Miracle-dz/UniFAR-FTUs huggingface dataset:
Pharmacokinetics of Intravenous Voriconazole in Obese Patients: Implications of CYP2C19 Homozygous Poor Metabolizer Genotype

There is a paucity of pharmacokinetic studies describing weight‐based dosing of intravenous voriconazole in obese patients. In this case report, we describe the pharmacokinetics of intravenous voriconazole in an obese CYP2C19 homozygous poor metabolizer and review previously reported data regarding the use of intravenous voriconazole in obese patients. A 17‐year‐old obese Hispanic male patient (body mass index 35 kg/m2) received intravenous voriconazole for the treatment of suspected aspergillosis. After 2.5 days of voriconazole 4 mg/kg intravenously every 12 hours based on adjusted body weight, the voriconazole area under the serum concentration–time curve over the course of a single (12‐hr) dosing interval and trough concentration were 86,100 ng · hr/ml and 6.2 µg/ml, respectively. Six days later, the voriconazole dosage was decreased. A trough concentration measured just before the dosage reduction (after 8.5 days of voriconazole 4 mg/kg intravenously every 12 hours based on adjusted body weight) remained elevated at 5.8 µg/ml. Genotyping revealed a CYP2C19 homozygous poor metabolizer (CYP2C19*2/*2). Voriconazole was subsequently discontinued due to QTc prolongation. These data and those from two recent publications suggest that voriconazole does not distribute extensively into human adipose tissue and that obese patients should be dosed on an adjusted body weight basis. If an obese patient dosed on total body weight is also a CYP2C19 poor metabolizer, serum voriconazole concentrations will be further elevated, potentially leading to drug‐induced toxicity.
Primary stability of a cementless acetabular cup in a cohort of patient‐specific finite element models

The primary stability achieved during total hip arthroplasty determines the long‐term success of cementless acetabular cups. Pre‐clinical finite element testing of cups typically use a model of a single patient and assume the results can be extrapolated to the general population. This study explored the variability in predicted primary stability of a Pinnacle® cementless acetabular cup in 103 patient‐specific finite element models of the hemipelvis and examined the association between patient‐related factors and the observed variability. Cups were inserted by displacement‐control into the FE models and then a loading configuration simulating a complete level gait cycle was applied. The cohort showed a range of polar gap of 284–1112 μm and 95th percentile composite peak micromotion (CPM) of 18–624 μm. Regression analysis was not conclusive on the relationship between patient‐related factors and primary stability. No relationship was found between polar gap and micromotion. However, when the patient‐related factors were categorised into quartile groups, trends suggested higher polar gaps occurred in subjects with small and shallow acetabular geometries and cup motion during gait was affected most by low elastic modulus and high bodyweight. The variation in primary stability in the cohort for an acetabular cup with a proven clinical track record may provide benchmark data when evaluating new cup designs. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1012–1023, 2018.
Size-Dependent Toxicity of Silver Nanoparticles to Bacteria, Yeast, Algae, Crustaceans and Mammalian Cells In Vitro

The concept of nanotechnologies is based on size-dependent properties of particles in the 1–100 nm range. However, the relation between the particle size and biological effects is still unclear. The aim of the current paper was to generate and analyse a homogenous set of experimental toxicity data on Ag nanoparticles (Ag NPs) of similar coating (citrate) but of 5 different primary sizes (10, 20, 40, 60 and 80 nm) to different types of organisms/cells commonly used in toxicity assays: bacterial, yeast and algal cells, crustaceans and mammalian cells in vitro. When possible, the assays were conducted in ultrapure water to minimise the effect of medium components on silver speciation. The toxic effects of NPs to different organisms varied about two orders of magnitude, being the lowest (∼0.1 mg Ag/L) for crustaceans and algae and the highest (∼26 mg Ag/L) for mammalian cells. To quantify the role of Ag ions in the toxicity of Ag NPs, we normalized the EC50 values to Ag ions that dissolved from the NPs. The analysis showed that the toxicity of 20–80 nm Ag NPs could fully be explained by released Ag ions whereas 10 nm Ag NPs proved more toxic than predicted. Using E. coli Ag-biosensor, we demonstrated that 10 nm Ag NPs were more bioavailable to E. coli than silver salt (AgNO3). Thus, one may infer that 10 nm Ag NPs had more efficient cell-particle contact resulting in higher intracellular bioavailability of silver than in case of bigger NPs. Although the latter conclusion is initially based on one test organism, it may lead to an explanation for “size-dependent“ biological effects of silver NPs. This study, for the first time, investigated the size-dependent toxic effects of a well-characterized library of Ag NPs to several microbial species, protozoans, algae, crustaceans and mammalian cells in vitro.
Negative Peer Relationships on Piracy Behavior: A Cross-Sectional Study of the Associations between Cyberbullying Involvement and Digital Piracy

