Miracle-dz/UniFAR-FTUs huggingface dataset:
All‐oral, interferon‐free treatment for chronic hepatitis C: cost‐effectiveness analyses

Interferon‐based standard of care treatments (SOC) for chronic hepatitis C are unable to provide high cure rates in certain subgroups of the infected population and can cause debilitating side effects. Clinical trials evaluating all‐oral, interferon‐free treatments have demonstrated high rates of sustained virologic response with no resistance or major adverse events in most populations. As these drug regimens move towards FDA approval, it will be important to assess their cost‐effectiveness in addition to their clinical efficacy. A decision‐analytic Markov model with a lifetime, societal perspective was used to evaluate the cost‐effectiveness of a generalized all‐oral drug regimen compared to SOC by modelling the progression of a 50‐year‐old, HCV‐positive cohort through disease natural history and treatment. In base case analysis, all‐oral treatment dominated SOC across a range of willingness‐to‐pay (WTP) thresholds with an incremental cost‐effectiveness ratio (ICER) of US$44 514/quality‐adjusted life year (QALY). In sensitivity analyses, the model was sensitive to all‐oral drug costs as well as rates of SVR and treatment uptake among noncirrhotic subjects, but robust to variations in all other parameters. All‐oral treatment was most cost‐effective among genotype 1 subjects but remained cost‐effective for genotypes 2 and 3 at WTP thresholds ≥$80 000/QALY. Quality‐adjusted life years gained per dollar spent were maximized in younger treatment cohorts. Using this model, the degree of cost‐effectiveness depended on the WTP threshold and the final cost set for approved drug combinations.
The role of vocal practice in constructing phonological working memory.

PURPOSE In this study, the authors looked for effects of vocal practice on phonological working memory. METHOD A longitudinal design was used, combining both naturalistic observations and a nonword repetition test. Fifteen 26-month-olds (12 of whom were followed from age 11 months) were administered a nonword test including real words, "standard" nonwords (identical for all children), and nonwords based on individual children's production inventory (in and out words). RESULTS A strong relationship was found between (a) length of experience with consonant production and (b) nonword repetition and between (a) differential experience with specific consonants through production and (b) performance on the in versus out words. CONCLUSIONS Performance depended on familiarity with words or their subunits and was strongest for real words, weaker for in words, and weakest for out words. The results demonstrate the important role of speech production in the construction of phonological working memory.
Determination of plasma fibrinogen and haptoglobin, hematological and blood biochemical changes in Bulgarian local goats with experimentally induced Staphylococcus aureus mastitis

The aim of the present study was to assess changes in acute phase proteins fibrinogen and haptoglobin, as well as hematological, blood biochemical, and microbiological alterations in local Bulgarian goats with experimentally induced Staphylococcus aureus mastitis. The experiments were conducted with 6 clinically healthy local Bulgarian goats, 2 to 6 years of age, weighing 46-57 kg. The experimental infection was done with a stationary phase culture of a field Staphylococcus aureus strain isolated from a cow with clinical mastitis. Blood haptoglobin in goats was considerably higher (P < 0.05) as early as 8 h after the pathogen's inoculation. The most significant differences from baseline values occurred 24 and 48 h (P < 0.01) after infection. Plasma fibrinogen increased significantly (P < 0.05) 8 h after infection and reached the highest mean concentration (9.12 g/L) by 72 h. Leukocytosis was established as early as 4 h after the experimental infection when leukocyte counts were significantly higher than baseline (P < 0.001). The analysis of results indicates that in experimentally induced Staphylococcus aureus mastitis, significantly higher (P < 0.05) levels of the leukocyte, fibrinogen, and haptoglobin are established as early as 8 h after the infection.
Meta‐analysis of observational studies: hepatitis C and survival after renal transplant

