bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sofosbuvir and Ribavirin Liver Pharmacokinetics in Patients Infected with Hepatitis C Virus
Authors: Babusis Darius , Curry Michael P. , Kirby Brian , Park Yeojin , Murakami Eisuke , Wang Ting , Mathias Anita , Afdhal Nezam , McHutchison John G. , Ray Adrian S. 
Published: February 2018

ABSTRACTSofosbuvir and ribavirin exert their anti-hepatitis C virus (anti-HCV) activity following metabolic activation in the liver. However, intrahepatic concentrations of the pharmacologically active nucleotide metabolites in humans are poorly characterized due to the inaccessibility of tissue and technical challenges with measuring nucleotide levels. A clinical study assessing the efficacy of sofosbuvir and ribavirin administered prior to liver transplantation to prevent HCV recurrence provided a unique opportunity to quantify nucleotide concentrations in human liver. We analyzed nucleotides using high-performance liquid chromatography coupled to tandem mass spectrometry in liver tissue from 30 HCV-infected patients with hepatocellular carcinoma who were administered sofosbuvir (400 mg/day) and ribavirin (1,000 to 1,200 mg/day) for 3 to 52 weeks prior to liver transplantation. Median total hepatic metabolite concentrations (the sum of nucleoside and mono-, di-, and triphosphates) were 77.1 μM for sofosbuvir and 361 μM for ribavirin in patients on therapy at the time of transplantation. Ribavirin and sofosbuvir efficiently loaded the liver, with total hepatic metabolite concentrations exceeding maximal levels in plasma by approximately 30-fold. Ribavirin metabolite levels suggest that its monophosphate is in great excess of its inhibition constant for IMP dehydrogenase and that its triphosphate is approaching the binding constant for incorporation by the HCV NS5B RNA-dependent RNA polymerase. In accordance with the potent antiviral activity of sofosbuvir, these results demonstrate that the liver triphosphate levels achieved following sofosbuvir administration greatly exceed the inhibition constant for HCV NS5B. In conclusion, this study expands the quantitative understanding of the pharmacology of sofosbuvir and ribavirin by establishing efficient hepatic delivery in the clinic. (This study has been registered at ClinicalTrials.gov under identifier NCT01559844.)
Deposition of Bacteria and Bacterial Spores by Bathroom Hot-Air Hand Dryers
Authors: Huesca-Espitia Luz del Carmen , Aslanzadeh Jaber , Feinn Richard , Joseph Gabrielle , Murray Thomas S. , Setlow Peter 
Published: February 2018

ABSTRACT

Hot-air hand dryers in multiple men's and women's bathrooms in three basic science research areas in an academic health center were screened for their deposition on plates of (i) total bacteria, some of which were identified, and (ii) a kanamycin-resistant
Bacillus subtilis
strain, PS533, spores of which are produced in large amounts in one basic science research laboratory. Plates exposed to hand dryer air for 30 s averaged 18 to 60 colonies/plate; but interior hand dryer nozzle surfaces had minimal bacterial levels, plates exposed to bathroom air for 2 min with hand dryers off averaged ≤1 colony, and plates exposed to bathroom air moved by a small fan for 20 min had averages of 15 and 12 colonies/plate in two buildings tested. Retrofitting hand dryers with HEPA filters reduced bacterial deposition by hand dryers ∼4-fold, and potential human pathogens were recovered from plates exposed to hand dryer air whether or not a HEPA filter was present and from bathroom air moved by a small fan. Spore-forming colonies, identified as
B. subtilis
PS533, averaged ∼2.5 to 5% of bacteria deposited by hand dryers throughout the basic research areas examined regardless of distance from the spore-forming laboratory, and these were almost certainly deposited as spores. Comparable results were obtained when bathroom air was sampled for spores. These results indicate that many kinds of bacteria, including potential pathogens and spores, can be deposited on hands exposed to bathroom hand dryers and that spores could be dispersed throughout buildings and deposited on hands by hand dryers.

