Miracle-dz/UniFAR-FTUs huggingface dataset:
Genotypic and phenotypic analysis of variants resistant to hepatitis C virus nonstructural protein 5A replication complex inhibitor BMS‐790052 in Humans: In Vitro and In Vivo Correlations

The NS5A replication complex inhibitor, BMS‐790052, inhibits hepatitis C virus (HCV) replication with picomolar potency in preclinical assays. This potency translated in vivo to a substantial antiviral effect in a single‐ascending dose study and a 14‐day multiple‐ascending dose (MAD) monotherapy study. However, HCV RNA remained detectable in genotype 1a–infected patients at the end of the MAD study. In contrast, viral breakthrough was observed less often in patients infected with genotype 1b, and, in several patients, HCV RNA declined and remained below the level of quantitation (<25 IU/mL) through the duration of treatment. Here, we report on the results of the genotypic and phenotypic analyses of resistant variants in 24 genotype 1–infected patients who received BMS‐790052 (1, 10, 30, 60, and 100 mg, once‐daily or 30 mg twice‐daily) in the 14‐day MAD study. Sequence analysis was performed on viral complementary DNA isolated from serum specimens collected at baseline and days 1 (4, 8, and 12 hours), 2, 4, 7, and 14 postdosing. Analyses of the sequence variants (1) established a correlation between resistant variants emerging in vivo with BMS‐790052 treatment and those observed in the in vitro replicon system (major substitutions at residues 28, 30, 31, and 93 for genotype 1a and residues 31 and 93 for genotype 1b); (2) determined the prevalence of variants at baseline and the emergence of resistance at different times during dosing; and (3) revealed the resistance profile and replicative ability (i.e., fitness) of the variants. Conclusion: Although resistance emerged during monotherapy with BMS‐790052, the substantial anti‐HCV effect of this compound makes it an excellent candidate for effective combination therapy. (HEPATOLOGY 2011)
Association between funding and quality of published medical education research.

CONTEXT Methodological shortcomings in medical education research are often attributed to insufficient funding, yet an association between funding and study quality has not been established. OBJECTIVES To develop and evaluate an instrument for measuring the quality of education research studies and to assess the relationship between funding and study quality. DESIGN, SETTING, AND PARTICIPANTS Internal consistency, interrater and intrarater reliability, and criterion validity were determined for a 10-item medical education research study quality instrument (MERSQI). This was applied to 210 medical education research studies published in 13 peer-reviewed journals between September 1, 2002, and December 31, 2003. The amount of funding obtained per study and the publication record of the first author were determined by survey. MAIN OUTCOME MEASURES Study quality as measured by the MERSQI (potential maximum total score, 18; maximum domain score, 3), amount of funding per study, and previous publications by the first author. RESULTS The mean MERSQI score was 9.95 (SD, 2.34; range, 5-16). Mean domain scores were highest for data analysis (2.58) and lowest for validity (0.69). Intraclass correlation coefficient ranges for interrater and intrarater reliability were 0.72 to 0.98 and 0.78 to 0.998, respectively. Total MERSQI scores were associated with expert quality ratings (Spearman rho, 0.73; 95% confidence interval [CI], 0.56-0.84; P < .001), 3-year citation rate (0.8 increase in score per 10 citations; 95% CI, 0.03-1.30; P = .003), and journal impact factor (1.0 increase in score per 6-unit increase in impact factor; 95% CI, 0.34-1.56; P = .003). In multivariate analysis, MERSQI scores were independently associated with study funding of $20 000 or more (0.95 increase in score; 95% CI, 0.22-1.86; P = .045) and previous medical education publications by the first author (1.07 increase in score per 20 publications; 95% CI, 0.15-2.23; P = .047). CONCLUSION The quality of published medical education research is associated with study funding.
The problems of high dynamic drive control under circumstances of elastic transmission

In the paper the theoretical, design as well as experimental aspects of the control of high dynamic drive with elastic coupling are considered. It is shown that the solutions of problem of vibration damping, suitable for the drives with low natural torsional frequency, give not good result at high dynamic. In this case the low frequency can be higher than several tens or 100 Hz and the next frequency of the multi-mass model can be thousand Hz and higher. Authors show the way of suppression of oscillations, based on the adequate PID speed controller. In the solutions only one sensor i.e. position encoder is used. The paper presents experience acquired during studying the problem, designing and investigating the laboratory plant based on the PMSM.
Curcumin as a promising antifungal of clinical interest.

