Large-scale viral genome analysis identifies novel clinical associations between hepatitis B virus and chronically infected patients

Chronic hepatitis B; HBeAg status; Viral genome variationHepatitis B crónica; Estado de HBeAg; Variación del genoma viralHepatitis B crònica; Estat de HBeAg; Variació del genoma viralDespite the high global prevalence of chronic hepatitis B (CHB) infection, datasets covering the whole hepatitis B viral genome from large patient cohorts are lacking, greatly limiting our understanding of the viral genetic factors involved in this deadly disease. We performed deep sequencing of viral samples from patients chronically infected with HBV to investigate the association between viral genome variation and patients’ clinical characteristics. We discovered novel viral variants strongly associated with viral load and HBeAg status. Patients with viral variants C1817T and A1838G had viral loads nearly three orders of magnitude lower than patients without those variants. These patients consequently experienced earlier viral suppression while on treatment. Furthermore, we identified novel variants that either independently or in combination with precore mutation G1896A were associated with the transition from HBeAg positive to the negative phase of infection. These observations are consistent with the hypothesis that mutation of the HBeAg open reading frame is an important factor driving CHB patient’s HBeAg status. This analysis provides a detailed picture of HBV genetic variation in the largest patient cohort to date and highlights the diversity of plausible molecular mechanisms through which viral variation affects clinical phenotype

UHRF1 is required for basal stem cell proliferation in response to airway injury

Cellular senescence is a cell fate characterized by an irreversible cell cycle arrest, but the molecular mechanism underlying this senescence hallmark remains poorly understood. Through an unbiased search for novel senescence regulators in airway basal cells, we discovered that the epigenetic regulator ubiquitin-like with PHD and ring finger domain-containing protein 1 (UHRF1) is critical for regulating cell cycle progression. Upon injury, basal cells in the mouse airway rapidly induce the expression of UHRF1 in order to stimulate stem cell proliferation and tissue repair. Targeted depletion of Uhrf1 specifically in airway basal cells causes a profound defect in cell cycle progression. Consistently, cultured primary human basal cells lacking UHRF1 do not exhibit cell death or differentiation phenotypes but undergo a spontaneous program of senescence. Mechanistically, UHRF1 loss induces G1 cell cycle arrest by abrogating DNA replication factory formation as evidenced by loss of proliferating cell nuclear antigen (PCNA) puncta and an inability to enter the first cell cycle. This proliferation defect is partially mediated by the p15 pathway. Overall, our study provides the first evidence of an indispensable role of UHRF1 in somatic stem cells proliferation during the process of airway regeneration

Kinetic modelling of peat water treatment with continuous electrocoagulation using aluminium electrodes

Peat water source could be utilized to mitigate water scarcity issues that are experienced by the local communities in Sarawak rural areas. However, this water source needs to be treated prior to domestic consumption due to the levels of humic substances being incomparable to the Malaysia water quality standards. As such, this study aims to formulate the kinetic models for peat water treatment with continuous electrocoagulation system by using aluminium electrodes. Correspondingly, the kinetic models are formulated with adsorption isotherm models and variable kinetic order models (VOK). Subsequent, the study has found that the formulation of VOK model with Freundlich isotherm model is well fitted to the experimental data due to the regression coefficient (R2) values being higher than 0.90 in comparison to VOK-Langmuir and VOK-Jovanovic models. Additionally, the formulated VOK-Freundlich model able to predict the removal of turbidity, chemical oxygen demand, and colour from peat water with continuous electrocoagulation treatment system. Overall, this study demonstrates that peat water treatment with continuous electrocoagulation system by using aluminium electrodes follows VOK-Freundlich kinetic model

Continuous electrocoagulation treatment system for partial desalination of tropical brackish peat water in Sarawak coastal peatlands

Sarawak coastal peatlands located on Borneo Island have vast availability of brackish peat water sources especially in some coastal rural areas. However, brackish peat water is currently underutilized as the source for water treatment plants due to excessive salinity levels. As such, this study aims to investigate the salinity reduction in brackish peat water sources for domestic consumption in Sarawak coastal peatlands by utilizing continuous electrocoagulation treatment with aluminium electrodes. Correspondingly, this study analyzes the effects of salinity percentage, electric current, and flow rate on salinity reduction with electrocoagulation treatment. This study has found that the treated salinity levels in brackish peat water with 30 % of salinity percentage meet the Malaysia Class I in National Water Quality Standard. The study has also identified both monolayer and multilayer adsorption that occurs in electrocoagulation treatment as the precursor to salinity reduction. In addition, the presence of in-situ aluminium hydroxide coagulants could adsorb some sodium chloride from brackish peat water with 70 % of salinity percentage at 2503 mg/g of maximum adsorption capacity and 2.65 min−1 of adsorption rate. This study has also found that electrocoagulation treatment could achieve 91.78 % of maximum salinity reduction efficiency at an optimum electric current of 5 A and flow rate of 1.2 L/min in brackish peat water with 30 % of salinity percentage. This treatment system costs only Ringgit Malaysia (RM) 0.29 or United States Dollars (USD) 0.06 per meter cubic of treated brackish peat water. Overall, this study demonstrates that continuous electrocoagulation treatment could partially desalinate brackish peat water with 30 % of salinity percentage in which the treated salinity levels could be utilized for domestic consumption in Sarawak coastal peatlands at reasonable cost