The present study examines the relationship between different roles in cyberbullying behaviors (cyberbullies, cybervictims, cyberbullies-victims, and uninvolved) and self-reported digital piracy. In a region of central Spain, 643 (49.3% females, 50.7% males) students (grades 7–10) completed a number of self-reported measures, including cyberbullying victimization and perpetration, self-reported digital piracy, ethical considerations of digital piracy, time spent on the Internet, and leisure activities related with digital content. The results of a series of hierarchical multiple regression models for the whole sample indicate that cyberbullies and cyberbullies-victims are associated with more reports of digital piracy. Subsequent hierarchical multiple regression analyses, done separately for males and females, indicate that the relationship between cyberbullying and self-reported digital piracy is sustained only for males. The ANCOVA analysis show that, after controlling for gender, self-reported digital piracy and time spent on the Internet, cyberbullies and cyberbullies-victims believe that digital piracy is a more ethically and morally acceptable behavior than victims and uninvolved adolescents believe. The results provide insight into the association between two deviant behaviors.
Sex Differences in Clinical Profiles and Quality of Care Among Patients With ST‐Segment Elevation Myocardial Infarction From 2001 to 2011: Insights From the China Patient‐Centered Evaluative Assessment of Cardiac Events (PEACE)‐Retrospective Study

Background China is experiencing a marked increase in ST‐segment elevation myocardial infarction hospitalizations, with 30% occurring among women and higher risk of in‐hospital death in relatively younger age groups (<70). Yet, little is known about sex differences in ST‐segment elevation myocardial infarction presentation and management. Methods and Results In a nationally representative sample of patients with ST‐segment elevation myocardial infarction admitted to 162 Chinese hospitals in 2001, 2006, and 2011, we examined sex differences in hospitalization rates, clinical profiles, and quality of care. Among 11 986 patients, the proportion of women was unchanged between 2001 and 2011. The estimated national rates of hospital admission per 100 000 people increased from 4.6 in 2001 to 18.0 in 2011 among men (3.9‐fold increase) and from 1.9 to 8.0 among women (4.2‐fold increase) (P trend<0.0001). The median age of women increased from 68 years in 2001 to 72 years in 2011 (P trend<0.001); however, there was no age change in men (63 years in 2011) (P trend=0.48). After accounting for age, women had a higher frequency of comorbidities. Although there were significant sex differences in the time interval of >12 hours between symptom onset and admission time in 2001, since 2006 delays in presentation were comparable between women and men. Fewer women without contraindications received evidence‐based therapies than men, including reperfusion (57.5% versus 44.2%), early aspirin (88.8% versus 85.9%), and clopidogrel (56.9% versus 52.5%, P<0.001 for all) and the differences were largely unchanged over time. Conclusions Women experienced a higher increase in hospitalization rates for ST‐segment elevation myocardial infarction in China between 2001 and 2011 and were less likely to receive evidence‐based therapies, especially reperfusion. In addition to efforts to improve quality of care generally, understanding the reasons for this sex disparity and addressing these differences in care should be a priority. Clinical Trial Registration URL: https://www.clinicaltrials. gov. Unique identifier: NCT01624883.
Bone–Biomaterial Interface : the effects of surface modified NiTi shape memory alloy on bone cells and tissue