OBJECTIVES The antifungal activity of curcumin was evaluated against 23 fungi strains and its in vitro inhibitory effect on the adhesion of Candida species to human buccal epithelial cells (BEC) was also investigated. METHODS The antifungal susceptibility was evaluated by broth microdilution assay following the CLSI (formerly the NCCLS) guidelines. The inhibitory effect of curcumin on the cell adhesion was performed with Candida species and BEC. RESULTS Paracoccidioides brasiliensis isolates were the most susceptible to curcumin while the growth of Aspergillus isolates was not affected. Curcumin was much more efficient than fluconazole in inhibiting the adhesion of Candida species to BEC, particularly those strains isolated from the buccal mucosa of AIDS patients. CONCLUSIONS The lack of antifungal compounds with reduced side effects highlights the importance of studying natural products for this purpose. Curcumin was a more potent antifungal than fluconazole against P. brasiliensis, the causal agent of the neglected disease paracoccidioidomycosis. Curcumin dramatically inhibited the adhesion of Candida species isolated from AIDS patients to BEC, demonstrating that curcumin is a promising lead compound that warrants further investigation into its therapeutical use in immunocompromised patients.
Inappropriate hospital use by patients receiving care for medical conditions: targeting utilization review.

OBJECTIVE To describe characteristics associated with inappropriate hospital use by patients in Manitoba in order to help target concurrent utilization review. Utilization review was developed to reduce inappropriate hospital use but can be a very resource-intensive process. DESIGN Retrospective chart review of a sample of adult patients who received care for medical conditions in a sample of Manitoba hospitals during the fiscal year 1993-94; assessment of patients at admission and for each day of stay with the use of a standardized set of objective, nondiagnosis-based criteria (InterQual). PATIENTS A total of 3904 patients receiving care at 26 hospitals. OUTCOME MEASURES Acute (appropriate) and nonacute (inappropriate) admissions and days of stay for adult patients receiving care for medical conditions. RESULTS After 1 week, 53.2% of patients assessed as needing acute care at admission no longer required acute care. Patients 75 years of age or older consumed more than 50% of the days of stay, and 74.8% of these days of stay were inappropriate. Four diagnostic categories accounted for almost 60% of admissions and days, and more than 50% of those days of stay were inappropriate. Patients admitted through the emergency department were more likely to require acute care (60.9%) than others (41.7%). Patients who were Treaty Indians had a higher proportion of days of stay requiring acute care than others (45.9% v. 32.8%). Patients' income and day of the week on admission (weekday v. weekend) were not predictive factors of inappropriate use. CONCLUSION Rather than conducting a utilization review for every patient, hospitals might garner more information by targeting patients receiving care for medical conditions with stays longer than 1 week, patients with nervous system, circulatory, respiratory or digestive diagnoses, elderly patients and patients not admitted through the emergency department.
Brain natriuretic peptide and severity of disease in non‐alcoholic cirrhotic patients

Background: Cirrhotic patients have a hyperdynamic systemic circulation. They have insidious cardiac problems besides well‐known complications. Brain natriuretic peptide (BNP) relaxes vascular smooth muscle and has a portal hypotensive action. The relations between BNP levels and severity of disease, cardiac dysfunction and esophageal varices were studied in non‐alcoholic cirrhotic patients.
Regulation of mRNA Translation and Cellular Signaling by Hepatitis C Virus Nonstructural Protein NS5A