Recent evidence has shown that anti‐HCV‐positive serologic status is significantly linked to lower patient and graft survival after renal transplant, but conflicting results have been given on this point. The aim of this study was to conduct a systematic review of the published medical literature concerning the impact of HCV infection on all‐cause mortality and graft loss after RT. The relative risk of all‐cause mortality and graft loss was regarded as the most reliable outcome end‐point. Study‐specific relative risks were weighted by the inverse of their variance to obtain fixed‐ and random‐effect pooled estimates for mortality and graft loss with HCV across the published studies. We identified eighteen observational studies involving 133 530 unique renal transplant recipients. The summary estimate for adjusted relative risk (aRR) of all‐cause mortality was 1.85 with a 95% confidence interval (CI) of 1.49; 2.31 (P < 0.0001); heterogeneity statistics, Ri = 0.87 (P‐value by Q‐test = 0.001). The overall estimate for adjusted RR of all‐cause graft loss was 1.76 (95% CI, 1.46; 2.11) (P < 0.0001), heterogeneity statistics, Ri = 0.65 (P‐value by Q‐test = 0.001). Stratified analysis did not change meaningfully these results. Meta‐regression showed that living donor rate had a favourable influence on patient (P = 0.031) and graft survival (P = 0.01), whilst diabetes mellitus having a detrimental role on patient survival (P = 0.001). This meta‐analysis of observational studies supports the notion that HCV‐positive patients after RT have an increased risk of mortality and graft loss. Further studies are in progress to understand better the mechanisms underlying the relationship between HCV and mortality or graft dysfunction after renal transplant.
An ORF1‐rearranged hepatitis E virus derived from a chronically infected patient efficiently replicates in cell culture

Hepatitis E is an increasingly reported disease in industrialized countries. Studies on the replication cycle of hepatitis E virus (HEV) are hampered due to the lack of efficient and robust cell culture systems for this virus. We describe the successful isolation of HEV derived from a chronically infected kidney transplant patient held under immunosuppressive therapy. Inoculation of serum sample 47832 onto the human lung carcinoma cell line A549 resulted in the replication of the virus as shown by RT‐qPCR. This novel human‐derived HEV strain is closely related to a wild boar‐derived genotype 3 strain, which did not replicate in A549 cells. It carries a 186 nucleotide insertion in the hypervariable ORF1‐region, derived from two parts of its ORF1. By passaging of the infected cells, a cell line continuously producing HEV particles was generated as demonstrated by RT‐qPCR, immuno‐electron microscopy, density gradient centrifugation and immunohistochemistry. Replication of the produced virus was demonstrated after its inoculation onto fresh A549 cells and two consecutive passages, whereas heating at 65 °C for 2 min abolished its infectivity. Several point mutations scattered along the whole genome were present in the HEV strain from the second passage; however, the ORF1 insertion was still present. Previously, cell culture isolation of two other HEV strains carrying insertions in their hypervariable regions, but originating from human ribosomal protein genes, has been described. The findings may indicate that cell culture adaptation of is mostly dependent on the length and position of the insertion, rather than from the sequence itself.
Effects of noise and speech intelligibility on listener comprehension and processing time of Korean-accented English.

PURPOSE This study evaluated the effects of noise and speech intelligibility on the processing of speech produced from native English; high-intelligibility, Korean-accented English; and moderate-intelligibility, Korean-accented English speakers. METHOD Both listener comprehension, determined by accuracy judgment on true/false sentences, and processing time, estimated from response latency, were assessed under the following 3 conditions: quiet, +10 dB signal-to-noise ratio (SNR), and +5 dB SNR. Fifty-four monolingual, English-speaking adults served as the listeners for this study. RESULTS While noise did not affect the time it took to process foreign-accented speech, it decreased the comprehension of the foreign-accented speech more so than the native speech. Decreasing English intelligibility also resulted in reduced listener comprehension. In addition, the processing time needed to comprehend the intended message depended on the intelligibility of the foreign-accented speaker. Listener comprehension negatively correlated with processing time. CONCLUSION The findings suggest that decreased speech intelligibility and adverse listening conditions can be major challenges for effective communication between foreign-accented speakers and native listeners. The results also indicate that foreign-accented speech requires more effortful processing relative to native speech under certain conditions, affecting both comprehension and processing efficiency.
Interaction of β-carboline alkaloids with RNA.

