bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined Recirculatory-compartmental Population Pharmacokinetic Modeling of Arterial and Venous Plasma S(+) and R(–) Ketamine Concentrations
Authors: Henthorn Thomas K. , Avram Michael J. , Dahan Albert , Gustafsson Lars L. , Persson Jan , Krejcie Tom C. , Olofsen Erik 
Published: May 2018

Abstract

What We Already Know about This Topic

What This Article Tells Us That Is New

Background
The pharmacokinetics of infused drugs have been modeled without regard for recirculatory or mixing kinetics. We used a unique ketamine dataset with simultaneous arterial and venous blood sampling, during and after separate S(+) and R(–) ketamine infusions, to develop a simplified recirculatory model of arterial and venous plasma drug concentrations.

Methods
S(+) or R(–) ketamine was infused over 30 min on two occasions to 10 healthy male volunteers. Frequent, simultaneous arterial and forearm venous blood samples were obtained for up to 11 h. A multicompartmental pharmacokinetic model with front-end arterial mixing and venous blood components was developed using nonlinear mixed effects analyses.

Results
A three-compartment base pharmacokinetic model with additional arterial mixing and arm venous compartments and with shared S(+)/R(–) distribution kinetics proved superior to standard compartmental modeling approaches. Total pharmacokinetic flow was estimated to be 7.59 ± 0.36 l/min (mean ± standard error of the estimate), and S(+) and R(–) elimination clearances were 1.23 ± 0.04 and 1.06 ± 0.03 l/min, respectively. The arm-tissue link rate constant was 0.18 ± 0.01 min–1, and the fraction of arm blood flow estimated to exchange with arm tissue was 0.04 ± 0.01.

Conclusions
Arterial drug concentrations measured during drug infusion have two kinetically distinct components: partially or lung-mixed drug and fully mixed-recirculated drug. Front-end kinetics suggest the partially mixed concentration is proportional to the ratio of infusion rate and total pharmacokinetic flow. This simplified modeling approach could lead to more generalizable models for target-controlled infusions and improved methods for analyzing pharmacokinetic-pharmacodynamic data.
Evaluation of Compliance with a Weight-based Nurse-driven Heparin Nomogram in a Tertiary Academic Medical Center
Authors: Schurr James W. , Stevens Craig A. , Bane Anne , Culbreth Sarah E. , Miller Amy Leigh , Connors Jean M. , Sylvester Katelyn W. 
Published: May 2018

Background:Recently, our institution adopted a weight-based nurse-driven heparin titration protocol that relies on nurses ordering laboratories, adjusting doses, and initiating boluses. Numerous institutions have implemented similar protocols with reported success.Methods:A single-center retrospective analysis was conducted at the Brigham and Women’s Hospital in Boston, Massachusetts that included all patients who were initiated on the weight-based nurse-driven heparin nomogram during a 30-day period. Nomogram compliance was defined as the rate of correct titrations per nomogram encounter and further separated into laboratory, titration, or dosing compliance. Spearman’s coefficient was utilized to determine the correlation between noncompliance and percentage of activated partial thromboplastin time (aPTT) values in range.Results:Overall, 211 patients were evaluated for inclusion, of which 95 patients were determined to meet criteria for evaluation. The total nomogram compliance rate was 84.6% ± 10.5%. Laboratory, titration, and dosing compliances were 77.6% ± 19.2%, 87.2% ± 14.5%, and 91.8% ± 10.6%, respectively. The percent of aPTT values in therapeutic range was 39.6% ± 24.6%. A moderate negative correlation between the percentage of aPTT values in range and the nomogram error rate was observed (r= −0.452,P< 0.001). This relationship was found to be driven by the rate of dosing error, which showed the strongest correlation with percentage of aPTT values out of range (r= −0.465,P= 0.001).Conclusions:Implementation of a nurse-driven heparin titration nomogram relies on compliance with the prescribed protocol. Dosing compliance had the lowest error rate, whereas dosing noncompliance had the strongest impact on percentage of aPTT values in range.
The Incidence of Myocardial Injury after Loading Doses of Clopidogrel versus Prasugrel in the Candidates for Percutaneous Coronary Intervention: A Randomized Controlled Trial
Authors: Rahmani Reza , Jiriaee Laya , Jiriaee Zahra , Shafiee Akbar , Zand Parsa Amir Farhang 
Published: May 2018

Introduction:
Prevention of myocardial injury is an essential issue in percutaneous coronary intervention (PCI). We compared the incidence of myocardial injury after loading doses of clopidogrel versus prasugrel in the candidates for PCI.