Whenever a foreign material is implanted into a human body an implant–tissue interface area forms between them. In this microenvironment, interactions take place between the implant and the surrounding tissue. The implantation of a biomaterial into tissue results in injury and initiation of the inflammatory response. This host response to biomaterials is an unavoidable series of events that occur when tissue homeostasis is disturbed by the implantation process. In bone tissue, biocompatible implants must initially be capable of strong bone implant contact and subsequently, allow the normal bone remodeling cycle around the implant. NiTi is a metal alloy composed of approximately a 50:50 ratio of nickel and titanium. It possesses shape memory and superelasticity properties, which make it an interesting biomaterial. NiTi has two phases: austenite and martensite. A decrease in temperature or applied stress induce the austenite-to-martensite transformation. Heating or removing the stress restores the parent austenite phase. The alloy in its martensite structure can be reshaped and strained several times more than a conventional metal alloy without irreversible deformation of the material. The alloy returns to its original shape as it changes from martensite-to-austenite. This transformation is seen as the macroscopic shape memory effect. This study further investigated the biocompatibility of NiTi, especially the bone cell response to both austenite and martensite. Different surface treatments were investigated in order to improve and possibly even control NiTi's bioactivity as a bone implant material. Osteoclasts grew and attached well on the austenite NiTi phase, but the results indicated that the biocompatibility of martensite NiTi was compromised. Oxidation of the NiTi surface improved osteoblast attachment and viability. This was due to the formation of a TiO2 surface layer of moderate thickness. Coating the NiTi surface with the extracellular matrix protein fibronectin was shown to enhance osteoblast proliferation and increase the number of cells in the G1 cell cycle stage. Austenite was more prone to show these effects than martensite. A sol-gel derived titania-silica surface treatment was observed to increase the bone implant contact of functional NiTi intramedullary nails. The surface treatment was most effective with the constant bending load provided by the NiTi nail.
Risk Factors for Internet Gaming Disorder: Psychological Factors and Internet Gaming Characteristics

Background: Understanding the risk factors associated with Internet gaming disorder (IGD) is important to predict and diagnose the condition. The purpose of this study is to identify risk factors that predict IGD based on psychological factors and Internet gaming characteristics; Methods: Online surveys were conducted between 26 November and 26 December 2014. There were 3568 Korean Internet game users among a total of 5003 respondents. We identified 481 IGD gamers and 3087 normal Internet gamers, based on Diagnostic and Statistical Manual for Mental Disorders (DSM-5) criteria. Logistic regression analysis was applied to identify significant risk factors for IGD; Results: The following eight risk factors were found to be significantly associated with IGD: functional and dysfunctional impulsivity (odds ratio: 1.138), belief self-control (1.034), anxiety (1.086), pursuit of desired appetitive goals (1.105), money spent on gaming (1.005), weekday game time (1.081), offline community meeting attendance (2.060), and game community membership (1.393; p < 0.05 for all eight risk factors); Conclusions: These risk factors allow for the prediction and diagnosis of IGD. In the future, these risk factors could also be used to inform clinical services for IGD diagnosis and treatment.
Phospholamban as a Crucial Determinant of the Inotropic Response of Human Pluripotent Stem Cell–Derived Ventricular Cardiomyocytes and Engineered 3-Dimensional Tissue Constructs

Background—Human (h) embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) serve as a potential unlimited ex vivo source of cardiomyocytes (CMs). However, a well-accepted roadblock has been their immature phenotype. hESC/iPSC-derived ventricular (v) CMs and their engineered cardiac microtissues (hvCMTs) similarly displayed positive chronotropic but null inotropic responses to &bgr;-adrenergic stimulation. Given that phospholamban (PLB) is robustly present in adult but poorly expressed in hESC/iPSC-vCMs and its defined biological role in &bgr;-adrenergic signaling, we investigated the functional consequences of PLB expression in hESC/iPSC-vCMs and hvCMTs. Methods and Results—First, we confirmed that PLB protein was differentially expressed in hESC (HES2, H9)- and iPSC-derived and adult vCMs. We then transduced hES2-vCMs with the recombinant adenoviruses (Ad) Ad-PLB or Ad-S16E-PLB to overexpress wild-type PLB or the pseudophosphorylated point–mutated variant, respectively. As anticipated from the inhibitory effect of unphosphorylated PLB on sarco/endoplasmic reticulum Ca2+-ATPase, Ad-PLB transduction significantly attenuated electrically evoked Ca2+ transient amplitude and prolonged the 50% decay time. Importantly, Ad-PLB–transduced hES2-vCMs uniquely responded to isoproterenol. Ad-S16E-PLB–transduced hES2-vCMs displayed an intermediate phenotype. The same trends were observed with H9- and iPSC-vCMs. Directionally, similar results were also seen with Ad-PLB–transduced and Ad-S16E–transduced hvCMTs. However, Ad-PLB altered neither the global transcriptome nor ICa,L, implicating a PLB-specific effect. Conclusions—Engineered upregulation of PLB expression in hESC/iPSC-vCMs restores a positive inotropic response to &bgr;-adrenergic stimulation. These results not only provide a better mechanistic understanding of the immaturity of hESC/iPSC-vCMs but will also lead to improved disease models and transplantable prototypes with adult-like physiological responses.
Application of Polyhydroxyalkanoates for Development of Targeted Forms of Pecticides

