bluuebunny/crossref_metadata_2025 huggingface dataset:
3D‐e‐Chem: Structural Cheminformatics Workflows for Computer‐Aided Drug Discovery
Authors: Kooistra Albert J. , Vass Márton , McGuire Ross , Leurs Rob , de Esch Iwan J. P. , Vriend Gert , Verhoeven Stefan , de Graaf Chris
Published: January 2018

eScience technologies are needed to process the information available in many heterogeneous types of protein–ligand interaction data and to capture these data into models that enable the design of efficacious and safe medicines. Here we present scientific KNIME tools and workflows that enable the integration of chemical, pharmacological, and structural information for: i) structure‐based bioactivity data mapping, ii) structure‐based identification of scaffold replacement strategies for ligand design, iii) ligand‐based target prediction, iv) protein sequence‐based binding site identification and ligand repurposing, and v) structure‐based pharmacophore comparison for ligand repurposing across protein families. The modular setup of the workflows and the use of well‐established standards allows the re‐use of these protocols and facilitates the design of customized computer‐aided drug discovery workflows.
Influence of provider factors and race on uptake of breast cancer gene expression profiling
Authors: Reeder‐Hayes Katherine E. , Wheeler Stephanie B. , Baggett Christopher D. , Zhou Xi , Meng Ke , Roberts Megan C. , Carey Lisa A. , Meyer Anne‐Marie
Published: January 2018

BACKGROUND

Gene expression profiling (GEP) has been rapidly adopted for early breast cancer and can aid in chemotherapy decision making. Study results regarding racial disparities in testing are conflicting, and may reflect different care settings. To the authors' knowledge, data regarding the influence of provider factors on testing are scarce.

METHODS

The authors used a statewide, multipayer, insurance claims database linked to cancer registry records to examine the impact of race and provider characteristics on GEP uptake in a cohort of patients newly diagnosed with breast cancer between 2005 and 2012. Incidence proportion models were used to examine the adjusted likelihood of testing. Models were stratified by lymph node status (N0 vs N1).

RESULTS

Among 11,958 eligible patients, 23% of black and 26% of non‐Hispanic white patients received GEP. Among patients with N0 disease, black individuals were 16% less likely to receive testing after adjustment for clinical factors and the provider's specialty and volume of patients with breast cancer (95% confidence interval, 0.77‐0.93). Adjustment for provider characteristics did not attenuate the effect of race on testing. Patients of middle‐volume providers were more likely to be tested compared with those with either high‐volume or low‐volume providers, whereas patients seeing a medical oncologist were more likely to be tested compared with those whose only providers were from surgical specialties.

CONCLUSIONS

Provider volume and specialty were found to be significant predictors of GEP use, but did not explain racial disparities in testing. Further research concerning the key contributors to lagging test use among black women is needed to optimize the equitable use of GEPs and support personalized treatment decision making for all patients. Cancer 2018;124:1743‐51. © 2018 American Cancer Society
Making Use of Cancer Genomic Databases
Authors: Creighton Chad J.
Published: January 2018

The vast amounts of genomic data now deposited in public repositories represent rich resources for cancer researchers. Large‐scale genomics initiatives such as The Cancer Genome Atlas have made available data from multiple molecular profiling platforms (e.g., somatic mutation, RNA and protein expression, and DNA methylation) for the same set of over 10,000 human tumors. There has been much collective effort toward providing user‐friendly software tools for biologists lacking computational skills to ask questions of large‐scale genomic datasets. At the same time, there remains a clear need for skilled bioinformatics analysts to answer the types of questions that cannot easily be addressed using the public user‐friendly software tools. This overview introduces the reader to the many resources available for working with cancer genomic databases. © 2018 by John Wiley & Sons, Inc.
CRISPR/Cas9‐Mediated Genome Editing in Epstein‐Barr Virus‐Transformed Lymphoblastoid B‐Cell Lines
Authors: Jiang Sizun , Wang Liang Wei , Walsh Michael J. , Trudeau Stephen J. , Gerdt Catherine , Zhao Bo , Gewurz Benjamin E.
Published: January 2018

Epstein‐Barr virus (EBV) efficiently transforms primary human B cells into immortalized lymphoblastoid cell lines (LCLs), which are extensively used in human genetic, immunological and virological studies. LCLs provide unlimited sources of DNA for genetic investigation, but can be difficult to manipulate, for instance because low retroviral or lentiviral transduction frequencies hinder experiments that require co‐expression of multiple components. This unit details Clustered Regularly Interspaced Short Palindromic Repeats (CRISPR)/Cas9 engineering for robust LCL genome editing. We describe the generation and delivery of single‐guide RNAs (sgRNAs), or dual‐targeting sgRNAs, via lentiviral transduction of LCLs that stably express Cas9 protein. CRISPR/Cas9 editing allows LCL loss‐of‐function studies, including knock‐out of protein‐coding genes or deletion of DNA regulatory elements, and can be adapted for large‐scale screening approaches. Low transfection efficiencies are a second barrier to performing CRISPR editing in LCLs, which are not typically lipid‐transfectable. To circumvent this barrier, we provide an optimized protocol for LCL nucleofection of Cas9/sgRNA ribonucleoprotein complexes (RNPs) as an alternative route to achieve genome editing in LCLs. These editing approaches can also be employed in other B‐cell lines, including Burkitt lymphoma and diffuse large B‐cell lymphoma cells, and are highly reproducible. © 2018 by John Wiley & Sons, Inc.
Pooled Lentiviral‐Delivery Genetic Screens
Authors: Piccioni Federica , Younger Scott T. , Root David E.
Published: January 2018