IMPORTANCE
While there is evidence that bathroom hand dryers can disperse bacteria from hands or deposit bacteria on surfaces, including recently washed hands, there is less information on (i) the organisms dispersed by hand dryers, (ii) whether hand dryers provide a reservoir of bacteria or simply blow large amounts of bacterially contaminated air, and (iii) whether bacterial spores are deposited on surfaces by hand dryers. Consequently, this study has implications for the control of opportunistic bacterial pathogens and spores in public environments including health care settings. Within a large building, potentially pathogenic bacteria, including bacterial spores, may travel between rooms, and subsequent bacterial/spore deposition by hand dryers is a possible mechanism for spread of infectious bacteria, including spores of potential pathogens if present.
Single-Cell Analysis of the Impact of Host Cell Heterogeneity on Infection with Foot-and-Mouth Disease Virus
Authors: Xin Xiu , Wang Hailong , Han Lingling , Wang Mingzhen , Fang Hui , Hao Yao , Li Jiadai , Zhang Hu , Zheng Congyi , Shen Chao 
Published: February 2018

ABSTRACT

Viral infection and replication are affected by host cell heterogeneity, but the mechanisms underlying the effects remain unclear. Using single-cell analysis, we investigated the effects of host cell heterogeneity, including cell size, inclusion, and cell cycle, on foot-and-mouth disease virus (FMDV) infection (acute and persistent infections) and replication. We detected various viral genome replication levels in FMDV-infected cells. Large cells and cells with a high number of inclusions generated more viral RNA copies and viral protein and a higher proportion of infectious cells than other cells. Additionally, we found that the viral titer was 10- to 100-fold higher in cells in G
2
/M than those in other cell cycle phases and identified a strong correlation between cell size, inclusion, and cell cycle heterogeneity, which all affected the infection and replication of FMDV. Furthermore, we demonstrated that host cell heterogeneity influenced the adsorption of FMDV due to differences in the levels of FMDV integrin receptors expression. Collectively, these results further our understanding of the evolution of a virus in a single host cell.

IMPORTANCE
It is important to understand how host cell heterogeneity affects viral infection and replication. Using single-cell analysis, we found that viral genome replication levels exhibited dramatic variability in foot-and-mouth disease virus (FMDV)-infected cells. We also found a strong correlation between heterogeneity in cell size, inclusion number, and cell cycle status and that all of these characteristics affect the infection and replication of FMDV. Moreover, we found that host cell heterogeneity influenced the viral adsorption as differences in the levels of FMDV integrin receptors' expression. This study provided new ideas for the studies of correlation between FMDV infection mechanisms and host cells.
Dynamics of Evolution of Poliovirus Neutralizing Antigenic Sites and Other Capsid Functional Domains during a Large and Prolonged Outbreak
Authors: Shaw Jing , Jorba Jaume , Zhao Kun , Iber Jane , Chen Qi , Adu Festus , Adeniji Adekunle , Bukbuk David , Baba Marycelin , Henderson Elizabeth , Dybdahl-Sissoko Naomi , McDonald Sharla , Weldon William C. , Gumede Nicksy , Oberste M. Steven , Kew Olen M. , Burns Cara C. 
Published: February 2018

ABSTRACT
We followed the dynamics of capsid amino acid replacement among 403 Nigerian outbreak isolates of type 2 circulating vaccine-derived poliovirus (cVDPV2) from 2005 through 2011. Four different functional domains were analyzed: (i) neutralizing antigenic (NAg) sites, (ii) residues binding the poliovirus receptor (PVR), (iii) VP1 residues 1 to 32, and (iv) the capsid structural core. Amino acid replacements mapped to 37 of 43 positions across all 4 NAg sites; the most variable and polymorphic residues were in NAg sites 2 and 3b. The most divergent of the 120 NAg variants had no more than 5 replacements in all NAg sites and were still neutralized at titers similar to those of Sabin 2. PVR-binding residues were less variable (25 different variants; 0 to 2 replacements per isolate; 30/44 invariant positions), with the most variable residues also forming parts of NAg sites 2 and 3a. Residues 1 to 32 of VP1 were highly variable (133 different variants; 0 to 6 replacements per isolate; 5/32 invariant positions), with residues 1 to 18 predicted to form a well-conserved amphipathic helix. Replacement events were dated by mapping them onto the branches of time-scaled phylogenies. Rates of amino acid replacement varied widely across positions and followed no simple substitution model. Replacements in the structural core were the most conservative and were fixed at an overall rate ∼20-fold lower than the rates for the NAg sites and VP1 1 to 32 and ∼5-fold lower than the rate for the PVR-binding sites. Only VP1 143-Ile, a non-NAg site surface residue and known attenuation site, appeared to be under strong negative selection.