Diagnostic Accuracy of the Electrocardiogram for Heart Failure With Reduced or Preserved Ejection Fraction

Current heart failure (HF) guidelines recommend electrocardiography (ECG) as an essential initial investigation in a patient's workup. 1 However, these recommendations were based on studies primarily including patients with HF with reduced ejection fraction (HFrEF). 1 , 2 , 3 Guidelines do not distinguish HFrEF from HF with preserved and mid-range ejection fraction (HFpEF and HFmrEF) in their ECG recommendations. We hypothesized that a normal ECG does not exclude HFpEF and has a considerably lower sensitivity for diagnosing HFpEF than HFrEF

Long-Term Treatment With Tenofovir Alafenamide for Chronic Hepatitis B Results in High Rates of Viral Suppression and Favorable Renal and Bone Safety

INTRODUCTION: The results from 2 phase 3 studies, through 2 years, in chronic hepatitis B infection showed tenofovir alafenamide (TAF) had similar efficacy to tenofovir disoproxil fumarate (TDF) with superior renal and bone safety. We report updated results through 5 years. METHODS: Patients with HBeAg-negative or HBeAg-positive chronic hepatitis B infection with or without compensated cirrhosis were randomized (2:1) to TAF 25 mg or TDF 300 mg once daily in double-blind (DB) fashion for up to 3 years, followed by open-label (OL) TAF up to 8 years. Efficacy (antiviral, biochemical, and serologic), resistance (deep sequencing of polymerase/reverse transcriptase and phenotyping), and safety, including renal and bone parameters, were evaluated by pooled analyses. RESULTS: Of 1,298 randomized and treated patients, 866 receiving TAF (DB and OL) and 432 receiving TDF with rollover to OL TAF at year 2 (n = 180; TDF→TAF3y) or year 3 (n = 202; TDF→TAF2y) were included. Fifty (4%) TDF patients who discontinued during DB were excluded. At year 5, 85%, 83%, and 90% achieved HBV DNA &lt;29 IU/mL (missing 5 failure) in the TAF, TDF→TAF3y, and TDF→TAF2y groups, respectively; no patient developed TAF or TDF resistance. Median estimated glomerular filtration rate (by using Cockcroft-Gault) declined &lt;2.5 mL/min, and mean declines of &lt;1% in hip and spine bone mineral density were seen at year 5 in the TAF group; patients in the TDF→TAF groups had improvements in these parameters at year 5 after switching to OL TAF. DISCUSSION: Long-term TAF treatment resulted in high rates of viral suppression, no resistance, and favorable renal and bone safety.</p

Identification and Specification of the Mouse Skeletal Stem Cell

SummaryHow are skeletal tissues derived from skeletal stem cells? Here, we map bone, cartilage, and stromal development from a population of highly pure, postnatal skeletal stem cells (mouse skeletal stem cells, mSSCs) to their downstream progenitors of bone, cartilage, and stromal tissue. We then investigated the transcriptome of the stem/progenitor cells for unique gene-expression patterns that would indicate potential regulators of mSSC lineage commitment. We demonstrate that mSSC niche factors can be potent inducers of osteogenesis, and several specific combinations of recombinant mSSC niche factors can activate mSSC genetic programs in situ, even in nonskeletal tissues, resulting in de novo formation of cartilage or bone and bone marrow stroma. Inducing mSSC formation with soluble factors and subsequently regulating the mSSC niche to specify its differentiation toward bone, cartilage, or stromal cells could represent a paradigm shift in the therapeutic regeneration of skeletal tissues

Automated Coding of Job Descriptions From a General Population Study: Overview of Existing Tools, Their Application and Comparison

OBJECTIVES: Automatic job coding tools were developed to reduce the laborious task of manually assigning job codes based on free-text job descriptions in census and survey data sources, including large occupational health studies. The objective of this study is to provide a case study of comparative performance of job coding and JEM (Job-Exposure Matrix)-assigned exposures agreement using existing coding tools. METHODS: We compared three automatic job coding tools [AUTONOC, CASCOT (Computer-Assisted Structured Coding Tool), and LabourR], which were selected based on availability, coding of English free-text into coding systems closely related to the 1988 version of the International Standard Classification of Occupations (ISCO-88), and capability to perform batch coding. We used manually coded job histories from the AsiaLymph case-control study that were translated into English prior to auto-coding to assess their performance. We applied two general population JEMs to assess agreement at exposure level. Percent agreement and PABAK (Prevalence-Adjusted Bias-Adjusted Kappa) were used to compare the agreement of results from manual coders and automatic coding tools. RESULTS: The coding per cent agreement among the three tools ranged from 17.7 to 26.0% for exact matches at the most detailed 4-digit ISCO-88 level. The agreement was better at a more general level of job coding (e.g. 43.8-58.1% in 1-digit ISCO-88), and in exposure assignments (median values of PABAK coefficient ranging 0.69-0.78 across 12 JEM-assigned exposures). Based on our testing data, CASCOT was found to outperform others in terms of better agreement in both job coding (26% 4-digit agreement) and exposure assignment (median kappa 0.61). CONCLUSIONS: In this study, we observed that agreement on job coding was generally low for the three tools but noted a higher degree of agreement in assigned exposures. The results indicate the need for study-specific evaluations prior to their automatic use in general population studies, as well as improvements in the evaluated automatic coding tools