Pooled cell‐based screens of mammalian genetic perturbations enable systematic large‐scale, even genome‐scale, evaluation of gene function. Pooled screens introduce genetic perturbations into a cell population through viral transduction such that each cell integrates into its DNA a single or small number of library perturbations with barcodes identifying the perturbations. One then selects and physically isolates the subset of cells that exhibit the phenotype of interest. Sequencing the barcodes in the hit cells reveals which genes favored or inhibited the hit phenotype. Various genetic perturbations are possible, including CRISPR gene knockout, ectopic gene expression, and RNA interference. Regardless of the type of library being screened or the type of cell model being tested, such screens involve many common steps and procedures. This unit describes detailed experimental protocols for the key steps, and also highlights some of the key factors to achieving a well‐powered, reproducible screen result. © 2018 by John Wiley & Sons, Inc.
CRISPR‐Cas9‐Edited Site Sequencing (CRES‐Seq): An Efficient and High‐Throughput Method for the Selection of CRISPR‐Cas9‐Edited Clones
Authors: Veeranagouda Yaligara , Debono‐Lagneaux Delphine , Fournet Hamida , Thill Gilbert , Didier Michel
Published: January 2018

The emergence of clustered regularly interspaced short palindromic repeats–Cas9 (CRISPR‐Cas9) gene editing systems has enabled the creation of specific mutants at low cost, in a short time and with high efficiency, in eukaryotic cells. Since a CRISPR‐Cas9 system typically creates an array of mutations in targeted sites, a successful gene editing project requires careful selection of edited clones. This process can be very challenging, especially when working with multiallelic genes and/or polyploid cells (such as cancer and plants cells). Here we described a next‐generation sequencing method called CRISPR‐Cas9 Edited Site Sequencing (CRES‐Seq) for the efficient and high‐throughput screening of CRISPR‐Cas9‐edited clones. CRES‐Seq facilitates the precise genotyping up to 96 CRISPR‐Cas9‐edited sites (CRES) in a single MiniSeq (Illumina) run with an approximate sequencing cost of $6/clone. CRES‐Seq is particularly useful when multiple genes are simultaneously targeted by CRISPR‐Cas9, and also for screening of clones generated from multiallelic genes/polyploid cells. © 2018 by John Wiley & Sons, Inc.
Method for Determining Crystal Grain Size by X‐Ray Diffraction
Authors: He Kai , Chen Nuofu , Wang Congjie , Wei Lishuai , Chen Jikun
Published: January 2018

The crystal grain size can be quantitatively calculated by Scherrer equation according to the diffraction peak broadening in the XRD curves. Actually, the results calculated by the Scherrer equation are the thickness that perpendicular to the crystal planes. However, in the actual XRD measurements, the broadening of the diffraction peaks is not only because of the Micro‐level changes of crystal such as grain size and lattice distortion, but also due to the instrumental broadening. Thus, the Scherrer equation is less reliable if the full width at half maximum caused by the physical broadening is smaller than that caused by the instrumental broadening. In this paper, it is concluded that the applicable range of the Scherrer equation will increases with the increasing diffraction angle. As an example of Scherrer equation's application, the calculation result for the maximum applicable scope of Si(100) films is 137 nm.
Collective memory of conflict is not all about politics—The Israeli case: Empirical, theoretical, and practical aspects
Authors: Nets‐Zehngut Rafi
Published: January 2018

The most important theme in conflict memory studies has been the “politics of memory.” This article, however, argues that memory is also significantly influenced by manyapoliticalfactors, which are typically underresearched. Based on numerous documents and interviews, the article examines the Israeli official, autobiographical, cultural, and historical memories, from 1949 to 2004, of the 1948 Palestinian exodus. Empirically and theoretically, the article offers various contributions, such as the first typology of the three manifestations of thepoliticalandapoliticaluses of memory, and traces 13apoliticalfactors. All these findings are translated intopracticalimplications for the use of peacemakers and others.
Unravelling the Effects of the Environmental Technology Portfolio on Corporate Sustainable Development
Authors: Wang Derek D.
Published: January 2018

A firm's environmental technology portfolio comprises of a heterogeneous class of technologies, each with distinct economic and environmental implications. Having a portfolio with a proper mix of different technologies is critical in achieving economic and environmental goals. Using data on major United States’ corporates, I identify five types of environmental technologies: pollution control, eco‐efficiency, green design, low‐carbon energy, and management systems. I find that the composition of the environmental technology portfolio affects a firm's performance. Most notably, raising the share of low‐carbon energy and pollution control technologies in the portfolio can negatively affect economic performance. But both low‐carbon energy and pollution control are effective in improving carbon productivity. The other technologies do not display significant impacts on firm performance. The results highlight that firms should take the differential effects of environmental technologies into consideration when designing an adequate technology portfolio to attain desired economic and environmental objectives. Copyright © 2018 John Wiley & Sons, Ltd and ERP Environment
Using field data to quantify chemical impacts on wildlife population viability
Authors: Hilbers Jelle P. , Hoondert Renske P. J. , Schipper Aafke M. , Huijbregts Mark A. J.
Published: January 2018