Methods:
In this randomized-controlled clinical trial, we enrolled 88 stable angina patients, candidate for PCI. Patients received either prasugrel (60 mg orally) (n = 42) or clopidogrel (600 mg orally) (n = 46). Serum levels of creatine phosphokinase muscle-brain type, cardiac troponin I, and high sensitive C-reactive protein were measured at baseline and 6 and 12 hours postprocedural. Primary endpoint was periprocedural myocardial infarction (MI), defined as elevation of cTn values (>5 times) in patients with normal baseline values or a rise of cTn values >20% if the baseline values are elevated.

Results:
Based on the levels of cTnI 6 hours after PCI, 1 patient (2.4%) had MI in the prasugrel group, whereas 4 patients (8.7%) had MI in the clopidogrel group. After 12 hours, 4 patients (9.5%) had MI in the prasugrel group versus 5 patients (10.9%) in the clopidogrel arm. There was no significant difference between the groups regarding the changes in cardiac specific enzyme levels. However, serum levels of cTnI were significantly lower in patients with myocardial injury in the prasugrel arm (P < 0.001).

Conclusions:
Prasugrel is an effective antiplatelet drug in preventing periprocedural MI.
Recognizing, diagnosing, and preventing child maltreatment: an update for pediatric clinicians
Authors: Danaher Fiona , Vandeven Andrea , Blanchard Aine , Newton Alice W. 
Published: May 2018

Purpose of review
Despite an increasing understanding of the impact of emotional trauma and physical abuse on children, clinicians and hospitals still sometimes miss the diagnosis of abuse. The literature in 2017 focused on creating standardized approaches to recognition and diagnosis of physical abuse and occult injury, including using the electronic medical record to provide triggers for consultation of the hospital Child Protection Program. The American College of Radiology updated their standardized approach to the evaluation of physical abuse in the child, and other authors gave us screening tools for commercial exploitation, as well as guidance about how to recognize risks for emotional abuse in families. The opioid epidemic and legalization of marijuana are both impacting children, and providers are searching for ways to provide support for parents with substance use disorders whilst considering the safety of children.
This article reviews relevant publications during the past year about issues of child maltreatment. It is intended to guide those providers in primary care or other medical disciplines who care for children and families.

Recent findings
Child maltreatment cases are still not always diagnosed, either because of provider bias (leading to under evaluation), or because clinicians lack experience or understanding of proper evaluation approaches. There are many new tools to assist in recognition of abuse, including screening instruments and flags that can be used in the electronic medical record to trigger a consult with the Child Protection Program. The evaluation and diagnosis of sexual abuse continues to evolve, with the literature providing advice about what is or is not normal on physical exam, as well as advice for providers who work with adolescent sexual assault victims. The debate about the validity of abusive head trauma (AHT) diagnoses continues, with sweden being the most recent center of controversy. With the opioid epidemic having such a significant effect on families and children, clinicians are struggling to support parents with substance use disorder while protecting children from the impact of their parents’ disease.

Summary
The past year in child abuse literature has yielded increased clarity in screening and diagnostic recommendations across the fields of physical abuse, AHT, sexual abuse, and commercial sexual exploitation of children (CSEC). The body of literature surrounding emotional abuse and neglect continues to grow, especially in light of the burgeoning opioid epidemic. Critically, the year's research reflects an evolving understanding of effective prevention and intervention initiatives to address child maltreatment.
Opportunistic fungal infection in children and management
Authors: Lam Joseph M. 
Published: May 2018

Purpose of review
An opportunistic mycosis is a fungal agent of low pathogenicity that specifically infects immunocompromised hosts. Advances in transplantation, preterm care, immunosuppressive therapies and intensive care, have lead to the emergence of pediatric patients with serious immunodeficiency who are vulnerable to nonpathogenic fungi.