IMPORTANCE
The high rate of poliovirus evolution is offset by strong selection against amino acid replacement at most positions of the capsid. Consequently, poliovirus vaccines developed from strains isolated decades ago have been used worldwide to bring wild polioviruses almost to extinction. The apparent antigenic stability of poliovirus obscures a dynamic of continuous change within the neutralizing antigenic (NAg) sites. During 7 years of a large outbreak in Nigeria, the circulating type 2 vaccine-derived polioviruses generated 120 different NAg site variants via multiple independent pathways. Nonetheless, overall antigenic evolution was constrained, as no isolate had fixed more than 5 amino acid differences from the Sabin 2 NAg sites, and the most divergent isolates were efficiently neutralized by human immune sera. Evolution elsewhere in the capsid was also constrained. Amino acids binding the poliovirus receptor were strongly conserved, and extensive variation in the VP1 amino terminus still conserved a predicted amphipathic helix.
Association between social health insurance and choice of hospitals among internal migrants in China: a national cross-sectional study
Authors: Wang Haiqin , Zhang Donglan , Hou Zhiying , Yan Fei , Hou Zhiyuan 
Published: February 2018

ObjectivesThere is a tendency to pursue higher-level hospitalisation services in China, especially for internal migrants. This study aims to investigate the choices of hospitalisation services among internal migrants, and evaluate the association between social health insurance and hospitalisation choices.MethodsData were from a 2014 nationally representative cross-sectional sample of internal migrants aged 15–59 years in China. Descriptive analyses were used to perform the distribution of healthcare facility levels for hospitalisation services, and multinomial logistic regression was applied to examine the association between social health insurance and hospitalisation choices.ResultsOf the 6121 inpatient care users, only 11.50% chose the primary healthcare facilities for hospitalisation services, 44.91% chose the secondary hospitals and 43.59% preferred the tertiary hospitals. The choices presented large regional variations across the country. Compared with the uninsured, social health insurance had no statistically significant effect on patient choices of healthcare facility levels among internal migrants in China, whereas socioeconomic status was positively associated with the choices.ConclusionsSocial health insurance had little influence on the hospital choice among the internal migrants. Thus, social health insurance should be consolidated and portable to enhance the proper incentive of health insurance on healthcare seeking behaviours.
Interventions to increase access to or uptake of physical health screening in people with severe mental illness: a realist review
Authors: Lamontagne-Godwin Frédérique , Burgess Caroline , Clement Sarah , Gasston-Hales Melanie , Greene Carolynn , Manyande Anne , Taylor Deborah , Walters Paul , Barley Elizabeth 
Published: February 2018

ObjectivesTo identify and evaluate interventions aimed at increasing uptake of, or access to, physical health screening by adults with severe mental illness; to examine why interventions might work.DesignRealist review.SettingPrimary, secondary and tertiary care.ResultsA systematic search identified 1448 studies, of which 22 met the inclusion criteria. Studies were from Australia (n=3), Canada (n=1), Hong Kong (n=1), UK (n=11) and USA (n=6). The studies focused on breast cancer screening, infection preventive services and metabolic syndrome (MS) screening by targeting MS-related risk factors. The interventions could be divided into those focusing on (1) health service delivery changes (12 studies), using quality improvement, randomised controlled trial, cluster randomised feasibility trial, retrospective audit, cross-sectional study and satisfaction survey designs and (2) tests of tools designed to facilitate screening (10 studies) using consecutive case series, quality improvement, retrospective evaluation and pre–post audit study designs. All studies reported improved uptake of screening, or that patients had received screening they would not have had without the intervention. No estimation of overall effect size was possible due to heterogeneity in study design and quality. The following factors may contribute to intervention success: staff and stakeholder involvement in screening, staff flexibility when taking physical measurements (eg, using adapted equipment), strong links with primary care and having a pharmacist on the ward.ConclusionsA range of interventions may be effective, but better quality research is needed to determine any effect size. Researchers should consider how interventions may work when designing and testing them in order to target better the specific needs of this population in the most appropriate setting. Behaviour-change interventions to reduce identified barriers of patient and health professional resistance to screening this population are required. Resource constraints, clarity over professional roles and better coordination with primary care need to be addressed.
JAK2 mediates lung fibrosis, pulmonary vascular remodelling and hypertension in idiopathic pulmonary fibrosis: an experimental study
Authors: Milara Javier , Ballester Beatriz , Morell Anselm , Ortiz José L , Escrivá Juan , Fernández Estrella , Perez-Vizcaino Francisco , Cogolludo Angel , Pastor Enrique , Artigues Enrique , Morcillo Esteban , Cortijo Julio 
Published: February 2018