Environmental pollution is an important driver of biodiversity loss. Yet, to date, the effects of chemical exposure on wildlife populations have been quantified for only a few species, mainly due to a lack of appropriate laboratory data to quantify chemical impacts on vital rates. In this study, we developed a method to quantify the effects of toxicant exposure on wildlife population persistence based on field monitoring data. We established field‐based vital‐rate‐response functions for toxicants, using quantile regression to correct for the influences of confounding factors on the vital rates observed, and combined the response curves with population viability modelling. We then applied the method to quantify the impact of DDE on three bird species: the White‐tailed Eagle, Bald Eagle, and Osprey. Population viability was expressed via five population extinction vulnerability metrics: population growth rate (r1), critical patch size (CPS), minimum viable population size (MVP), probability of population extirpation (PE), and median time to population extirpation (MTE). We found that past DDE exposure concentrations increased population extirpation vulnerabilities of all three bird species. For example, at DDE concentrations of 25 mg/kg wet mass of egg (the maximum historic exposure concentration reported in literature for the Osprey), r1 became small (White‐tailed Eagle and Osprey) or close to zero (Bald Eagle), the CPS increased up to almost the size of Connecticut (White‐tailed Eagle and Osprey) or West Virginia (Bald Eagle), the MVP increased up to approximately 90 (White‐tailed Eagle and Osprey) or 180 breeding pairs (Bald Eagle), the PE increased up to almost certain extirpation (Bald Eagle) or only slightly elevated levels (White‐tailed Eagle and Osprey) and the MTE became within decades (Bald Eagle) or remained longer than a millennium (White‐tailed Eagle and Osprey). Our study provides a method to derive species‐specific field‐based response curves of toxicant exposure, which can be used to assess population extinction vulnerabilities and obtain critical levels of toxicant exposure based on maximum permissible effect levels. This may help conservation managers to better design appropriate habitat restoration and population recovery measures, such as reducing toxicant levels, increasing the area of suitable habitat or reintroducing individuals.
The primacy of bears as seed dispersers in salmon‐bearing ecosystems
Authors: Harrer Laurie E. F. , Levi Taal
Published: January 2018

Salmon–bear ecosystems that historically existed throughout most of the northern temperate and boreal regions of planet earth now persist only in the North Pacific. Extensive research on salmon–bear interactions has focused on the role that bears (Ursus arctosandU. americanus) play in provisioning terrestrial systems with marine‐derived nutrients, but little attention has been paid to how the much higher bear population densities in salmon‐bearing ecosystems then affect ecological communities. Salmon‐supported brown bears secondarily consume large quantities of fruit and may thus serve as important seed dispersers, but the relative seed dispersal services provided by bears and birds are unknown. We sought to (1) quantify the number of seeds dispersed by bears relative to birds, and (2) by brown bears relative to black bears, and to (3) assess whether the two sympatric bears temporally partition berry resources as a result of competitively dominant brown bears switching to feed on salmon, thus opening niche space for black bears. We used a combination of motion‐triggered camera traps and environmentalDNA(eDNA) from residual saliva to quantify the roles of birds, black bears, and brown bears as seed dispersers of devil's club (Oplopanax horridus), the dominant understory shrub at our field site in northern southeast Alaska. Brown bears were the numerically dominant seed dispersers, particularly before salmon became widely available, after which black bears became common seed dispersers, likely due to alleviation of interference competition. Birds accounted for only a small fraction of seed dispersal. This is the first demonstration of a temperate plant being primarily dispersed by mammalian gut passage. Our results suggest that bears are uniquely important seed dispersers, which may influence plant community composition in salmon‐bearing ecosystems.
Drivers and demographic consequences of seasonal mass changes in an alpine ungulate
Authors: Douhard Mathieu , Guillemette Simon , Festa‐Bianchet Marco , Pelletier Fanie
Published: January 2018

We know little about the determinants and demographic consequences of the marked seasonal mass changes exhibited by many northern and alpine mammals. We analysed 43 years of data on individual winter mass loss (the difference between mass in early June and mass in mid‐September the previous year) and summer mass gain (the difference between mass in mid‐September and in early June of the same year) in adult bighorn sheep (Ovis canadensis). We calculated relative seasonal mass change as a proportion of individual body mass at the start of each season. We first examined the effects of weather and population density on relative changes in body mass. We then assessed the consequences of relative seasonal mass changes on reproduction. Mean April–May temperature was the main driver of relative seasonal mass changes: warm springs reduced both relative winter mass loss and summer mass gain of both sexes, likely partially due to a trade‐off between growth rate of plants and duration of access to high‐quality forage. Because these effects cancelled each other, spring temperature did not influence mass in mid‐September. Mothers that lost relatively more mass during the winter had lambs that gained less mass during summer, likely because these females allocated fewer resources to lactation. Winter survival of lambs increased with their summer mass gain. In males, relative mass loss during winter, which includes the rut, did not influence the probability of siring at least one lamb, possibly indicating that greater mating effort did not necessarily translate into greater reproductive success. Our findings improve our understanding of how weather influences recruitment and underline the importance of cryptic mechanisms behind the effects of climate change on demographic traits.
Coordination of 3‐Methylindole‐Based Tripodal Tetraphosphine Ligands to Iron(+II), Cobalt(+II), and Nickel(+II) and Investigations of their Subsequent Two‐Electron Reduction
Authors: van de Watering Fenna F. , Stroek Wowa , Ivar van der Vlugt Jarl , de Bruin Bas , Dzik Wojciech I. , Reek Joost N. H.
Published: January 2018

