bluuebunny/crossref_metadata_2025_split huggingface dataset:
Hepatitis B virus Quantification and Detection of YMDD Mutants in a Single Reaction by Real-Time PCR and Annealing Curve Analysis
Authors: Shih Yi-Hsien , Yeh Shiou-Hwei , Chen Pei-Jer , Chou Wen-Pin , Wang Hurng-Yi , Liu Chun-Jen , Lu Su-Feng , Chen Ding-Shinn 
Published: April 2022

Background Long-term antiviral therapy, although effective for treatment of hepatitis B, might select the emergence of drug-resistant hepatitis B virus (HBV) mutants. Detection of HBV mutants and determination of viral titre are two crucial parameters for monitoring treatment response and occurrence of mutants. In this study, we take lamivudine resistance as an example to develop a method that can determine both parameters in a single-tube PCR reaction. Methods The method contained two consecutive steps: in the first step, real-time PCR was used for quantification; in the second step, a novel annealing curve analysis was used for detecting YMDD mutants. For accurate quantification, PCR primers and hybridization probes were chosen from highly conserved regions to ensure the equivalent amplification of all HBV genotypes. Within the sensor probe, there were signature nucleotide polymorphisms that could effectively differentiate YMDD mutants from wild type by distinct melting temperatures (Tm) values. The clinical applicability of the assay was tested in serial samples from 90 patients receiving lamivudine treatment. Results This assay could readily differentiate YMDD, YIDD and YVDD mutants by their distinct Tm values. The quantification results showed great consistency in a linear range from 103 to 1011 copies/ml. Moreover, this assay could detect YMDD mutants accounting for ≤10% of the total viral population. Its clinical feasibility has been verified in primary specimens. Conclusions The newly designed YMDD detection method is simple, sensitive, cost-effective, time-saving and provides a useful tool for follow-up of patients treated with lamivudine or other antiviral drugs.
Pharmacokinetics of Elvitegravir and Etravirine following Coadministration of Ritonavir-Boosted Elvitegravir and Etravirine
Authors: Ramanathan Srinivasan , Kakuda Thomas N , Mack Rebecca , West Steve , Kearney Brian P 
Published: April 2022

Background This crossover, open-label clinical study evaluated the potential for clinically relevant drug interactions between ritonavir-boosted elvitegravir (elvitegravir/r), an HIV integrase inhibitor, and etravirine, a non-nucleoside reverse transcriptase inhibitor. Methods Healthy volunteers were randomized into one of two groups, each with two arms. Group 1 ( n=20) followed a sequence of 10-day dosing of elvitegravir/r (150/100 mg once daily) and elvitegravir/r plus etravirine (200 mg twice daily) or the reverse ( n=10 per sequence). Group 2 ( n=14) followed a sequence of 10-day dosing of etravirine and etravirine plus elvitegravir/r or the reverse ( n=7 per sequence), all under fed conditions. Elvitegravir, ritonavir and etravirine pharmacokinetics were determined on days 10 and 20 using non-compartmental analyses. Lack of pharmacokinetic alteration bounds for 90% confidence intervals (CI) about the geometric mean ratio (GMR; coadministration versus alone) were 70–143% for elvitegravir and ritonavir pharmacokinetics (maximum concentration [Cmax], concentration at the end of the dosing interval [Ctau] and area under the plasma concentration–time curve [AUCtau; 0–24 h] and 80–125% for etravirine pharmacokinetics (AUCtau 0–12 h). Results Of the 34 enrolled participants, 31 completed the study. There were three discontinuations, but none were caused by adverse events (AEs). The most common treatment-emergent AE was headache. Elvitegravir pharmacokinetic GMR was 6–7% higher following elvitegravir/r plus etravirine dosing versus elvitegravir/r. The GMR for etravirine and ritonavir AUCtau were 2.4% and 12.3% lower, respectively. Importantly, the 90% CI for elvitegravir and etravirine pharmacokinetics and AUCtau and Cmax for ritonavir were within the lack of alteration bounds. Conclusions Elvitegravir/r and etravirine do not undergo clinically relevant drug interactions and can be coadministered without dose adjustment.
Safety, pharmacokinetics and antiviral effect of BILB 1941, a novel hepatitis C virus RNA polymerase inhibitor, after 5 days oral treatment
Authors: Erhardt Andreas , Deterding Katja , Benhamou Yves , Reiser Markus , Forns Xavier , Pol Stanislas , Calleja José Luis , Ross Susanne , Spangenberg Hans Christian , Garcia-Samaniego Javier , Fuchs Michael , Enríquez Jaime , Wiegand Johannes , Stern Jerry , Wu Kate , Kukolj George , Marquis Martin , Beaulieu Pierre , Nehmiz Gerhard , Steffgen Jürgen 
Published: April 2022