BackgroundPulmonary hypertension (PH) is a common disorder in patients with idiopathic pulmonary fibrosis (IPF) and portends a poor prognosis. Recent studies using vasodilators approved for PH have failed in improving IPF mainly due to ventilation (V)/perfusion (Q) mismatching and oxygen desaturation. Janus kinase type 2 (JAK2) is a non-receptor tyrosine kinase activated by a broad spectrum of profibrotic and vasoactive mediators, but its role in PH associated to PH is unknown.ObjectiveThe study of JAK2 as potential target to treat PH in IPF.Methods and resultsJAK2 expression was increased in pulmonary arteries (PAs) from IPF (n=10; 1.93-fold; P=0.0011) and IPF+PH (n=9; 2.65-fold; P<0.0001) compared with PA from control subjects (n=10). PA remodelling was evaluated in human pulmonary artery endothelial cells (HPAECs) and human pulmonary artery smooth muscle cells (HPASMCs) from patients with IPF in vitro treated with the JAK2 inhibitor JSI-124 or siRNA-JAK2 and stimulated with transforming growth factor beta. Both JSI-124 and siRNA-JAK2 inhibited the HPAEC to mesenchymal transition and the HPASMCs to myofibroblast transition and proliferation. JAK2 inhibition induced small PA relaxation in precision-cut lung slice experiments. PA relaxation was dependent of the large conductance calcium-activated potassium channel (BKCa). JAK2 inhibition activated BKCa channels and reduced intracellular Ca2+. JSI-124 1 mg/kg/day, reduced bleomycin-induced lung fibrosis, PA remodelling, right ventricular hypertrophy, PA hypertension and V/Q mismatching in rats. The animal studies followed the ARRIVE guidelines.ConclusionsJAK2 participates in PA remodelling and tension and may be an attractive target to treat IPF associated to PH.
Effect of grain type and dried distillers grains plus solubles oil concentration on site of digestion in cattle fed finishing diets
Authors: Rodenhuis Mary A. , Keomanivong Faithe E. , Bauer Marc L. , Swanson Kendall C. 
Published: February 2018

The objective of this experiment was to determine the effects of grain type (rolled corn vs. rolled barley) and oil concentration of dried corn distillers grains plus solubles (DDGS; moderate = 7.9% vs. low = 4.5% ether extract) on site of digestion. Seven ruminally and duodenally cannulated Holstein steers (716 ± 8.9 kg) were used in a 4 × 7 Youden square with experimental periods of 24 d. True ruminal organic matter (OM) and crude protein (CP) digestibility (% of intake) as well as intestinal (% of entering duodenum) and total tract starch digestibility was greater (P ≤ 0.03) in steers fed diets containing barley than in steers fed diets containing corn. Ruminal disappearance and ruminal, intestinal, and total tract OM, CP, and starch digestibility were not influenced (P ≥ 0.11) by feeding diets containing DDGS with differing oil concentration. Total tract lipid digestibility (%) was greater (P < 0.001) in steers fed diets containing moderate-oil DDGS than low-oil DDGS. These data indicate that including a low-oil DDGS, as compared with a moderate-oil DDGS, in finishing diets containing rolled corn or rolled barley does not influence intake or site of digestion of nonlipid components.
External Auditory Canal Dimensions, Age, and Cerumen Retention or Impaction in Persons With Down Syndrome
Authors: Dy Alexander Edward S. , Lapeña José Florencio F. 
Published: February 2018

Objective: To investigate associations between age, external auditory canal (EAC) dimensions, and cerumen retention/impaction among persons with Down syndrome (DS). Methods: This cross-sectional study evaluated EAC dimensions, cerumen retention/impaction, and middle ear status with pneumatoscopy after extraction in 130 persons with DS. Descriptive and inferential statistics correlated age, presence of impacted/retained cerumen, and EAC diameter. Results: Of 260 ears in 67 males and 63 females with average age of 9.48 years, 72.3% (188) had EAC of ≤4 mm. Those ≤1 year were 4.97 times more likely to have cerumen problems than those >1 year (95% CI, 1.45-17.02, P = .011). The odds of having cerumen problems with an EAC diameter of ≤4 mm were 3.31 times higher than with a diameter of 5 mm (95% CI, 1.46-7.50, P = .004), and odds of having cerumen impaction were as much as 6.19 times higher (95% CI, 2.38-16.08, P < .001). Male gender and low-lying external ear were also associated with increased odds of cerumen problems. Conclusion: There is a high prevalence of cerumen retention/impaction in persons with DS compared to the general Philippine population and a higher prevalence rate for EAC stenosis than elsewhere. A canal diameter of 4 mm and below and age 1 year or less are associated with a significantly higher likelihood of cerumen retention/impaction.
Rare MYC-amplified Neuroblastoma With Large Cell Histology
Authors: Matsuno Ryosuke , Gifford Andrew J , Fang Junming , Warren Mikako , Lukeis Robyn E , Trahair Toby , Sugimoto Tohru , Marachelian Araz , Asgharzadeh Shahab , Maris John M , Ikegaki Naohiko , Shimada Hiroyuki 
Published: February 2018