We report the coordination chemistry of indole based tripodal tetraphosphine ligands to iron(II), cobalt(II) and nickel(II). These complexes are formed by simple synthetic protocols and were characterized by a combination of spectroscopic techniques and single‐crystal X‐ray analysis. The molecular structures as determined by X‐ray diffraction show that the geometry of the nickel and cobalt complexes are distorted trigonal bipyramidal. The monocationic iron(II) complexes also have distorted trigonal bipyramidal geometries, but the dicationic analogue has an octahedral geometry. Two‐electron reduction of the cobalt(+II) and the nickel(+II) complexes in the presence of N2 did not lead to the coordination of N2. In contrast, two‐electron reduction of the iron(+II) complexes did lead to coordination of dinitrogen to the iron center. The Fe0N2L1H complex has a trigonal bipyramidal geometry, and the N–N bond length of the coordinated dinitrogen ligand is longer than that of free dinitrogen, indicating that coordination to this iron(0) complex results in activation of the N≡N bond.
Quadratus lumborum block in management of severe pain after uterine artery embolization
Authors: Ben‐David B. , Kaligozhin Z. , Viderman D.
Published: January 2018

Background and objectives

The quadratus lumborum (QL) block has been widely used for acute postoperative pain management after numerous surgical procedures including urological, abdominal, gynaecological and orthopaedic surgical procedures. The local anaesthetic spread in this area can provide unilateral sensory block in T6‐L2 dermatomes. We performed bilateral quadratus lumborum block for the management of acute pain after the uterine artery embolization (UAE).

Methods

A 43‐year‐old woman was admitted to the gynaecology department of Mother and Child Hospital, University Medical Center, for uterine artery embolization. Shortly, after successful completion of the UAE procedure, the patient began to complain of severe pain in the lower abdomen rated as a 9 on a verbal analogue scale (VAS) of 0–10. Intravenous tramadol 100 mg was infused over 30 min with minimal reduction in pain. Trimeperidine 20 mg was then infused over 30 min. Pain scores, however, remained 7–8/10 on the VAS. It was therefore decided to place a bilateral single‐shot ultrasound‐guided quadratus lumborum block.

Results

The procedure was well tolerated and brought notable pain relief. VAS declined from 8/10 to 5/10 after 30 min and to 3/10 at 60 min. Over the ensuing 24 h, VAS pain intensity remained 2–3/10. No further analgesics were necessary.

Conclusion

A randomized control clinical trial is warranted to assess the efficacy of QL blockade and to compare it with other analgesic options in uterine artery embolization. Bilateral quadratus lumborum blockade may be an excellent pain control option after uterine artery embolization.

Significance

Uterine artery embolization is associated with significant postprocedural pain which can prove difficult to manage with opioids. Bilateral quadratus lumborum block may be an excellent pain control option ‐ one that might significantly reduce not only pain, but also the need for opioids and perhaps even the need for hospitalization.
A social–ecological perspective for riverscape management in the Columbia River Basin
Authors: Hand Brian K , Flint Courtney G , Frissell Chris A , Muhlfeld Clint C , Devlin Shawn P , Kennedy Brian P , Crabtree Robert L , McKee W Arthur , Luikart Gordon , Stanford Jack A
Published: January 2018

Riverscapes are complex, landscape‐scale mosaics of connected river and stream habitats embedded in diverse ecological and socioeconomic settings. Social–ecological interactions among stakeholders often complicate natural‐resource conservation and management of riverscapes. The management challenges posed by the conservation and restoration of wild salmonid populations in the Columbia River Basin (CRB) of western North America are one such example. Because of their ecological, cultural, and socioeconomic importance, salmonids present a complex management landscape due to interacting environmental factors (eg climate change, invasive species) as well as socioeconomic and political factors (eg dams, hatcheries, land‐use change, transboundary agreements). Many of the problems in the CRB can be linked to social–ecological interactions occurring within integrated ecological, human–social, and regional–climatic spheres. Future management and conservation of salmonid populations therefore depends on how well the issues are understood and whether they can be resolved through effective communication and collaboration among ecologists, social scientists, stakeholders, and policy makers.
How Does Natural Gas Fit Into a Rapidly Changing World?
Authors: Smead Richard G.
Published: January 2018

It is time once again to take stock of where we are and where we are going in the coming year.
Fluoride Removal from Aqueous Solutions Using Poly(Styrene Sulfonate)/Nanoalumina Multilayer Thin Films
Authors: Prathna Thanjavur Chandrasekaran , Raichur Ashok M.
Published: January 2018