β-Carboline alkaloids are present in medicinal plants such as Peganum harmala L. , which have been used as folk medicine in anticancer therapy. Recently, they have drawn attention because of their antitumor activities. Despite considerable interest and investigations on alkaloid-DNA complexes, reports on alkaloid-RNA interaction are very limited. This study is the first attempt to investigate the binding of β-carboline alkaloids (harmine, harmane, harmaline, harmalol, and tryptoline) with yeast RNA. The effect of alkaloid complexation on RNA aggregation and condensation was investigated in aqueous solution at physiological conditions, using constant RNA concentration (6.25 mM) and various alkaloid:polynucleotide (phosphate) ratios of 1:240, 1:160, 1:80, 1:40, 1:20, 1:10, 1:5, 1:2, and 1:1. Fourier transform infrared and UV-visible spectroscopic methods were used to determine the ligand-binding modes, the binding constants, and the stability of alkaloid-RNA complexes in aqueous solution. Spectroscopic evidence showed major binding of alkaloids to RNA with overall binding constants of K(harmine)-RNA = 2.95 × 10⁷ M⁻¹, K(harmane)-RNA = 5.62 × 10⁵ M⁻¹, K(harmaline)-RNA = 7.47 × 10⁵ M⁻¹, K(harmalol)-RNA = 4.32 × 10⁵ M⁻¹, and K(tryptoline)-RNA = 3.21 × 10⁵ M⁻¹. The affinity of alkaloids-RNA binding is in the order of harmine > harmaline > harmane > harmalol > tryptoline. No biopolymer secondary structural changes were observed upon alkaloid interaction and RNA remains in the A-family structure in these complexes.
Changes in liver fibrosis in HIV/HCV‐coinfected patients following different outcomes with peginterferon plus ribavirin therapy

There is scarce information about the impact of antiviral treatment on subsequent progression of liver fibrosis in HIV‐infected patients with chronic hepatitis C who experience different outcomes following peginterferon‐ribavirin therapy. We conducted a retrospective study of a cohort of HIV/HCV‐coinfected patients with longitudinal assessment of liver fibrosis using elastometry. Patients were split out into four groups according to the prior peginterferon‐ribavirin response: sustained virological response (SVR), relapse (R), partial response (PR) and null response (NR). A group of untreated, coinfected patients was taken as control. Significant liver fibrosis progression (sLFP) was defined as a shift from baseline Metavir estimates ≤F2 to F3‐F4, or by >30% increase in liver stiffness in patients with baseline F3‐F4. Conversely, significant liver fibrosis regression (sLFR) was defined as a shift from baseline Metavir estimates F3‐F4 to ≤F2, or by >30% reduction in liver stiffness in patients that kept on F3‐F4. A total of 498 HIV/HCV‐coinfected patients were examined. They were classified as follows: 138 (27.7%) SVR, 40 (8%) R, 61 (12.2%) PR, 71 (14.3%) NR and 188 (37.8%) naive. After a mean follow‐up of 53.3 months, sLFP occurred less frequently in patients with SVR (7.2%) compared with R (25%; P = 0.002), PR (23%; P = 0.002), NR (29.6%; P < 0.001) and naïve (19.7%; P = 0.002). Conversely, sLFR was 26.1% in SVR compared with 10% in R (P = 0.03), 14.8% in PR (P = 0.06), 16.9% in NR (P = 0.07) and 10.6% in naïve (P < 0.001). Sustained clearance of serum HCV‐RNA following a course of antiviral treatment is the major determinant of liver fibrosis regression in HIV/HCV‐coinfected patients.
Age and gender differences in the relationship between hepatitis C infection and all stages of Chronic kidney disease

Chronic kidney disease (CKD) is a worldwide health issue with heavy economic burden. Chronic hepatitis C virus (HCV) infection is a common cause of CKD, which can significantly impact the progression and mortality among patients with CKD. The prevalence of both illnesses is high in Taiwan. A multicentre and population‐based cross‐sectional study including 24 642 subjects was conducted to explore the association of HCV infection with the prevalence and severity of CKD. The measurements of metabolic parameters, eGFR and CKD stages were compared between subjects with HCV seropositivity and seronegativity. The analyses of association between HCV infection with CKD stages and evaluation of potential risk factors of CKD were performed by gender and age (≤ and >45 years). HCV‐seropositive subjects accounted for 6.9% and had a significantly older age. The prevalence of CKD increased in those with HCV seropositivity (16.5%). Significantly higher prevalence of CKD stages ≥3 in HCV‐seropositive subjects was noticed (7.8%). Age (>45 year), male gender, alcohol drinking, hypertension, creatinine and HCV infection were the significant factors associated with the presence of CKD. HCV seropositivity was an independent risk factor of developing CKD and associated with an increased risk of having CKD of all stages. The higher prevalence of earlier stage of CKD warrants longitudinal studies with frequent testing on renal function and sufficient duration to determine the changes of eGFR over time. Implementation of effective treatment intervention is also required for these subjects to prevent the progression of CKD to late stages.
Predictors of early treatment discontinuation in a cohort of patients treated with boceprevir‐based therapy for hepatitis C infection