Recent findings
The advent of the use of biologic agents in pediatric disease as well as the advances in care of preterm and immunosuppressed patients opens up a new cohort of patients at risk of opportunistic mycotic infections. Recent cases of cutaneous histioplasmosis as the presenting sign of hyper-IgM syndrome and the case of cutaneous blastomycosis in a patient treated with infliximab underscore the need to have a high clinical suspicion for deep fungal infections in immunosuppressed patients.

Summary
The current review will focus on the cutaneous manifestations of cutaneous infections by Aspergillus, Blastomyces, histoplasmosis, and mucormycosis. Greater understanding of these diseases and high-quality research in identification and treatment can enhance care of patients in the coming future.
Caffeine Sodium Benzoate for Electroconvulsive Therapy Augmentation
Authors: Bozymski Kevin M. , Potter Teresa G. , Venkatachalam Vasu , Pandurangi Ananda K. , Crouse Ericka L. 
Published: May 2018

Objectives
Because of an ongoing manufacturer shortage of injectable caffeine sodium benzoate (CSB), patients at our health system were given CSB compounded in-house to increase seizure response during electroconvulsive therapy (ECT). Therefore, we aimed to evaluate its effectiveness and safety as an ECT augmentation agent.

Methods
Medical records of patients who received compounded CSB at Virginia Commonwealth University Health System were reviewed to identify adults receiving it as part of an index ECT treatment course between June 2012 and December 2016. The primary outcome was change in electroencephalogram seizure duration from pre–caffeine session to initial caffeine session. Data were also collected on demographics, motor seizure duration, maximum heart rate, mean arterial pressure, and concurrent medication use for these sessions and the last caffeine session.

Results
Seven-one patients were included in the study, predominantly white females with a mean age of 58.6 years. The most common indication for ECT was major depressive disorder resistant to pharmacotherapy (71.8%), followed by catatonia associated with another mental disorder (19.7%). Electroencephalogram seizure duration increased by 24.1 seconds on average with first CSB use (P < 0.0001), allowing 24 more patients overall to achieve goal of at least 30 seconds (P < 0.0001). No clinically significant changes in maximum heart rate or mean arterial pressure were observed, nor did any patients require an abortive agent for prolonged seizure. Five patients (7%) discontinued CSB prematurely: 4 related to adverse effects and 1 secondary to ineffectiveness.

Conclusions
We confirm results of prior studies of the utility of CSB and add that compounded CSB is effective for ECT augmentation, maintaining effectiveness throughout the index course with minimal safety concerns.
Interaction between polymorphisms in cell-cycle genes and environmental factors in regulating cholinesterase activity in people with exposure to omethoate
Authors: Duan Xiaoran , Yang Yongli , Wang Sihua , Feng Xiaolei , Wang Tuanwei , Wang Pengpeng , Yao Wu , Cui Liuxin , Wang Wei 
Published: May 2018

Cholinesterase activity (ChA), the effective biomarker for organophosphate pesticide exposure, is possibly affected by single nucleotide polymorphisms (SNPs) in cell-cycle-related genes. One hundred and eighty workers with long-term exposure to omethoate and 115 healthy controls were recruited to explore the gene–gene and gene–environment interactions. The acetylthiocholine and dithio-bis-(nitrobenzoic acid) method was used to detect the cholinesterase activities in whole blood, erythrocytes and plasma. Genetic polymorphisms were determined by the PCR-RFLP and direct PCR electrophoresis methods. Statistical results showed that the cholinesterase activities of whole blood, erythrocytes and plasma in the exposure group were significantly lower than those in the control group (
p
< 0.001), and erythrocyte cholinesterase activities were associated with gender, smoking and drinking in the exposure group (
p
< 0.05). Single-locus analyses showed that there is a statistically significant difference in the ChA among the genotypes CC, CA and AA of the
p21
rs1801270 locus in the control group (
p
= 0.033), but not in the exposure group. A significant interaction between genes and environmental factors (i.e.
p53
,
p21
,
mdm2,
gender, smoking and drinking) affecting ChA was found through a generalized multifactor dimensionality reduction analysis. These obtained markers will be useful in further marker-assisted selection in workers with exposure to omethoate.
scQuery: a web server for comparative analysis of single-cell RNA-seq data
Authors: Alavi Amir , Ruffalo Matthew , Parvangada Aiyappa , Huang Zhilin , Bar-Joseph Ziv 
Published: May 2018