Polyhydroxyalkanoates (PHAs) - biodegradable biocompatible polyesters of microbial origin - are among the most promising materials, which can be used in various areas. The authors' collection of highly productive strains and original technologies were used to synthesize PHAs. Biodegradation behavior of two PHAs, poly(3-hydroxybutyrate) and poly(3- hydroxybutyrate-co-3-hydroxyvalerate), was studied in natural environments (soils, freshwater ecosystems, marine environments) of different climatic zones. PHAs are degraded in all studied environments but their biodegradation is influenced by the chemical structure of the polymer, its geometry and the technique used to process it, climate, weather, and the type of the natural ecosystem. Poly(3-hydroxybutyrate-co-3- hydroxyvalerate) has been used to design experimental sustained- release formulations of different pesticides in the form of pellets, films and microgranules. The kinetics of polymer degradation and the dynamics of model pesticide (insecticides α- hexachlorcyclohexane and lindane, and herbicide Zellek Super) release show that the rate and extent of pesticide release from the polymer matrix into the soil depends on the geometry of the carrier and the proportion of the pesticide loaded into it (polymer/pesticide mass ratio). Experiments with the creeping bentgrass (Agrostis stolonifera L.) show that the formulations of the herbicide constructed as microgranules and films can be successfully used to suppress the growth of grasses. This study demonstrates that biodegradable polyhydroxyalkanoates can be used effectively to construct environmentally friendly sustained- release PHA-pesticide systems that can be placed into the soil together with seeds.
C4 Photosynthesis Promoted Species Diversification during the Miocene Grassland Expansion

Identifying how organismal attributes and environmental change affect lineage diversification is essential to our understanding of biodiversity. With the largest phylogeny yet compiled for grasses, we present an example of a key physiological innovation that promoted high diversification rates. C4 photosynthesis, a complex suite of traits that improves photosynthetic efficiency under conditions of drought, high temperatures, and low atmospheric CO2, has evolved repeatedly in one lineage of grasses and was consistently associated with elevated diversification rates. In most cases there was a significant lag time between the origin of the pathway and subsequent radiations, suggesting that the ‘C4 effect’ is complex and derives from the interplay of the C4 syndrome with other factors. We also identified comparable radiations occurring during the same time period in C3 Pooid grasses, a diverse, cold-adapted grassland lineage that has never evolved C4 photosynthesis. The mid to late Miocene was an especially important period of both C3 and C4 grass diversification, coincident with the global development of extensive, open biomes in both warm and cool climates. As is likely true for most “key innovations”, the C4 effect is context dependent and only relevant within a particular organismal background and when particular ecological opportunities became available.
Fine Mapping of CsVYL, Conferring Virescent Leaf Through the Regulation of Chloroplast Development in Cucumber