In this real‐world cohort, 49% of patients stopped boceprevir‐based hepatitis C therapy early, with only 20% stopping due to treatment futility. Having more comorbidities was significantly associated with early discontinuation. Tolerability of boceprevir‐based regimens may be substantially worse than reported in clinical trials, particularly for patients with comorbidities.
Gene expression analysis in serial liver fine needle aspirates

No method with low morbidity presently exists for obtaining serial hepatic gene expression measurements in humans. While hepatic fine needle aspiration (FNA) has lower morbidity than core needle biopsy, applicability is limited due to blood contamination, which confounds quantification of gene expression changes. The aim of this study was to validate FNA for assessment of hepatic gene expression. Liver needle biopsies and FNA procedures were simultaneously performed on 17 patients with chronic hepatitis C virus infection with an additional FNA procedure 1 week later. Nine patients had mild/moderate fibrosis and eight advanced fibrosis. Gene expression profiling was performed using Affymetrix microarrays and TaqMan qPCR; pathway analysis was performed using Ingenuity. We developed a novel strategy that applies liver‐enriched normalization genes to determine the percentage of liver in the FNA sample, which enables accurate gene expression measurements overcoming biases derived from blood contamination. We obtained almost identical gene expression results (ρ = 0.99, P < 0.0001) comparing needle biopsy and FNA samples for 21 preselected genes. Gene expression results were also validated in dogs. These data suggest that liver FNA is a reliable method for serial hepatic tissue sampling with potential utility for a variety of preclinical and clinical applications.
Dental fear in adults: a meta-analysis of behavioral interventions.

OBJECTIVES The aim of this meta-analytic and systematic quantitative approach is to examine the effects of behavioral interventions for dental anxiety and dental phobia. METHODS Eighty studies were identified where dental fear treatment with behavioral methods was evaluated. Thirty-eight of 80 met entry criteria and were included in a meta-analysis. RESULTS The calculated effect sizes (ESs) for self-reported anxiety after intervention indicate positive changes in 36 of the 38 studies and no changes in two. The overall ES = 1.8 (95% CI: 1.6, 1.8). The percent of subjects with post-treatment dental visits in the first 6 months post-treatment varied between 50 and 100%. The overall ES for attendance at dental visits, weighted by sample size, is 1.4 (95% CI: 1.3, 1.6). The homogeneity analysis indicates that the studies cannot be adequately described in one ES. The reported percentage of subjects with a dental visit between 6 months and 4 years post-treatment varied from 48 to 100%. The overall weighted ES for visiting the dentist, adjusted for drop-outs in the studies, is 1.2 (95% CI: 0.99, 1.4). CONCLUSIONS Despite extensive heterogeneity, changes in self-reported anxiety represent medium to large ESs. Patients signing up for a behavioral intervention for dental fear can be expected to report a significant reduction in their fear, and this effect generally seems to be lasting. Mean long-term attendance ( >4 years after treatment) is 77%.
Identification of a natural intergenotypic recombinant hepatitis delta virus genotype 1 and 2 in Vietnamese HBsAg‐positive patients