Background BILB 1941 is a potent and specific non-nucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase in vitro. Methods In a double-blind sequential group comparison, 96 male HCV genotype 1 patients with minimal to mild liver fibrosis (Ishak or Metavir score 0–2) were randomized (8 to active treatment and 2 to placebo per dose group) and treated with 10–450 mg BILB 1941 every 8 h over 5 days. Viral load (VL) was measured using Roche Cobas TaqMan® assays. Results VL decreased by ≥1 log10 IU/ml in 2/8, 2/8, 1/8, 2/7, 0/8, 2/8 and 4/5 patients on 60, 80, 100, 150, 200, 300 and 450 mg, respectively. No response was seen with placebo. HCV subtype 1b showed better response than 1a, the effect of other covariables including prior interferon treatment was not significant. NS5B population sequencing and phenotyping identified baseline samples with reduced BILB 1941 susceptibility, but did not detect an on-treatment emergence of resistant mutants. Plasma drug levels were linear until 300 mg. No serious adverse events (AEs) were reported. AEs were mainly gastrointestinal-related (most frequent diarrhoea) and frequency increased with dose. On 450 mg, all five active-treated patients discontinued (four for gastrointestinal intolerance and one for increased aspartate aminotransferase and alanine aminotransferase levels) and the trial was discontinued. Conclusions BILB 1941 monotherapy demonstrated antiviral activity against HCV genotype 1, but gastrointestinal intolerance precluded testing of higher doses.
Modelling Hepatitis C virus Kinetics: The Relationship between the Infected Cell Loss rate and the Final Slope of Viral Decay
Authors: Dahari Harel , Shudo Emi , Cotler Scott J , Layden Thomas J , Perelson Alan S 
Published: April 2022

Background Patients infected with hepatitis C virus (HCV) who respond to treatment with interferon-α plus ribavirin exhibit biphasic or triphasic viral load decreases. While the rapid first phase is indicative of the effectiveness of therapy in blocking viral production (e), the slope of the final phase ( X), that is, the second phase in biphasic decreases and the third phase in triphasic decreases, depends on the infected cell loss rate (δ). In standard models, X is approximately εδ when the viral clearance rate c>>δ, as has been previously estimated. Methods The relationship among e, S, X and the baseline fraction of HCV-infected hepatocytes (π) was investigated in a model that included proliferation of hepatocytes. Results We found that X was not proportional to e, but rather obeyed a complex relationship that could lead to dramatic increases in estimates of 8 as e increased. In particular, when ε<99%, X moderately underestimated 8 in patients with a small π, whereas δ might be up to 10-fold larger than λ in patients with a large π. Interestingly, when ε>99%, δ∼λ regardless of π. Conclusions Our results indicated that in patients undergoing therapy who achieved a 2 log10 reduction in viral load (ε<99%), previously estimated δ values might represent only a minimal estimate of the infected cell loss rate. Moreover, combining interferon-α with new antiviral agents to achieve ε>99% should allow for a more accurate estimate of 8 in HCV RNA kinetic studies. This might be important when using viral kinetics to estimate the effect of the immune response on viral elimination and the attainment of sustained virological response.
Plasma efavirenz concentrations and the association with CYP2B6-516 G >T polymorphism in HIV-infected Thai children
Authors: Puthanakit Thanyawee , Tanpaiboon Pranoot , Aurpibul Linda , Cressey Tim R , Sirisanthana Virat 
Published: April 2022