In the present study, fluoride removal from drinking water is investigated using layer‐by‐layer (LbL) fabricated poly(sodium 4‐styrene‐sulfonate) (PSS)/Al2O3 thin films. The surface morphology of the fabricated thin films is characterized using atomic force microscopy and field emission‐scanning electron microscopy. Optical profilometry is used to determine the self‐assembly of the multilayer thin films. The effect of various parameters such as adsorbent dosage, contact time, initial fluoride content, number of bilayers, surface area, and pH is thoroughly studied. Fluoride removal increases with the number of bilayers and number of slides (total surface area). The amount of fluoride adsorbed increases from 11.32 to 26 mg L−1 when the number of substrates increases from 1 to 5. A 68% removal of fluoride is observed when 20 bilayers of PSS/Al2O3 thin films with three slides at an initial fluoride concentration of 5 mg L−1 are used, thereby bringing down the fluoride concentration level below the World Health Organization permissible limit. Slide reusability studies reveal that the fabricated thin films can be used for ten cycles without affecting the fluoride removal properties of the film. This study demonstrates the potential application of immobilized PSS/Al2O3 thin films as an effective adsorbent for drinking water purification.
Exosomes originating from MSCs stimulated with TGF‐β and IFN‐γ promote Treg differentiation
Authors: Zhang Qingyi , Fu Lin , Liang Yahui , Guo Zikuan , Wang Lisheng , Ma Cong , Wang Hengxiang
Published: January 2018

Mesenchymal stem cells (MSCs) have been approved as a cellular drug for the treatment of a variety of immune‐related diseases by the government of many countries'. Previous investigations, including ours, have shown that exosomes secreted by MSCs (MSC‐ex) are one of the main factors responsible for the therapeutic effect of MSCs. However, the immune modulation activities and the contents of MSC‐ex derived from cells under different incubation conditions differ dramatically. Therefore, the optimal way to ensure effectiveness is by identifying and preparing MSC‐ex with confirmed potent immunosuppressive activity. The aim of this study was to investigate and analyze the composition and function of MSC‐ex secreted by MSCs stimulated by different cytokines to obtain exosomes with more potent immunosuppressive activity. To achieve this aim, umbilical cord‐derived MSCs were treated with PBS, TGF‐β, IFN‐γ, or TGF‐β plus IFN‐γ for 72 hr. Then, exosomes were isolated from the culture supernatants. Common exosome markers, such as CD9, CD63, and CD81, were detected and analyzed by FCM. At the same time, the TGF‐β, IFN‐γ, IDO, and IL‐10 content in exosomes was detected, and the influence of exosmes from defferent groups on the induction of mononuclear cell transformation into Tregs was analyzed via FCM. Our results show that the TGF‐β combined with IFN‐γ exosome group more effectively promoted the transformation of mononuclear cells to Tregs, and the analysis showed that IDO may play an important role. This study might provide a novel strategy to treat GVHD as well as other immune‐associated disorders.
Do Mothers Spend More on Daughters While Fathers Spend More on Sons?
Authors: Nikiforidis Lambrianos , Durante Kristina M. , Redden Joseph P. , Griskevicius Vladas
Published: January 2018

Do parents favor some children over others? The overwhelming majority of parents state that they treat their children equally, but parents rarely track their spending on each child. We investigate in four studies whether mothers and fathers favor specific children depending on the biological sex of the child. Evidence from the field, laboratory, and community (online panel) showed that parents exhibit systematic biases when forced to choose between spending on sons and daughters. Mothers consistently favored daughters, whereas fathers consistently favored sons. For example, parents were more likely to choose a real prize and give a real U.S. Treasury bond to the child of the same sex as themselves. These parenting biases were found in two different cultures and appear to be driven by parents identifying more strongly with children of the same sex as the parent.
Increased non‐AIDS mortality among persons with AIDS‐defining events after antiretroviral therapy initiation
Authors: Pettit April C , Giganti Mark J , Ingle Suzanne M , May Margaret T , Shepherd Bryan E , Gill Michael J , Fätkenheuer Gerd , Abgrall Sophie , Saag Michael S , Del Amo Julia , Justice Amy C , Miro Jose M , Cavasinni Matthias , Dabis François , Monforte Antonella D , Reiss Peter , Guest Jodie , Moore David , Shepherd Leah , Obel Niels , Crane Heidi M , Smith Colette , Teira Ramon , Zangerle Robert , Sterne Jonathan AC , Sterling Timothy R ,   for the Antiretroviral Therapy Cohort Collaboration (ART‐CC) investigators
Published: January 2018

Introduction

HIV‐1 infection leads to chronic inflammation and to an increased risk of non‐AIDS mortality. Our objective was to determine whether AIDS‐defining events (ADEs) were associated with increased overall and cause‐specific non‐AIDS related mortality after antiretroviral therapy (ART) initiation.

Methods

We included HIV treatment‐naïve adults from the Antiretroviral Therapy Cohort Collaboration (ART‐CC) who initiated ART from 1996 to 2014. Causes of death were assigned using the Coding Causes of Death in HIV (CoDe) protocol. The adjusted hazard ratio (aHR) for overall and cause‐specific non‐AIDS mortality among those with an ADE (all ADEs, tuberculosis (TB), Pneumocystis jiroveci pneumonia (PJP), and non‐Hodgkin's lymphoma (NHL)) compared to those without an ADE was estimated using a marginal structural model.