SummarySingle cell RNA-Seq (scRNA-seq) studies often profile upward of thousands of cells in heterogeneous environments. Current methods for characterizing cells perform unsupervised analysis followed by assignment using a small set of known marker genes. Such approaches are limited to a few, well characterized cell types. To enable large scale supervised characterization we developed an automated pipeline to download, process, and annotate publicly available scRNA-seq datasets. We extended supervised neural networks to obtain efficient and accurate representations for scRNA-seq data. We applied our pipeline to analyze data from over 500 different studies with over 300 unique cell types and show that supervised methods greatly outperform unsupervised methods for cell type identification. A case study of neural degeneration data highlights the ability of these methods to identify differences between cell type distributions in healthy and diseased mice. We implemented a web server that compares new datasets to collected data employing fast matching methods in order to determine cell types, key genes, similar prior studies, and more.
Engineered Genetic Redundancy Relaxes Selective Constraints upon Endogenous Genes in Viral RNA Genomes
Authors: Ambrós Silvia , De la Iglesia Francisca , Rosario Sttefany M. , Butković Anamarija , Elena Santiago F. 
Published: May 2018

1AbstractGenetic redundancy, understood as the functional overlap of different genes, is a double-edge sword. At the one side, it is thought to serve as a robustness mechanism that buffers the deleterious effect of mutations hitting one of the redundant copies, thus resulting in pseudogenization. At the other side, it is considered as a source of genetic and functional innovation. In any case, genetically redundant genes are expected to show an acceleration in the rate of molecular evolution. Here we tackle the role of genetic redundancy in viral RNA genomes. To this end, we have evaluated the rates of compensatory evolution for deleterious mutations affecting an essential function, the suppression of RNA silencing plant defense, of tobacco etch potyvirus (TEV). TEV genotypes containing deleterious mutations in presence/absence of engineered genetic redundancy were evolved and the pattern of fitness and virulence recovery evaluated. Genetically redundant genotypes suffered less from the effect of deleterious mutations and showed relatively minor changes in fitness and virulence. By contrast, non-genetically redundant genotypes had very low fitness and virulence at the beginning of the evolution experiment that were fully recovered by the end. At the molecular level, the outcome depended on the combination of the actual mutations being compensated and the presence/absence of genetic redundancy. Reversions to wild-type alleles were the norm in the non-redundant genotypes while redundant ones either did not fix any mutation at all or showed a higher nonsynonymous mutational load.
Nitrone-Trolox conjugate as an inhibitor of lipid oxidation: Towards synergistic antioxidant effects
Authors: Socrier L. , Rosselin M. , Gomez Giraldo A. M. , Chantemargue B. , Di Meo F. , Trouillas P. , Durand G. , Morandat S. 
Published: May 2018

1AbstractFree radical scavengers like α-phenyl-N-tert-butylnitrone (PBN) and 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) have been widely used as protective agents in various biomimetic and biological models. A series of three amphiphilic Trolox and PBN derivatives have been designed by adding to the parent molecules both a perfluorinated chain and a sugar group in order to render them amphiphilic. In this work, we have studied the interaction of these derivatives with lipid membranes and how it correlates to their antioxidant properties.The three derivatives form monolayers at the air/water interface. We next investigated the ability of each derivative to interact with 1,2-dilinoleoyl-sn-glycero-3-phosphocholine (DLPC) as well as their efficiency to inhibit the AAPH-induced oxidation of DLPC liposomes. The location of these derivatives in the membrane is a key parameter to rationalize their antioxidant efficiency. The derivative bearing both the PBN and the Trolox antioxidant moieties on the same fluorinated carrier exhibited a synergistic antioxidant effect by delaying the oxidation process. Molecular dynamics (MD) simulations supported the understanding of the mechanism of action, highlighting various key physical-chemical descriptors.Graphical abstractHighlights‒Amphiphilic fluorinated antioxidants efficiently inhibit lipid oxidation‒The perfluorinated chain allows the insertion into membranes‒The nature of the antioxidant is a key parameter in the antioxidant efficiency‒The combination of Trolox and PBN results in a synergistic antioxidant effectCondensed running titleTrolox derivatives limit lipid oxidation
Vector-mediated viral transmission favours less virulent viruses
Authors: Remnant Emily J. , Mather Niklas , Gillard Thomas L. , Yagound Boris , Beekman Madeleine 
Published: May 2018