Background Although MYCN (aka N-myc) amplification is reported in ∼20% of neuroblastomas, MYC (aka C-myc) amplification appears to be a rare event in this disease. As of today, only 2 MYC-amplified neuroblastomas have been briefly mentioned in the literature. Methods We studied here the clinicopathological features of 3 MYC-amplified neuroblastomas. Results All 3 patients (2 females and 1 male) had stage 4 disease. One female is currently alive and well 52 months after the diagnosis, while the other female and male patients died of disease 24 and 20 months after the diagnosis, respectively. Further analysis on 2 tumors revealed unfavorable histology with MYC protein overexpression but with neither MYCN amplification nor MYCN protein overexpression. Both of these tumors exhibited “large cell neuroblastoma” histology with enlarged, uniquely open nuclei and nucleolar hypertrophy, along with “aberrant” desmin expression. Conclusions MYC-amplified neuroblastomas are extremely rare and seem to present with distinct clinicopathological features.
A retrospective review of the role of B-mode and color Doppler ultrasonography in the investigation of primary hyperparathyroidism: Features that differentiate benign from malignant lesions
Authors: Fang Cheng , Konstantatou Eleni , Mulholland Nicola J , Baroncini Serena , Husainy Mohammad A , Schulte Klaus-Martin , Sidhu Paul S 
Published: February 2018

Purpose To identify the variant features encountered in parathyroid abnormalities and document those suggesting malignant change. Materials and methods Data were collected from a cohort of patients who underwent investigation for primary hyperparathyroidism over a 10-year period. Ultrasonographic features: shape, presence of calcification, cystic changes, heterogeneous echogenicity, vascularity, capsular thickening, local invasion, and vascularity were reviewed retrospectively and were used to correlate with final histological findings. Results One hundred forty-seven patients with histology and concurrent ultrasonographic scans were reviewed, and divided into benign parathyroid lesions (nodular hyperplasia ( n = 44), adenoma ( n = 93)) and parathyroid carcinoma ( n = 10). Parathyroid carcinomas were significantly larger than benign parathyroid lesions ( P = 0.030). Benign parathyroid lesions showed variant sonographic features: irregular shape (16.8%), heterogenous echogenicity (24.1%), calcification (1.5%), capsular thickening (1.5%), and cystic change (19.7%). A significantly higher proportion of parathyroid carcinomas demonstrated heterogenous echogenicity ( P = 0.022), capsular thickening ( P = 0.023), and infiltrative margin ( P < 0.0001) than benign parathyroid lesions. Of the 137 benign parathyroid lesions, 38 (27.7%), 76 (55.5%), 23 (16.8%) were avascular, vascular, and hypervascular, respectively. Of the 10 parathyroid carcinomas, 4 (40%), 3 (30%), and 3 (30%) of lesions were avascular, vascular, and hypervascular, respectively. The vascularity of the lesions did not differ significantly between the parathyroid carcinoma and benign parathyroid lesions ( P = 0.281). Conclusion Ultrasonographic features such as irregular shape, heterogeneous echogenicity, cystic change, and vascularity are nondiscriminatory features between benign or malignant lesions. Large lesion size together with the presence of calcification, capsular thickening, or infiltrative margin strongly raises the suspicion of a malignant parathyroid lesion, and management should be altered.
Optimization of Work Schedules Executed using the Flow Shop Model, Assuming Multitasking Performed by Work Crews
Authors: Krzemiński M. 
Published: February 2018

AbstractThe problem described in this paper deals with construction project scheduling for multi-object projects. The use of the flow shop model allows for quick execution through optimal, simultaneous means of production. The correct order of tasks according to assumed criteria is the subject of a lot of research. In this paper, we have focused on the aspect of multi-project work crews. In practice, we often observe cases where overburdened crews are supported by ones with downtime. This paper presents a newly developed model used to smoothe out schedules in terms of maintaining crew work continuity. A full description of the algorithm and example usage are presented.