Results

The adjusted hazard of overall non‐AIDS mortality was higher among those with any ADE compared to those without any ADE (aHR 2.21, 95% confidence interval (CI) 2.00 to 2.43). The adjusted hazard of each of the cause‐specific non‐AIDS related deaths were higher among those with any ADE compared to those without, except metabolic deaths (malignancy aHR 2.59 (95% CI 2.13 to 3.14), accident/suicide/overdose aHR 1.37 (95% CI 1.05 to 1.79), cardiovascular aHR 1.95 (95% CI 1.54 to 2.48), infection aHR (95% CI 1.68 to 2.81), hepatic aHR 2.09 (95% CI 1.61 to 2.72), respiratory aHR 4.28 (95% CI 2.67 to 6.88), renal aHR 5.81 (95% CI 2.69 to 12.56) and central nervous aHR 1.53 (95% CI 1.18 to 5.44)). The risk of overall and cause‐specific non‐AIDS mortality differed depending on the specific ADE of interest (TB, PJP, NHL).

Conclusions

In this large multi‐centre cohort collaboration with standardized assignment of causes of death, non‐AIDS mortality was twice as high among patients with an ADE compared to without an ADE. However, non‐AIDS related mortality after an ADE depended on the ADE of interest. Although there may be unmeasured confounders, these findings suggest that a common pathway may be independently driving both ADEs and NADE mortality. While prevention of ADEs may reduce subsequent death due to NADEs following ART initiation, modification of risk factors for NADE mortality remains important after ADE survival.
Factors associated with perceived accuracy of the Undetectable = Untransmittable slogan among men who have sex with men: Implications for messaging scale‐up and implementation
Authors: Rendina H Jonathon , Parsons Jeffrey T
Published: January 2018

Introduction

Recent research has shown high efficacy of HIV treatment for reducing the risk of HIV transmission to sexual partners. As the efficacy of treatment as prevention (TasP) has proliferated, a new messaging campaign, Undetectable = Untransmittable, has been gaining popularity. The purpose of this paper was to assess factors associated with the perceived accuracy of this TasP messaging strategy among a large and diverse sample of gay, bisexual, and other men who have sex with men (GBMSM) in order to inform subsequent efforts at large‐scale and implementation of the HIV prevention message.

Methods

We conducted a nationwide survey of GBMSM in the U.S. recruited from an online social networking site and a mobile sexual networking app. We analysed data from 12,222 GBMSM separately by HIV status to examine sociodemographic and behavioural factors associated with ratings of the accuracy of the Undetectable = Untransmittable message, which included the option to indicate not understanding what “undetectable” meant.

Results

Among HIV‐negative and unknown men, multivariable linear regression indicated that being on pre‐exposure prophylaxis (PrEP), identifying as gay or queer (versus bisexual or straight), recent serodiscordant condomless anal sex (CAS), testing every six months or more often, less concern about sexually transmitted infection (STI) infection, and lower perceived risk of HIV infection were the factors with the largest independent effect on rating the Undetectable = Untransmittable statement as more accurate. Fewer factors emerged as associated with accuracy ratings among HIV‐positive participants—reporting an undetectable viral load, a lifetime acquired immune deficiency syndrome (AIDS) diagnosis, and lower concern about STI infection were the factors most strongly associated with rating the statement as more accurate.

Conclusions

The findings of the current study highlight variability in the perceived accuracy of the Undetectable = Untransmittable message, suggesting potential subgroups who might benefit from targeted educational campaigns, perhaps broadcast utilizing sexual networking apps. Numerous factors, particularly among HIV‐negative and unknown GBMSM, were associated with rating the message as more accurate. In particular, being on PrEP and testing regularly were two of the variables most strongly associated with higher accuracy ratings among HIV‐negative GBMSM, suggesting HIV prevention services as potential points of intervention for increasing HIV knowledge and decreasing HIV stigma.
Monocyte subsets exhibit transcriptional plasticity and a shared response to interferon in SIV-infected rhesus macaques
Authors: Nowlin Brian T , Wang John , Schafer Jamie L , Autissier Patrick , Burdo Tricia H , Williams Kenneth C
Published: January 2018

The progression to AIDS is influenced by changes in the biology of heterogeneous monocyte subsets. Classical (CD14++CD16–), intermediate (CD14++CD16+), and nonclassical (CD14+CD16++) monocytes may represent progressive stages of monocyte maturation or disparate myeloid lineages with different turnover rates and function. To investigate the relationship between monocyte subsets and the response to SIV infection, we performed microarray analysis of monocyte subsets in rhesus macaques at three time points: prior to SIV infection, 26 days postinfection, and necropsy with AIDS. Genes with a 2-fold change between monocyte subsets (2023 genes) or infection time points (424 genes) were selected. We identify 172 genes differentially expressed among monocyte subsets in both uninfected and SIV-infected animals. Classical monocytes express genes associated with inflammatory responses and cell proliferation. Nonclassical monocytes express genes associated with activation, immune effector functions, and cell cycle inhibition. The classical and intermediate subsets are most similar at all time points, and transcriptional similarity between intermediate and nonclassical monocytes increases with AIDS. Cytosolic sensors of nucleic acids, restriction factors, and IFN-stimulated genes are induced in all three subsets with AIDS. We conclude that SIV infection alters the transcriptional relationship between monocyte subsets and that the innate immune response to SIV infection is conserved across monocyte subsets.
TLR8 ligation induces apoptosis of monocytic myeloid-derived suppressor cells
Authors: Dang Yushe , Rutnam Zina J , Dietsch Gregory , Lu Hailing , Yang Yi , Hershberg Robert , Disis Mary L
Published: January 2018