Background Concerns have been raised about the possibility of subtherapeutic efavirenz (EFV) plasma levels in children with the current dosing guideline. Single nucleotide polymorphisms of the hepatic cytochrome P450 isoenzyme 2B6 (CYP2B6) gene have been associated with high inter-individual variations in EFV plasma concentrations. Our objective was to determine the adequacy of EFV dosing and explore the influence of CYP2B6-516G>T polymorphisms on EFV plasma concentrations in Thai HIV-infected children. Methods A total of 63 HIV-infected children receiving EFV for ≥4 weeks were assessed. Children received EFV daily doses on the basis of body weight bands. Between 12 to 16 h after EFV intake, a blood sample was drawn to measure the EFV plasma concentration and to determine the CYP2B6-516G>T polymorphism using HPLC and direct gene sequencing, respectively. Results The median age (range) was 12.3 years (3.1- 18.7). The mean (±SD) EFV plasma concentration was 3,138 ng/ml (3,313). Eight (13%), 45 (71%) and 10 (16%) children had an EFV concentration <1,000 ng/ ml, 1,000-4,000 ng/ml and >4,000 ng/ml, respectively. CYP2B6-516 G/G, G/T and T/T genotypes were found in 48%, 41% and 11% children, respectively. The CYP2B6-516G>T allele frequency was 31.75%. The mean (±SD) EFV concentration for children with G/G, G/T and T/T genotypes were 1,604 ng/ml (729), 2,635 ng/ml (1,199) and 11,582 ng/ml (2,972), respectively ( P<0.001). A correlation between EFV concentrations >4,000 ng/ml and psychiatric side effects was observed ( P=0.02), but there was no association with rash, hepatotoxicity or central nervous system disturbances. Conclusions Current EFV dosing guidelines provide adequate plasma drug concentrations in Thai HIV-infected children. CYP2B6-516G>T polymorphisms significantly affect the drug metabolism of EFV in children.
Geriatric assessment for older adults receiving less-intensive therapy for acute myeloid leukemia: report of CALGB 361101
Authors: Ritchie Ellen K. , Klepin Heidi D. , Storrick Elizabeth , Major Brittny , Le-Rademacher Jennifer , Wadleigh Martha , Walker Alison , Larson Richard A. , Roboz Gail J. 
Published: April 2022

Abstract
Geriatric assessment (GA) predicts survival among older adults with acute myeloid leukemia (AML) treated intensively. We evaluated the predictive utility of GA among older adults treated with low-intensity therapy on a multisite trial. We conducted a companion study (CALGB 361101) to a randomized phase 2 trial (CALGB 11002) of adults ≥60 years and considered “unfit” for intensive therapy, testing the efficacy of adding bortezomib to decitabine therapy. On 361101, GA and quality of life (QOL) assessment was administered prior to treatment and every other subsequent cycle. Relationships between baseline GA and QOL measures with survival were evaluated using Kaplan-Meier estimation and Cox proportional hazards models. One-hundred sixty-five patients enrolled in CALGB 11002, and 96 (52%) of them also enrolled in 361101 (median age, 73.9 years). Among participants, 85.4% completed ≥1 baseline assessment. In multivariate analyses, greater comorbidity (hematopoietic cell transplantation-specific comorbidity index &gt;3), worse cognition (Blessed Orientation-Memory-Concentration score &gt;4), and lower European Organization for Research and Treatment of Cancer global QOL scores at baseline were significantly associated with shorter overall survival (P &lt; .05 each) after adjustment for Karnofsky Performance Status, age, and treatment arm. Dependence in instrumental activities of daily living and cognitive impairment were associated with 6-month mortality (hazard ratio [HR], 3.5; confidence interval [CI], 1.2-10.4; and HR, 3.1; CI, 1.1-8.6, respectively). GA measures evaluating comorbidity, cognition, and self-reported function were associated with survival and represent candidate measures for screening older adults planned to receive lower-intensity AML therapies. This trial was registered at www.clinicaltrials.gov as #NCT01420926 (CALGB 11002).
Proteomics analysis: inhibiting the expression of P62 protein by chloroquine combined with dacarbazine can reduce the malignant progression of uveal melanoma
Authors: Fei Xifeng , Xie Xiangtong , Qin Ruwei , Wang Anqi , Meng Xuan , Sun Fei , Zhao Yifan , Jiang Dongyi , Chen Hanchun , Huang Qiang , Ji Xiaoyan , Wang Zhimin 
Published: April 2022

Abstract
Background
Although uveal melanoma (UM) at the early stage is controllable to some extent, it inevitably ultimately leads to death due to its metastasis. At present, the difficulty is that there is no way to effectively tackle the metastasis. It is hypothesized that these will be treated by target molecules, but the recognized target molecule has not yet been found. In this study, the target molecule was explored through proteomics.