Leaf color mutants in higher plants are ideal materials for investigating the structure and function of photosynthetic system. In this study, we identified a cucumber vyl (virescent-yellow leaf) mutant in the mutant library, which exhibited reduced pigment contents and delayed chloroplast development process. F2 and BC1 populations were constructed from the cross between vyl mutant and cucumber inbred line ‘Hazerd’ to identify that the vyl trait is controlled by a simply recessive gene designated as CsVYL. The CsVYL gene was mapped to a 3.8 cM interval on chromosome 4 using these 80 F2 individuals and BSA (bulked segregation analysis) approach. Fine genetic map was conducted with 1542 F2 plants and narrowed down the vyl locus to an 86.3 kb genomic region, which contains a total of 11 genes. Sequence alignment between the wild type (WT) and vyl only identified one single nucleotide mutation (C→T) in the first exon of gene Csa4G637110, which encodes a DnaJ-like zinc finger protein. Gene Expression analysis confirmed the differences in transcription level of Csa4G637110 between wild type and mutant plants. Map-based cloning of the CsVYL gene could accelerate the study of chloroplast development and chlorophyll synthesis of cucumber.
Long-Term Vegetation Productivity and Trend Under Two Stocking Levels on Chihuahuan Desert Rangeland

Abstract Vegetation changes were evaluated over an 11-year period (1995–2005) on 2 light- and 2 conservative-stocked Chihuahuan Desert pastures in south central New Mexico. Grazing treatments were applied to the pastures over a 5-year period from 1997 through 2001. Pastures were not grazed in the 1995–1996 and 2002–2005 periods due to drought. During the 1997–2001 grazing period, grazing use of primary forage species averaged 29% and 40% on light- and conservative-stocked rangelands, respectively. Grazing intensity was consistently higher on conservative-stocked than light-stocked pastures. During our study heavy grazing occurred only in 1 year on pastures with conservative stocking. There were no differences in species or species categories (grasses, forbs, shrubs) of autumn standing crop and basal cover between light-and conservative-stocked pastures. Standing crop of total vegetation and perennial grasses showed large fluctuations among the years due to variable rainfall. Under both treatments, total herbaceous standing crop was unchanged, but perennial grass standing crop declined by over 50% when the last 3 years of study were compared with the first 3 years of study. Broom snakeweed (Gutierrezia sarothrae Pursh), a poisonous half shrub, increased in standing crop and cover during the study. Basal cover of total perennial grasses declined less under light than conservative stocking during the study period. However, climatic conditions exerted the overriding influence on vegetation standing crop and basal cover. Our study indicates that light stocking in the Chihuahuan Desert does not increase perennial grass production compared to conservative grazing but it could have a small benefit in maintaining perennial grass cover during drought. We believe our findings have broad application in the Chihauhuan Desert, but caution they might not apply well to other arid rangeland types.
Examining Survival Outcomes of 852 Women With Advanced Ovarian Cancer: A Multi-institutional Cohort Study

Introduction This study examines patterns of clinical practice in the management of women with advanced high-grade serous ovarian carcinoma (HGSC). Methods A total of 852 patients with advanced HGSC were included in this retrospective cohort analysis. Patients underwent primary cytoreductive surgery (PCS) or neoadjuvant chemotherapy (NACT). Wilcoxon rank-sum test and χ2 test were applied. Univariate- and multivariate-analyses were performed, and survival outcomes were measured using Kaplan–Meier curves. Results A total of 449 (53%) of 852 patients underwent PCS, and 403(47%) of 852 patients underwent NACT. The median 5-year overall survival (OS) was 3.89 in PCS and 2.48 in NACT. Patients with 0 mm residual had OS of 4.66, compared with 1- to 9-mm residual (OS = 2.80) and 10-mm residual or longer (OS = 2.50). The survival advantage harbored by the extent of surgical cytoreduction was more pronounced in PCS compared with NACT (P < 0.001). Patients who had PCS with 1- to 9-mm residual had similar OS to NACT patients with 0-mm residual (P = 0.17) and superior OS to NACT with 1- to 9-mm residual (P < 0.001). Conclusions In this multicenter study, 53% of women with advanced HGSC seen by a gynecologic oncologist were selected for PCS. Survival was longer in patients who underwent PCS than patients who underwent NACT. Within each group, survival was highest in those who had complete cytoreduction to 0-mm residual disease. We believe all patients with advanced HGSC should be assessed by a gynecologic oncologist for the feasibility of surgical resection. Primary cytoreductive surgery should be the favorable treatment modality with the goal of complete resection to 0 mm residual disease. Importantly, if 0 mm residual is not feasible, PCS to a residual of 1 to 9 mm should be attempted given the survival advantage in this group over patients who were treated with NACT.