretreatment factors associated with the primary outcome were HBV DNA, CD4 T-cell count, and aspartate aminotransferase, but only pretreatment HBV DNA remained associated with long-term suppression (P &lt; 0.0001). HBV therapy group was not significantly associated with the primary outcome at 24 weeks; however, longitudinally, a greater proportion in the dual-therapy group achieved HBV DNA below 200 IU/ml (P = 0.007). A higher proportion of hepatitis B e antigen-negative patients (n = 57) achieved HBV DNA below 200 IU/ml at any point, regardless of the therapy group. All 12 patients with emergence of lamivudine-resistant mutants were in the monotherapy group.ConclusionsTDF-based dual HBV-active antiretroviral therapy is preferred to treat HIV-HBV co-infected patients. In resource-limited settings in which TDF may not be universally available, lamivudine or emtricitabine HBV monotherapy is a reasonable option in patients with low HBV replication

Design issues for second generation stream processing engines

Borealis is a second-generation distributed stream processing engine that is being developed at Brandeis University, Brown University, and MIT. Borealis inherits core stream processing functionality from Aurora [13] and distribution functionality from Medusa [49]. Borealis modifies and extends both systems in non-trivial and critical ways to provide advanced capabilities that are commonly required by newly-emerging stream processing applications. In this paper, we outline the basic design and functionality of Borealis. Through sample real-world applications, we motivate the need for dynamically revising query results and modifying query specifications. We then describe how Borealis addresses these challenges through an innovative set of features, including revision records, time travel, and control lines. Finally, we present a highly flexible and scalable QoS-based optimization model that operates across server and sensor networks and a new fault-tolerance model with flexible consistency-availability trade-offs