Myeloid-derived suppressor cells (MDSCs) accumulate in tumors and the peripheral blood of cancer patients and demonstrate cancer-promoting activity across multiple tumor types. A limited number of agents are known to impact MDSC activity. TLR8 is expressed in myeloid cells. We investigated expression of TLR8 on MDSC and the effect of a TLR8 agonist, motolimod, on MDSC survival and function. TLR8 was highly expressed in monocytic MDSC (mMDSC) but absent in granulocytic MDSC (gMDSC). Treatment of human PBMC with motolimod reduced the levels of mMDSC in volunteers and cancer donors versus control (P < 0.001). Motolimod did not impact levels of gMDSC. The reduction of mMDSC was due to induced cell death by TLR8 ligation. Pretreatment of PBMC with a FAS neutralizing antibody inhibited motolimod-induced reduction of mMDSC (P < 0.001). Finally, we demonstrated that mMDSC impeded IL-2 secretion by CD3/CD28-activated T cells; IL-2 secretion was partially restored when cells were cocultured with motolimod (142 ± 36 pg/ml vs. 59 ± 13 pg/ml; P = 0.03). There is increasing evidence that MDSCs contribute to the progression of cancer by inhibiting tumor-directed T cells. TLR8 agonists may synergize with cancer immunotherapeutic approaches to enhance the antitumor effects of the adaptive immune response.
Identification and quantification of VOCs by proton transfer reaction time of flight mass spectrometry: An experimental workflow for the optimization of specificity, sensitivity, and accuracy
Authors: Romano Andrea , Hanna George B.
Published: January 2018

Proton transfer reaction time of flight mass spectrometry (PTR‐ToF‐MS) is a direct injection MS technique, allowing for the sensitive and real‐time detection, identification, and quantification of volatile organic compounds. When aiming to employ PTR‐ToF‐MS for targeted volatile organic compound analysis, some methodological questions must be addressed, such as the need to correctly identify product ions, or evaluating the quantitation accuracy. This work proposes a workflow for PTR‐ToF‐MS method development, addressing the main issues affecting the reliable identification and quantification of target compounds. We determined the fragmentation patterns of 13 selected compounds (aldehydes, fatty acids, phenols). Experiments were conducted under breath‐relevant conditions (100% humid air), and within an extended range of reduced electric field values (E/N = 48–144 Td), obtained by changing drift tube voltage. Reactivity was inspected using H3O+, NO+, and O2+ as primary ions. The results show that a relatively low (<90 Td) E/N often permits to reduce fragmentation enhancing sensitivity and identification capabilities, particularly in the case of aldehydes using NO+, where a 4‐fold increase in sensitivity is obtained by means of drift voltage reduction. We developed a novel calibration methodology, relying on diffusion tubes used as gravimetric standards. For each of the tested compounds, it was possible to define suitable conditions whereby experimental error, defined as difference between gravimetric measurements and calculated concentrations, was 8% or lower.
Blenderized Enteral Nutrition Diet Study: Feasibility, Clinical, and Microbiome Outcomes of Providing Blenderized Feeds Through a Gastric Tube in a Medically Complex Pediatric Population
Authors: Gallagher Kelsey , Flint Annika , Mouzaki Marialena , Carpenter Andrea , Haliburton Beth , Bannister Louise , Norgrove Holly , Hoffman Lisa , Mack David , Stintzi Alain , Marcon Margaret
Published: January 2018

Background

Chronically ill children often require feeding via gastrostomy tubes (G‐tubes). Commercial formula is most commonly used for enteral feeding; however, caregivers have been requesting blenderized tube feeds (BTFs) as an alternative. The objective of this study was to evaluate the feasibility of using BTFs in a medically complex pediatric population and assess their impact on clinical outcomes, as well as the microbiota.

Methods

Twenty pediatric participants were included. Participants were G‐tube dependent and receiving ≥75% of their daily energy requirements from commercial formula. Over 4 weeks, participants were transitioned from commercial formula to BTF and were monitored for 6 months for changes in nutrient intake, gastrointestinal symptoms, oral feeding, medication use, and caregiver perceptions. Changes to intestinal microbiota were monitored by 16S rDNA‐based sequencing.

Results

Transition onto BTF was feasible in 17 participants, and 1 participant transitioned to oral feeds. Participants required 50% more calories to maintain their body mass index while on BTFs compared with commercial formula. BTF micronutrient content was superior to commercial formula. Prevalence of vomiting and use of acid‐suppressive agents significantly decreased on BTFs. Stool consistency and frequency remained unchanged, while stool softener use increased. The bacterial diversity and richness in stool samples significantly increased, while the relative abundance of Proteobacteria decreased. Caregivers were more satisfied with BTFs and unanimously indicated they would recommend BTFs.

Conclusion

Initiation and maintenance of BTFs is not only feasible in a medically complex pediatric population but can also be associated with improved clinical outcomes and increased intestinal bacterial diversity.
Longitudinal Profiles of Metabolism and Bioenergetics Associated with Innate Immune Hormonal Inflammatory Responses and Amino‐Acid Kinetics in Severe Sepsis and Systemic Inflammatory Response Syndrome in Children
Authors: Spanaki Anna Maria , Tavladaki Theonymfi , Dimitriou Helen , Kozlov Andrey V. , Duvigneau J. Catharina , Meleti Eftychia , Weidinger Adelheid , Papakonstantinou Evangelos , Briassoulis George
Published: January 2018

Background

Experimental data indicate that sepsis influences the mitochondrial function and metabolism. We aim to investigate longitudinal bioenergetic, metabolic, hormonal, amino‐acid, and innate immunity changes in children with sepsis.