Hepatitis D virus (HDV) infection is acquired as a co‐ /superinfection of Hepatitis B virus (HBV) and can modulate the pathophysiology of chronic hepatitis B and related liver diseases including hepatocellular carcinoma. Among the eight distinct HDV genotypes reported, relatively few studies have attempted to investigate the prevalence of HDV mixed genotypes and RNA recombination of HDV. With a recorded prevalence of 10–20% HBV infection in Vietnam, this study investigated the HDV variability, HDV genotypes and HDV recombination among twenty‐one HDV isolates in Vietnamese HBsAg‐positive patients. HDV subgenomic and full‐length genome sequences were obtained using newly established HDV‐specific RT‐PCR techniques. The nucleotide homology was observed from 74.6% to 99.4% among the investigated full‐length genome of the HDV isolates. We observed HDV genotype 1 and HDV genotype 2 in the investigated Vietnamese patients. Although no HDV genotype mixtures were observed, we report here a newly identified recombinant of HDV genotypes (HDV 1 and HDV 2). The identified recombinant HDV isolate C03 revealed sequence homology to both HDV genotype 1 (nt1 to nt907) and HDV genotype 2 (nt908 to nt1675; HDAg coding region) with a breakpoint at nt908. Our findings demonstrate the prevalence of intergenotypic recombination between HDV genotypes 1 and 2 in a Vietnamese HBsAg‐positive patient. Extended investigation on the distribution and prevalence of HDV, HDV mixed genotypes and recombinant HDV genotypes in a larger Vietnamese population offers vital insights into understanding of the micro‐epidemiology of HDV and subsequent pathophysiology in chronic HBV‐ /HDV‐related liver diseases.
Interferon–ribavirin therapy induces serum antibodies determining ‘rods and rings’ pattern in hepatitis C patients

A cytoplasmic antigen associated to inosine‐5'‐monophosphatedehydrogenase 2 eliciting specific antibodies (antirods and rings, RR) has been identified in patients with chronic hepatitis C who were exposed to pegylated interferon (PI) and ribavirin (RBV). The significance of anti‐RR in these patients merits to be investigated. Sera from 88 chronic hepatitis C virus (HCV)‐infected patients undergoing PI‐RBV therapy were analysed for the presence of RR pattern by indirect immunofluorescence on HEp‐2 substrate (Inova Diagnostics, San Diego, CA, USA). Anti‐RR antibodies developed de novo in 32 patients independently of any demographic and virological feature, but with a significant association with cumulative exposure to PI‐RBV (P = 0.0089; chi‐square test). RR pattern was significantly more frequent in relapsers than in patients achieving sustained virological response (56% vs 30%; P = 0.0282, chi‐square test). Anti‐RR titre ranged from 1:80 to 1:1280, but significantly declined following treatment cessation. Anti‐RR develop de novo in a substantial proportion of patients exposed to PI‐RBV in relation to the duration of treatment exposure. Further investigations are necessary to unravel the mechanisms leading to the formation of these autoantibodies.
Comparison of liver biopsy and noninvasive techniques for liver fibrosis assessment in patients infected with HCV‐genotype 4 in Egypt

In Egypt, as elsewhere, liver biopsy (LB) remains the gold standard to assess liver fibrosis in chronic hepatitis C (CHC) and is required to decide whether a treatment should be proposed. Many of its disadvantages have led to develop noninvasive methods to replace LB. These new methods should be evaluated in Egypt, where circulating virus genotype 4 (G4), increased body mass index and co‐infection with schistosomiasis may interfere with liver fibrosis assessment. Egyptian CHC‐infected patients with G4 underwent a LB, an elastometry measurement (Fibroscan©), and serum markers (APRI, Fib4 and Fibrotest©). Patients had to have a LB ≥15 mm length or ≥10 portal tracts with two pathologists blinded readings to be included in the analysis. Patients with hepatitis B virus co‐infection were excluded. Three hundred and twelve patients are reported. The performance of each technique for distinguishing F0F1 vs F2F3F4 was compared. The area under receiver operating characteristic curves was 0.70, 0.76, 0.71 and 0.75 for APRI, Fib‐4, Fibrotest© and Fibroscan©, respectively (no influence of schistosomiasis was noticed). An algorithm using the Fib4 for identifying patients with F2 stage or more reduced by nearly 90% the number of liver biopsies. Our results demonstrated that noninvasive techniques were feasible in Egypt, for CHC G4‐infected patients. Because of its validity and its easiness to perform, we believe that Fib4 may be used to assess the F2 threshold, which decides whether treatment should be proposed or delayed.