AbstractWhile it is well-established that the ectoparasitic miteVarroa destructoris largely responsible for the widely-reported decline of populations of the Western honeybeeApis mellifera, the exact role the mite plays in honeybee health remains unclear. The last few years have seen a surge in studies associating RNA viruses vectored by the mite with the death of honeybee colonies.Varroafacilitates the spread of RNA viruses because it feeds on developing bee brood and transfers haemolymph from bee-to-bee. Such a change in transmission, from horizontal and vertical to vector-based, is predicted to lead to an increase in virulence of RNA viruses, thus potentially providing an explanation for the observed association betweenVarroaand certain viruses. Here we document the effect of changing the route of transmission of honeybee viruses contained in the haemolymph of honeybee pupae. We find that a change in mode of transmission rapidly increases viral titres of two honeybee viruses, Sacbrood virus (SBV) and Black queen cell virus (BQCV). This increase in viral titre is accompanied by an increase in virulence. In contrast, the virus most often associated withVarroa, Deformed wing virus (DWV), shows a reduction in viral titre in the presence of SBV and BQCV. In addition, DWV does not cause mortality to honeybee pupae in isolation. Most likely a change in mode of transmission due to the arrival of a vector quickly eliminates the most virulent honeybee viruses resulting in an association betweenVarroaand less virulent viruses such as DWV. Our work therefore provides empirical evidence for an alternative explanation for the widely-observed association betweenVarroaand DWV.
Next-generation Sequence-analysis Toolkit (NeST): A standardized bioinformatics framework for analyzing Single Nucleotide Polymorphisms in next-generation sequencing data
Authors: Ravishankar Shashidhar , Schmedes Sarah E. , Patel Dhruviben S. , Plucinski Mateusz , Udhayakumar Venkatachalam , Talundzic Eldin , Vannberg Fredrik 
Published: May 2018

AbstractRapid advancements in next-generation sequencing (NGS) technologies have led to the development of numerous bioinformatics tools and pipelines. As these tools vary in their output function and complexity and some are not well-standardized, it is harder to choose a suitable pipeline to identify variants in NGS data. Here, we present NeST (NGS-analysis Toolkit), a modular consensus-based variant calling framework. NeST uses a combination of variant callers to overcome potential biases of an individual method used alone. NeST consists of four modules, that integrate open-source bioinformatics tools, a custom Variant Calling Format (VCF) parser and a summarization utility, that generate high-quality consensus variant calls. NeST was validated using targeted-amplicon deep sequencing data from 245 Plasmodium falciparum isolates to identify single-nucleotide polymorphisms conferring drug resistance. The results were verified using Sanger sequencing data for the same dataset in a supporting publication [28]. NeST offers a user-friendly pipeline for variant calling with standardized outputs and minimal computational demands for easy deployment for use with various organisms and applications.
Structure of the human volume regulated anion channel
Authors: Kefauver J. M. , Saotome K. , Dubin A. E. , Pallesen J. , Cottrell C.A. , Cahalan S.M. , Qiu Z. , Hong G. , Crowley C.S. , Whitwam T. , Lee W.H. , Ward A.B. , Patapoutian A. 
Published: May 2018

AbstractSWELL1 (LRRC8A) is the only essential subunit of the Volume Regulated Anion Channel (VRAC), which regulates cellular volume homeostasis and is activated by hypotonic solutions. SWELL1, together with four other LRRC8 family members, forms a vastly heterogeneous cohort of VRAC channels with different properties; however, SWELL1 alone is also functional. Here, we report a high-resolution cryo-electron microscopy structure of full-length human homo-hexameric SWELL1. The structure reveals a trimer of dimers assembly with symmetry mismatch between the pore-forming domain and the cytosolic leucine-rich repeat (LRR) domains. Importantly, mutational analysis demonstrates that a charged residue at the narrowest constriction of the homomeric channel is an important pore determinant of heteromeric VRAC. This structure provides a scaffold for further dissecting the heterogeneity and mechanism of activation of VRAC.