ABSTRACT The NS5A nonstructural protein of hepatitis C virus (HCV) has been shown to inhibit the cellular interferon (IFN)-induced protein kinase R (PKR). PKR mediates the host IFN-induced antiviral response at least in part by inhibiting mRNA translation initiation through phosphorylation of the α subunit of eukaryotic initiation factor 2 (eIF2α). We thus examined the effect of NS5A inhibition of PKR on mRNA translation within the context of virus infection by using a recombinant vaccinia virus (VV)-based assay. The VV E3L protein is a potent inhibitor of PKR. Accordingly, infection of IFN-pretreated HeLa S3 cells with an E3L-deficient VV (VVΔE3L) resulted in increased phosphorylation levels of both PKR and eIF2α. IFN-pretreated cells infected with VV in which the E3L locus was replaced with theNS5A gene (VVNS5A) displayed diminished phosphorylation of PKR and eIF2α in a transient manner. We also observed an increase in activation of p38 mitogen-activated protein kinase in IFN-pretreated cells infected with VVΔE3L, consistent with reports that p38 lies downstream of the PKR pathway. Furthermore, these cells exhibited increased phosphorylation of the cap-binding initiation factor 4E (eIF4E), which is downstream of the p38 pathway. Importantly, these effects were reduced in cells infected with VVNS5A. NS5A was also found to inhibit activation of the p38-eIF4E pathway in epidermal growth factor-treated cells stably expressing NS5A. NS5A-induced inhibition of eIF2α and eIF4E phosphorylation may exert counteracting effects on mRNA translation. Indeed, IFN-pretreated cells infected with VVNS5A exhibited a partial and transient restoration of cellular and viral mRNA translation compared with IFN-pretreated cells infected with VVΔE3L. Taken together, these results support the role of NS5A as a PKR inhibitor and suggest a potential mechanism by which HCV might maintain global mRNA translation rate during early virus infection while favoring cap-independent translation of HCV mRNA during late infection.
Cognitive impairment in relapsing—remitting multiple sclerosis can be predicted by imaging performed several years earlier

Cognitive deficits in multiple sclerosis (MS) are common and correlate with contemporary MRI brain abnormalities, particularly atrophy, but the ability of imaging early in the disease to predict later cognitive impairment remains to be determined. Thirty relapsing—remitting MS patients recruited within three years of the onset of the disease, and in whom MRI had been performed at baseline and a year later, were assessed neuropsychologically five years later. Imaging parameters accounting for significant variance in cognitive performance were identified using multiple regressions, once confounding variables were controlled. Patients performed significantly worse than expected on tests of attention/speed of information processing and half of them had experienced some decline in IQ in relation to premorbid estimates. The rate of global brain atrophy in the first year of the study accounted for significant variance in the overall cognitive performance, and in memory and attention/speed of information processing. Poor performance on attention tests was associated with high T1-weighted lesion volume and reduced magnetization transfer ratio (MTR) in normal-appearing white matter (NAWM). These results suggest that neuroaxonal loss was identified early in the disease, and its rate of progression, predicted cognitive impairment later in the disease. Neuroaxonal loss is likely to affect commissural and association fibres that subserve the cognitive processes impaired in MS. Multiple Sclerosis 2008; 14: 197—204. http://msj.sagepub. com
New algorithm for polynomial matrix determinant based on FFT

Fast Fourier Transform algorithm, the powerful technique of Discrete Fourier Transform, is used here to compute the determinant of a polynomial matrix. The new algorithm presented in the paper has been implemented in the POLYNOMIAL Toolbox for MATLAB™, Version 2.0 and its performance highly exceeds that of older procedures used in Version 1.6. The new method is both much less costly and much more reliable and also naturally handles polynomial matrices with complex coefficients. Experimental testing results are also reported in the paper.
Management of swallowing in thrombolysed stroke patients: Implementation of a new protocol