Methods
Transgenic enhanced green fluorescent protein (EGFP) inbred nude mice, which spontaneously display a tumor microenvironment (TME), were used as model animal carriers. The UM cell line 92.1 was inoculated into the brain ventricle stimulating metastatic growth of UM, and a graft re-cultured Next, the UM cell line 92.1-A was obtained through monoclonal amplification, and a differential proteomics database, between 92.1 and ectopic 92.1-A, was established. Finally, bioinformatics methodologies were adopted to optimize key regulatory proteins, and in vivo and in vitro functional verification and targeted drug screening were performed.

Results
Cells and tissues displaying green fluorescence in animal models were determined as TME characteristics provided by hosts. The data of various biological phenotypes detected proved that 92.1-A were more malignant than 92.1. Besides this malignancy, the key protein p62 (SQSTM1), selected from 5267 quantifiable differential proteomics databases, was a multifunctional autophagy linker protein, and its expression could be suppressed by chloroquine and dacarbazine. Inhibition of p62 could reduce the malignancy degree of 92.1-A.

Conclusions
As the carriers of human UM orthotopic and ectopic xenotransplantation, transgenic EGFP inbred nude mice clearly display the characteristics of TME. In addition, the p62 protein optimized by the proteomics is the key protein that increases the malignancy of 92.1 cells, which therefore provides a basis for further exploration of target molecule therapy for refractory metastatic UM.
Dissociated optic nerve fiber layer-like appearance indicating an internal limiting membrane defect associated with an epiretinal membrane: two case reports
Authors: Ishida Yuichiro , Ota Naomichi , Tsuboi Kotaro , Kamei Motohiro 
Published: April 2022

Abstract
Background
We report for the first time a way to predict the 2-dimensional extension of an internal limiting membrane (ILM) defect by detecting the area with dissociated optic nerve fiber layer (DONFL)-like spots in the preoperative optical coherence tomography (OCT) en-face images.

Case presentations
Case 1 was a 67-year-old man with metamorphopsia and decreased vision in his right eye. His best-corrected visual acuity (BCVA) was 20/100, with a pterygium, a moderate nuclear cataract, and an epiretinal membrane (ERM). Case 2 was a 73-year-old man with metamorphopsia and decreased vision in his left eye. His BCVA was 20/25, with a moderate nuclear cataract and an ERM. Both patients underwent simultaneous cataract surgery and pars plana vitrectomy with ERM and ILM peeling. Brilliant Blue G staining, performed before ERM and ILM peeling, revealed an unstained area. A careful evaluation of the area showed that it was not covered by either the ERM or ILM. A postoperative evaluation of the preoperative OCT images obtained from these cases showed DONFL-like low-brightness spots in the ILM defect area on the OCT en-face images.

Conclusions
OCT en-face images may indicate the area of the ILM defect. To avoid iatrogenic damage to the retinal nerve fiber layer by touching/pinching it with forceps, detecting areas with DONFL-like spots in the preoperative OCT en-face images may be useful to predict an ILM defect.
Cumulative lifetime violence severity, social determinants and anxiety in a national sample of Canadian men
Authors: Scott-Storey Kelly , O’Donnell Sue , Busolo David , DiTommaso Enrico , Malcolm Jeannie , Taylor Petrea , Vincent Charlene D. , Wuest Judith 
Published: April 2022

Abstract
Background
Despite anxiety disorders being the ninth leading cause of disability and associated with social inequities, little attention has been given to how intersections among social determinants of health and chronic stressors such as cumulative lifetime violence affect the likelihood of experiencing anxiety disorders. Our purpose was to explore the relationships among cumulative lifetime violence severity as target and perpetrator, social determinants of health and generalized anxiety disorder in Canadian men.

Methods
Using a community sample of 592 Canadian men who self-identified as having experienced violence, we developed and tested an evidence-based model of generalized anxiety disorder including indicators of cumulative lifetime violence, gender, social location, socio-economic disparity, personal resources and other chronic stressors using logistic regression.