Methods

Sixty‐eight children (sepsis, 18; systemic inflammatory response syndrome [SIRS], 23; healthy controls, 27) were enrolled. Plasma amino acids were determined by high‐performance liquid chromatography (HPLC); flow‐cytometry expressed as mean fluorescence intensity (MFI) of heat shock protein (HSP) levels from monocytes (m) and neutrophils (n); resistin, adiponectin, and extracellular (e) HSPs evaluated by ELISA; ATP levels in white blood cells by luciferase luminescent assay; lipid peroxidation products (TBARS) by colorimetric test; nitrite and nitrate levels by chemiluminescent assay; biliverdin reductase (BVR) activity by enzymatic assay; and energy‐expenditure (EE) by E‐COVX.

Results

Resistin, eHSP72, eHSP90α, and nitrate were longitudinally higher in sepsis compared with SIRS (p<0.05); mHSP72, nHSP72, VO2, VCO2, EE, and metabolic pattern were repressed in sepsis compared with SIRS (p<0.05). Septic patients had lower ATP and TBARS compared with controls on day 1, lower ATP compared with SIRS on day 3 (p<0.05), but higher levels of BVR activity. Sepsis exhibited higher phenylalanine levels on day 1, serine on day 3; lower glutamine concentrations on days 3 and 5 (p<0.05). Resistin, inversely related to ATP, was independently associated with sepsis, along with mHSP72 and eHSP90α (p<0.05); TBARS and VO2 were independently associated with organ failure (p<0.05)). Septic nonsurvivors had malnutrition, persistently repressed metabolism, mHSP72, and induced resistin and adiponectin (p<0.05).

Conclusions

A pattern of early longitudinal induction of metabolic‐hormones and eHSP72/HSP90α, repression of bioenergetics and innate immunity, hypo‐metabolism, and amino‐acid kinetics changes discriminate sepsis from SIRS; malnutrition, hypo‐metabolism, and persistently increased resistin and adiponectin are associated with poor outcome.
Kinetic Studies of Oxidative Addition Reaction of Arylplatinum(II) Complex Containing 4,4′‐Bipyridine and Calculation of Activation Parameters
Authors: Shafaatian Bita , Ghaedrahmat Hadis
Published: January 2018

New complexes of arylplatinum(II) and arylplatinum(IV) containing a bridging ligand, 4,4′‐bipyridine, were synthesized by the reaction of starting material of platinum(II) including para‐tolyl groups,[(p‐MeC6H4)2Pt(SMe2)2], with the 4,4′‐bipyridine ligand in 1:1 molar stoichiometry. In the synthesized complexes, the ligand was bonded to the platinum center through the nitrogen donor atoms. To investigate the kinetic reaction of the platinum(II) complex with iodomethane (CH3‐I) as a reagent, the oxidative addition reaction of this reagent with Pt(II) was performed in dichloromethane and a Pt(IV) complex with the octahedral geometry was formed. The synthesized complexes have been characterized by different spectroscopic methods such as FT‐IR, 1H NMR, UV–vis, and elemental analysis. Moreover, the conductivity measurements showed nonelectrolyte characteristics for these complexes. The obtained data showed that the complexes have 1:1 metal‐to‐ligand molar ratio. Also, the oxidative addition reaction of CH3I with the arylplatinum(II) complex at different temperatures was used for obtaining kinetic parameters such as rate constants, activation energy, entropy, and enthalpy of activation using the Microsoft Excel solver. From the acquired data, an SN2 mechanism was suggested for the oxidative addition reaction.
Influence of squeezing and interface slippage on the performance of water‐lubricated tilting‐pad thrust bearing during start‐up and shutdown
Authors: Wang Zhanchao , Liu Ying , Wang Yuechang , Liu Xiangfeng , Wang Yuming
Published: January 2018

The film thickness varied because of the swing of the tilting‐pad thrust bearing, which introduced the squeezing effect in the start‐up and shutdown periods. The interface slippage might occur between the water and the pad surface, because of the effects of water polarity and surface energy of the material. To study the performance of the water‐lubrication tilting‐pad thrust bearing during start‐up and shutdown, a transient model considering the effects of squeezing and interface slippage was established. The effects of squeezing and interface slippage on film‐thickness distribution, nondimensional minimum film thickness, circumferential angle, and friction torque were studied. The theoretical friction torque was consistent with the experimental result quite well. The result demonstrated that the effect of squeezing was higher in the opening process than in the closing process; the interface slippage effect influenced the start‐up and shutdown significantly, blocking the formation of the water film. The friction torque of the bearings increased if the interface slippage existed, because the solid contact friction‐force increase was higher than the fluid shear‐force decrease in the mixed lubrication. When both effects worked simultaneously, the interface slippage dominated in the start‐up period. During the shutdown situation, as the rotational speed sustained a loss, the interface slippage was abated, where the influence of the squeezing effect dominated gradually.