Abstract Purpose: There is a paucity of evidence regarding dysphagia management post-thrombolysis. The aim of this case–control study was to evaluate the impact of a dysphagia management protocol on patient outcomes. Thrombolysis has been completed at our metropolitan hospital since 2011 and a dysphagia management protocol was developed in 2012. Method: Chart auditing was completed for 83 participants in three groups: pre-protocol (n = 12) (2011), post-protocol (n = 28) (2012–2014), and non-thrombolysed stroke patients (n = 43). Result: Following the implementation of this clinical protocol, the average time patient remained nil by mouth reduced by 9.5 h, the percentage of patients who were malnourished or at risk reduced by 24% and the number of patients who developed aspiration pneumonia reduced by 11%. The cost of hospital stay reduced by $1505. Service compliance with best practice in dysphagia management in thrombolysed patients increased from 67% to 96% in the thrombolysed patient groups. Conclusion: The outcomes suggest that a clinical protocol for dysphagia management in thrombolysed patients has the potential to improve service outcomes, reduce complications from dysphagia, have financial benefits for the hospital and increase service compliance. Furthermore, the results lend support for speech pathology services to manage dysphagia on weekends.
Relief Rallies after FOMC Announcements as a Resolution of Uncertainty

We find substantial positive average stock returns after FOMC announcements accompanied by the release of the Summary of Economic Projections (SEP) and press conference by the Fed Chair. A simple trading strategy of buying index futures contracts five minutes before the announcement and closing the position 55 minutes after the release would have generated an annualized Sharpe ratio of 2.10. We show that the market uncertainty, measured by the VIX index, declines significantly after FOMC meetings followed by SEP releases. After controlling for changes in the VIX, the positive post-announcement returns disappear, suggesting that these returns are related to the resolution of uncertainty after the announcement.
Patient-reported Outcomes of Tarsal Coalitions Treated With Surgical Excision

Purpose: There are little patient-reported data on functional outcomes of tarsal coalition resection in children and adolescents. The purpose of this study is to evaluate the medium-term (>2 y) outcomes in patients who have had surgical excision of their symptomatic tarsal coalition and to compare patient-based outcomes in patients who have calcaneonavicular (CN) coalitions to those with talocalcaneal (TC) coalitions. Methods: A billing query was conducted to identify patients who had surgical excision of their tarsal coalition between 2003 and 2008. Eligible patients were mailed questionnaires consisting of a modified American Orthopaedic Foot and Ankle Society (AOFAS) score and the University of California at Los Angeles (UCLA) activity scale. Patients were also specifically asked if their activity level was limited by their foot pain. Only patients who returned questionnaires were included. Demographics and diagnostic images were reviewed. A nonresponder analysis was completed. Complications such as infection and reoperation were reported. Results: Sixty-three patients (22 females, 41 males) who returned questionnaires were included in the analysis. Twenty-four patients had bilateral surgery. TC coalitions were present in 20 patients (32%); CN coalitions were present in 43 patients (68%). Overall, mean modified AOFAS score was 88.3 and mean UCLA activity score was 8.33 at an average of 4.62 years after surgery. Patients who had TC coalitions had similar modified AOFAS scores (88.4) and UCLA activity scores (8.4) when compared with those with CN coalitions (88.0 and 8.3, both not significant). Of the 73% (46/63) patients who reported that their activity levels were not limited by their foot pain, the mean AOFAS score was 93.9 and the mean UCLA activity score was 8.9; 32 of these were CN and 14 were TC coalitions. Of the 27% (17/63) patients who reported that their activity levels were limited by their foot pain, the mean AOFAS score was 72.9 and the mean UCLA activity score was 6.9; 11 of these were CN and 6 were TC coalitions. There was a statistically significant difference in these groups both in modified AOFAS score (P<0.0001) and UCLA activity score (P=0.006). There was no difference in outcomes between those who were treated for a TC and CN coalition. Conclusions: Patient-reported outcomes after surgical excision of tarsal coalition reveal that >70% of patients’ activities are not limited by pain and their functional outcome is terrific. A few patients continue to have problems with ongoing foot pain and activity limitations. The type of coalition does not seem to be an indicative factor in determining outcome.
Validation of Western common recurrent chromosomal aberrations in Korean chronic lymphocytic leukaemia patients with very low incidence