Results
Most men (76.4%, n = 452) reported experiences as both target and perpetrator. The model accounted for 50.8% of the variance in anxiety severity χ2 (8) = 264.43, p = .000). The prevalence of probable generalized anxiety disorder was 30.9%, a rate higher than that found among Canadian men in general in the same period. Remarkably, the likelihood of generalized anxiety disorder increased by a factor of 5.30 for each increase of 1 in cumulative lifetime violence severity, and six-fold for feeling overwhelmed by demands of everyday life (aOR = 6.26). Masculine discrepancy stress, having been born in Canada, unemployment, and food insecurity also contributed significantly to increasing the likelihood of generalized anxiety disorder. Both social support and mastery had significant aORs < 1, suggesting possible protective effects. Together these findings delineate characteristics and social determinants that may heighten vulnerability to generalized anxiety disorder and influence its progression among men who have experienced lifetime violence.

Conclusions
These findings are the first evidence that Canadian men with lifetime violence histories are a sub-group disproportionately affected by chronic stressors and socio-economic disparities and that together the presence and/or severity of these factors increases their vulnerability to generalized anxiety disorder. Our results highlight the importance of strengths-based trauma- and violence-informed approaches to care, including practical resources to reduce the stress of everyday life, improve social support, and reinforce personal control and choice.
Validity and reliability of the Neilands sexual stigma scale among Kenyan gay, bisexual, and other men who have sex with men
Authors: Korhonen Christine J. , Flaherty Brian P. , Wahome Elizabeth , Macharia Pascal , Musyoki Helgar , Battacharjee Parinita , Kimani Joshua , Doshi Monika , Mathenge John , Lorway Robert R. , Sanders Eduard J. , Graham Susan M. 
Published: April 2022

Abstract
Background
We evaluated the validity and reliability of the Neilands sexual stigma scale administered to 871 gay, bisexual, and other men who have sex with men (GBMSM) at two research locations in Kenya.

Methods
Using cross-validation, exploratory factor analysis (EFA) was performed on a randomly selected subset of participants and validated using confirmatory factor analysis (CFA) on the remaining participants. Associations of the initial and final stigma scale factors with depressive symptoms, alcohol use, and other substance use were examined for the entire dataset.

Results
EFA produced a two-factor scale of perceived and enacted stigma. The CFA model fit to the two-factor scale was improved after removing three cross-loaded items and adding correlated errors (chi-squared = 26.5, df 17, p = 0.07). Perceived stigma was associated with depressive symptoms (beta = 0.34, 95% CI 0.24, 0.45), alcohol use (beta = 0.14, 95% CI 0.03, 0.25) and other substance use (beta = 0.19, 95% CI 0.07, 0.31), while enacted stigma was associated with alcohol use (beta = 0.17, 95% CI 0.06, 0.27).

Conclusions
Our findings suggest enacted and perceived sexual stigma are distinct yet closely related constructs among GBMSM in Kenya and are associated with poor mental health and substance use.
Strengthening the service experiences of women impacted by gambling-related intimate partner violence
Authors: O’Mullan Cathy , Hing Nerilee , Nuske Elaine , Breen Helen , Mainey Lydia 
Published: April 2022

AbstractBackgroundWhile problem gambling does not directly cause intimate partner violence (IPV), it exacerbates that violence significantly. Women experiencing both gambling harm and IPV often find themselves in challenging situations; furthermore, stigma and shame frequently act as barriers to seeking help from health and social service agencies. Despite the links between problem gambling and IPV, little is known about women’s experiences of using support services for both IPV and gambling related issues. This paper explores positive experiences of help-seeking for gambling-related IPV in Australia by adopting a strengths-based research approach.MethodsQualitative, unstructured interviews were conducted for a larger study exploring the nature of the relationship between problem gambling and IPV. To gain new insights into the service experiences of women impacted by gambling related IPV, interviews with 48 women with lived experience of IPV relating to a male partner’s gambling, and 24 women with lived experience of IPV relating to their own gambling were reanalysed using thematic analysis.ResultsThree themes emerged from the data signifying or demonstrating strength-based responses: ‘Commitment to Integrated and Collaborative Responses’; ‘Therapeutic Support’; and ‘Instrumental Support’. The themes highlight the importance of recognising the intersectionality of gambling related IPV and supporting the person ‘at the centre of the service’. Tangible and instrumental supports, such as emergency accommodation and financial assistance, were also central to the recovery process.ConclusionEffective service responses are dependent on understanding how problem gambling and IPV intersect. Importantly, service providers must recognise and address the many facets of each woman’s situation and the shame associated with resolving interdependent and complex issues. Responding to the needs of women impacted by gambling related IPV requires both individual-level awareness and organisational support; recommendations to strengthen service provision are provided.