In Asia, the incidence of chronic lymphocytic leukaemia (CLL) is lower than in Western countries. Only a few studies of CLL have been conducted in Korea, and no long‐term clinical outcome data are available. We assessed the frequency of common chromosomal aberrations in Korean CLL patients using interphase fluorescence in situ hybridization (FISH) and investigated their relationship to clinical outcomes. Between 2000 and 2011, conventional cytogenetic studies were performed in 58 patients, and FISH results were available in 48 patients. We used six DNA probes for the detection of del(13q14), trisomy 12, del(11q22), del(17p13), IGH rearrangement and del(6q23). Chromosomal aberrations were identified in 15 of 58 patients (26%) with conventional cytogenetic studies and in 25 of 48 patients (52%) with interphase FISH, including six patients with complex karyotypes. In contrast with the results of Western studies, trisomy 12 was the most common aberration, followed by IGH rearrangement, del(13q14), del(11q22) and del(17p13). Deletion of 6q23 was not observed, and isolated del(13q14) was less frequent than in Western studies. Compared with the other types of chromosomal aberrations, patients with del(11q22) and del(17p13) were more likely to be Rai stage 3–4 and Binet stage C, resulting in poor responses to chemotherapy and worse outcomes. In contrast, patient with trisomy 12 and isolated del(13q14) showed better responses and superior survival outcomes. The incidence of CLL is lower in Korea than in Western countries, and the frequency of chromosomal aberrations differs, perhaps reflecting differences in the pathogenic mechanism between ethnicities. Large prospective studies are needed to further assess the prognostic value of these results in Korean CLL patients. Copyright © 2013 John Wiley & Sons, Ltd.
Genetic variants associated with longer telomere length are associated with increased lung cancer risk among never‐smoking women in Asia: a report from the female lung cancer consortium in Asia

Recent evidence from several relatively small nested case‐control studies in prospective cohorts shows an association between longer telomere length measured phenotypically in peripheral white blood cell (WBC) DNA and increased lung cancer risk. We sought to further explore this relationship by examining a panel of seven telomere‐length associated genetic variants in a large study of 5,457 never‐smoking female Asian lung cancer cases and 4,493 never‐smoking female Asian controls using data from a previously reported genome‐wide association study. Using a group of 1,536 individuals with phenotypically measured telomere length in WBCs in the prospective Shanghai Women's Health study, we demonstrated the utility of a genetic risk score (GRS) of seven telomere‐length associated variants to predict telomere length in an Asian population. We then found that GRSs used as instrumental variables to predict longer telomere length were associated with increased lung cancer risk (OR = 1.51 (95% CI = 1.34–1.69) for upper vs. lower quartile of the weighted GRS, p value = 4.54 × 10−14) even after removing rs2736100 (p value = 4.81 × 10−3), a SNP in the TERT locus robustly associated with lung cancer risk in prior association studies. Stratified analyses suggested the effect of the telomere‐associated GRS is strongest among younger individuals. We found no difference in GRS effect between adenocarcinoma and squamous cell subtypes. Our results indicate that a genetic background that favors longer telomere length may increase lung cancer risk, which is consistent with earlier prospective studies relating longer telomere length with increased lung cancer risk.
Elevated levels of DNA methylation at the OPRM1 promoter in blood and sperm from male opioid addicts.

OBJECTIVE The OPRM1 gene was studied for DNA methylation in opioid dependence and possible paternal contribution to epigenetic inheritance of altered methylation profiles. PARTICIPANTS AND METHODS DNA was extracted from blood and sperm from 13 male opioid addicts and 21 male control subjects. DNA methylation was determined by pyrosequencing in 24 CpG sites at the OPRM1 promoter region. RESULTS The authors found significantly increased overall methylation in blood DNA from addicted subjects (Kruskal-Wallis [K-W] p = 0.013). Seven CpG sites showed significantly hypermethylated blood DNA from cases when compared with blood DNA from controls (p < 0.05 at CpGs 5, 9, 10, 11, 18, 23, and 24). In sperm-derived DNA from addicts, the methylation was significantly increased at CpG 2 (p = 0.012), and overall methylation did not reach significant difference (K-W p = 0.523). CONCLUSIONS Increased DNA methylation in the OPRM1 gene is associated with opioid dependence. Hypermethylated CpG sites located in OPRM1 promoter may potentially block the binding of Sp1 and other transcription activators, thus leading to OPRM1 silencing. The increased DNA methylation in sperm may suggest a way of epigenetic heritability of opioid abuse or dependence phenotypes.